Note: Descriptions are shown in the official language in which they were submitted.
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SYSTEM AND METHOD OF MULTI-DRUG DELIVERY
BACKGROUND
[1] The field of the present disclosure relates generally to medicinal
products and, more specifically, to a drug dosage form that enables
simultaneous,
immediate release of more than one drug enclosed within a capsule upon
ingestion by a patient, and a delivery system for the drug dosage that ensures
compliance with intake instructions by the patient.
[2] Oral administration of medicaments such as drugs, supplements, and
other nutritional or therapeutic agents is typically done with tablet and
capsule
dosage forms. A capsule generally includes a hollow shell having an interior
for
storing powder or liquid-based drugs therein, and a tablet may be fabricated
from
a compressed powder of the medicinal substance. For at least some known
ailments, it may be beneficial to administer more than one type of medicament
to
the patient. As such, tablets and capsules may be fabricated to enable
administration or intake of two or more drugs to the patient in a single dose
or
single dosage form. For example, at least some known capsules contain a
mixture of drugs in liquid or powder form within the interior of the hollow
shell. In
addition, at least some known tablets include a first drug encapsulated within
a
second drug. However, encapsulating the first drug within the second drug may
hinder dissolution of the first drug, and may reduce the dissolution of the
first and
second drugs. In addition, drugs administered in powder or liquid form may
dissolve at a rate unsuitable for a desired efficacy.
[3] In addition, many known prescription medicines have complicated
instructions and dosing regimens. For example, some prescriptions require the
oral administration of multiple drug forms containing different types of drugs
and/or require administration at different times in the day. Other medicines
are to
be taken in the morning, afternoon, or evening, some with or without food,
some
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with or without certain types of food, and in particular quantities. As such,
it may
be difficult for a patient to remember and comply with the administration
instructions for a drug or a group of drugs. Failure to comply with such
administration instructions can result in suboptimal efficacy.
SUMMARY
[4] In one aspect, a multi-drug delivery system is provided. The system
includes a first capsule including a first capsule body having a first
interior, and a
first tablet and a second tablet included within the first interior. The first
tablet
includes a first drug, and the second tablet includes at least a second drug
different from the first drug. For example, the second tablet may include a
second
and third drug, each of which are different from the first drug and each
other. The
first tablet and the second tablet are configured for simultaneous release
upon
dissolution of the first capsule body within a patient. The system also
includes a
second capsule, co-packaged with the first capsule, including a second capsule
body having a second interior, and a third tablet included within the second
interior. The third tablet may include either the first drug, the second drug
and/or
one or more other drugs. At least 75% 10% of the first drug in the first
tablet
dissolves after 60 minutes and at least 70% 10% or 70% 20% or 70% 30% or
70% 40% of the second and third drugs in the second tablet dissolve after 30
minutes when using USP apparatus 2 at 50 rpm, pH 6.8, and 37.5 0.5 C.
[5] In some embodiments, the first tablet may include a gonadotropin-
releasing hormone antagonist. For example, the first tablet may include
elagolix,
relugolix, another gonadotropin-releasing hormone antagonist and/or a
combination of gonadotropin-releasing hormone antagonists. In some
embodiments, the first tablet may include elagolix.
[6] In some embodiments, the first tablet may include between about
175 mg to about 325 mg of the gonadotropin-releasing hormone antagonist and
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the second tablet may include between about 0.75 mg and about 1.25 mg of
estradiol; the second tablet may further include between about 0.1 mg and
about
1 mg of norethindrone acetate; after about 15 minutes, the release of
estradiol is
equal to or greater than 70% 10% or 70% 20% or 70% 30% or 70% 40%.
[7] In some examples, the first capsule may be marked with a first
identifier and the second capsule may be marked with a second identifier
different
from the first identifier such that the first capsule and the second capsule
are
visually distinguishable; the first identifier may be configured to indicate
the first
capsule is intended for administration within a first time window in the day,
and the
second identifier may be configured to indicate the second capsule is intended
for
administration within a second time window in the day different from the first
time
window. In some examples, the first identifier may be configured to indicate
the
first capsule is intended for administration at the first time window that is
before
noon, and the second identifier may be configured to indicate the second
capsule
is intended for administration at the second time window that is after noon;
the
first identifier may be a first color included on the first capsule, and the
second
identifier may be a second color included on the second capsule.
[8] In some examples, the system may include a package having a
plurality of compartments configured to house the first capsule and the second
capsule. The package may include a blister card that defines the plurality of
compartments, wherein the first capsule and the second capsule housed in the
plurality of compartments are accessible by puncturing a seal in the blister
card;
the package may have information printed thereon related to when to administer
the first capsule and the second capsule to the patient; the blister card may
have
a first row of the plurality of compartments and a second row of the plurality
of
compartments, wherein the first capsule is housed in the first row, wherein
the
second capsule is housed in the second row, and wherein the first row and the
second row are visually distinct.
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[9] In another aspect, a capsule for use in delivering drugs to a patient
is
provided. The capsule includes a capsule body having an interior, and at least
one first tablet and a second tablet included within the interior. The at
least one
first tablet includes a first drug, and the second tablet includes at least a
second
drug different from the first drug. The at least one first tablet and the
second
tablet are configured for simultaneous release upon dissolution of the capsule
body within the patient.
[10] In some embodiments, the first tablet may include between about
175 mg and about 325 mg of a gonadotropin-releasing hormone antagonist, such
as elagolix, and the second tablet comprises between about 0.75 mg and about
1.25 mg of estradiol; the second tablet may further comprise between about 0.1
mg and about 1.0 mg of norethindrone acetate. In some examples, wherein after
16 minutes, the release of estradiol is equal to or greater than 70% 10% or
70% 20% or 70% 30% or 70% 40%; the capsule body may be oblong to define
a longitudinal axis, wherein the at least one first tablet and the second
tablet are
arranged in a serial relationship along the longitudinal axis within the
interior; the
at least one first tablet and the second tablet may be distinct tablets that
have
been formed separately from each other and then secured within the interior;
the
capsule body may not contain drugs in powder form; the capsule body may not
include a barrier extending between the first tablet and the second tablet,
and
wherein the first tablet and the second tablet are not bonded together within
the
interior; the first capsule may include gelatin.
[11] In yet another aspect, a method of delivering drugs to a patient is
provided. The method includes delivering a first capsule to the patient,
wherein
the first capsule includes a first capsule body having a first interior, and a
first
tablet and a second tablet included within the first interior. The first
tablet includes
a first drug, and the second tablet includes at least a second drug different
from
the first drug. The first tablet and the second tablet are configured for
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simultaneous release upon dissolution of the first capsule body within a
patient.
The method also includes delivering a second capsule, which is co-packaged
with
the first capsule, to the patient after a predetermined amount of time has
elapsed
after administration of the first capsule. The second capsule includes a
second
capsule body having a second interior, and a third tablet included within the
second interior. The third tablet includes the first drug.
[12] In some embodiments, the first tablet comprises the first tablet
comprises between about 175 and 325 mg of gonadotropin-releasing hormone
antagonist and the second tablet comprises between about 0.75 mg and 1.25 mg
of estradiol and between about 0.1 mg and 1.0 mg of norethindrone; after 20
minutes, the release of estradiol is equal to or greater than 70% 10% or
70% 20% or 70% 30% or 70% 40%; delivering a second capsule includes
delivering the second capsule at least 5 hours after administration of the
first
capsule; includes providing a package comprising a plurality of compartments
configured to house the first capsule and the second capsule therein; and/or
further includes housing a plurality of first capsules and a plurality of
second
capsules within the package, such that the number of first capsules and the
number of second capsules housed within the package are each a multiple of the
number of days in a week.
[13] In some embodiments, a multi-drug tablet includes a first tablet and
a second tablet coated on the first tablet; the second tablet may be
positioned in
the center of the first tablet; and/or the multi-tablet includes crospovidone.
[14] In some embodiments, a medication container assembly includes a
first set of a plurality of compartments each compartment configured to
support a
first capsule; a second set of a plurality of compartments each compartment
configured to support a second capsule; wherein, the first capsule comprises a
first interior; a first tablet within the first interior, the first tablet
comprising a first
drug; and a second tablet within the first interior, the second tablet
comprising at
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least a second drug different from the first drug, wherein the first tablet
and the
second tablet are configured for simultaneous release upon dissolution of the
first
capsule body within a patient; and the second capsule comprises a second
capsule body comprising a second interior; and a third tablet within the
second
interior, the third tablet comprising the at least one drug selected from the
group
consisting of: the first drug, the second drug, or a third drug.
[15] In some embodiments, a multi-drug capsule includes a first tablet,
the first tablet comprising a first drug; a second tablet co-packaged with the
first
tablet and, the second tablet comprising at least a second drug different from
the
first drug; and a third drug different from the first and second drug, wherein
the
first tablet and the second tablet are configured for simultaneous release
upon
dissolution of the capsule within a patient; wherein using USP apparatus 2 at
50
rpm, pH 6.8, and 37.5 0.5 C, at least 75% 10% of the first drug in the first
tablet
dissolves after 60 minutes and at least 70% 10% or 70% 20% or 70% 30% or
70% 40% of the second and third drugs in the second tablet dissolve after 30
minutes.
[16] In some embodiments, a multi-drug capsule includes a first tablet,
the first tablet comprising a first drug; a second tablet co-packaged with the
first
tablet and, the second tablet comprising at least a second drug different from
the
first drug; and a third drug different from the first and second drug, wherein
the
first tablet and the second tablet are configured for simultaneous release
upon
dissolution of the capsule within a patient; wherein using USP apparatus 1 at
100
rpm, pH 6.8, and 37.5 0.5 C, at least 75% 10% of the first drug in the first
tablet
dissolves after 45 minutes and at least 90% 10% or 90% 20% or 90% 30% or
90% 40% of the second and third drugs in the second tablet dissolve after 30
minutes.
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[17] In some examples, the first tablet comprises elagolix, the first tablet
has between about 175 mg to about 325 mg of elagolix and the second tablet has
between about 0.75 mg and about 1.25 mg of estradiol.
[18] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone acetate; and following administration of a single dose of the
composition to healthy adult subjects results in a mean peak concentration
(Cmax) for said elagolix of about 1218.4 ng/mL to about 2185 ng/mL; a mean
peak concentration (Cmax) for said estradiol of about 0.0424 ng/mL to about
0.0775 ng/mL; a mean peak concentration (Cmax) for said norethindrone acetate
of about 4.56 ng/mL to about 8.0 ng/mL; a mean Area Under the Curve (AUC(0)
for said elagolix of about 3293.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean
Area Under the Curve (AUC(o) for said estradiol of about 0.688 ng.hr/mL to
about
1.1375 ng.hr/mL; and a mean Area Under the Curve (AUC(o) for said
norethindrone acetate of about 17.6 ng.hr/mL to about 33.125 ng.hr/mL.
[19] In another aspect, a multi-drug capsule composition includes 300
mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone acetate; and administration of a single dose of the composition
to
healthy adult subjects results in a mean peak concentration, Cmax for said
elagolix of about 1218.4 ng/ml to about 2185 ng/mL; a mean peak concentration,
Cmax for said estradiol of about 0.0424 ng/ml to about 0.0775 ng/ml; and a
mean
peak concentration, Cmax for said norethindrone acetate of about 4.56 ng/ml to
about 8.0 ng/ml.
[20] In one example, the multi-drug composition has a mean Area Under
the Curve, AUC(t) for said elagolix of about 3296.6 ng.hr/mL to about 5892.5
ng.hr/mL; a mean Area Under the Curve, AUC(t) for said estradiol of about
0.688
ng.hr/mL to about 1.1375 ng.hr/mL; and a mean Area Under the Curve, AUC(t) for
said norethindrone acetate of about 17.6 ng.hr/mL to about 33.125 ng.hr/mL.
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[21] In one aspect, multi-drug capsule composition includes 300 mg of
free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone
acetate; and administration of a single dose of the composition to healthy
adult
subjects results in a mean Area Under the Curve, AUC(t) for said elagolix of
about
3293.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean Area Under the Curve, AUC(t)
for said estradiol of about 0Ø688 ng.hr/mL to about 1.1375 ng.hr/mL; and a
mean
Area Under the Curve, AUC(t) for said norethindrone acetate of about 17.6
ng.hr/mL to about 33.125 ng.hr/mL.
[22] In one example, administration of the multi-drug capsule to healthy
adult subjects results in a mean peak concentration, Cmax for said elagolix of
about 1218.4 ng/mL to about 2185 ng.hr/mL; a mean peak concentration, Cmax
for said estradiol of about 0.0424 ng.hr/mL to about 0.0775 ng/mL ng/m I; and
a
mean peak concentration, Cmax for said norethindrone acetate of about 4.56
ng.hr/mL to about 8.0 ng/ml.
[23] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone acetate; and using USP apparatus 2 at 50 rpm, pH 6.8, and
37.5 0.5 C, at least 75% of the first drug in the first tablet dissolves after
60
minutes and at least 70% of the second and third drugs in the second tablet
dissolve after 30 minutes. In another aspect, a method of safely treating
heavy
menstrual bleeding associated with uterine leiomyomas (fibroids) in a pre-
menopausal female patient is provided. The method comprising once daily oral
administration to said patient of: (a) 300 mg of free acid equivalent of
elagolix; (b)
1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate, wherein said
method
results in a mean Cmax for said elagolix of about 1218.4 ng.hr/mL to about
2185
ng/mL; for said estradiol of about 0.0424 ng/mL to about 0.0775 ng/mL; for
said
norethindrone acetate of about 4.56 ng/mL to about 8.0 ng/mL, and a mean
AUC(t) for said elagolix of about 3293.6ng.hr/mL to about 5892.5 ng.hr/mL; for
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said estradiol of about 0Ø688 ng.hr/mL to about 1.1375 ng.hr/mL; and for
said
norethindrone acetate of about 17.6 ng.hr/mL to about 33.125 ng.hr/mL, and
wherein, after a treatment duration of about 6 months, said patient achieves
equal
to or greater than about 2 g/dL increase in hemoglobin as compared to baseline
where the patient did not receive elagolix, estradiol, and norethindrone.
[24] In another aspect, an oral capsule for use in delivering drugs to a
patient comprises: a capsule body comprising an interior; a first tablet
within the
interior, the at least one first tablet comprising a first drug; and a second
tablet
within the interior, the second tablet comprising at least a second drug
different
from the first drug, wherein the first tablet and the second tablet are
configured for
simultaneous release upon dissolution of the capsule body within the patient,
wherein using USP apparatus 1 at 100 rpm, pH 6.8, and 37.5 0.5 C, at least 75%
of the first drug in the first tablet dissolves after 45 minutes and at least
90% of the
second and third drugs in the second tablet dissolve after 30 minutes.
[25] In another aspect, an oral multi-drug capsule composition is
provided that is bioequivalent to any of the foregoing compositions.
[26] In another aspect, a method of delivering co-packaged drugs to a
patient for oral use is provided. The method comprises delivering a first
capsule
to the patient, wherein the first capsule includes: a first capsule body
including a
first interior; a first tablet within the first interior, the first tablet
including a first
drug; and a second tablet within the first interior, the second tablet
including at
least a second drug different from the first drug, wherein the first tablet
and the
second tablet are configured for simultaneous release upon dissolution of the
first
capsule body within the patient; and delivering a second capsule, co-packaged
with the first capsule, to the patient after a predetermined amount of time
has
elapsed after administration of the first capsule, wherein the second capsule
includes: a second capsule body including a second interior; and a third
tablet
within the second interior, the third tablet including the first drug.
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BRIEF DESCRIPTION OF THE DRAWINGS
[27] FIG. 1 is an illustration of an example multi-drug delivery system
that includes a first capsule and a second capsule of drugs.
[28] FIG. 2 is an internal view of an example capsule housing two
tablets.
[29] FIG. 3 is an internal view of an example capsule housing a single
tablet.
[30] FIG. 4A is an internal view of a first example multi-drug tablet
having a first tablet encapsulating a second tablet.
[31] FIG. 4B is an internal view of a second example multi-drug tablet
having a first tablet encapsulating a second tablet.
[32] FIG. 5 is internal view of a third example multi-drug tablet having a
bilayer, the bilayer having a first layer of a first drug and a second layer
of a
second and third drug.
[33] FIG. 6 is an internal view of a fourth example multi-drug tablet
having a first tablet coated with a mixture of a third and fourth drug.
[34] FIG. 7 internal view of a fifth example multi-drug tablet having a
bilayer, the bilayer having a first layer of a first drug and a second layer
of an
embedded tablet.
[35] FIG. 8 is an internal view of an example capsule according to FIG. 1
having a first tablet, and four mini-tablets.
[36] FIG. 9 is an internal view of an example capsule according to FIG. 1
containing melt granules and a tablet.
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[37] FIG. 10 is a flow chart showing Process of Examples 1 E2/NETA
tablet-in-elagolix tablet and Example 2 E2/NETA tablet embedded on the surface
of elagolix tablet.
[38] FIG. 11A is a flow chart showing Process of Example 3-1: bilayer
tablet E2/NETA layer: fluid-bed granulation, spraying API solution onto
lactose.
[39] FIG. 11 B is a flow chart showing the process of Example 3-2:
bilayer tablet E2/NETA layer: fluid-bed granulation, spraying binder onto API
mixture.
[40] FIG. 11C is a flow chart showing the process of Example 3-3:
bilayer tablet, direct blend of E2/NETA layer, with disintegrant.
[41] FIG. 11D is a flow chart showing the process of Example 3-4:
bilayer tablet, direct blend of E2/NETA layer without disintegrant.
[42] FIG. 12 is a flow chart showing the process of Example 4: Coating
of elagolix core tablet with solution of E2/NETA.
[43] FIG. 13 is a flow chart showing the process of Example 5: bilayer
tablet, E2/NETA embedded in the placebo layer.
[44] FIG. 14 is a flow chart showing the process of Example 6: Elagolix
tablet and E2/NETA tablet in a capsule.
[45] FIG. 15 is a flow chart showing the process of Example 7:
minitablets of elagolix and one E2/NETA tablet in a capsule.
[46] FIG. 16 is a flow chart showing the process of Example 8: elagolix
granules and one E2/NETA tablet filled in a capsule.
[47] FIG. 17 is a perspective view of an example package that may be
used to house and transport the multi-drug delivery system shown in FIG. 1.
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[48] FIG. 18 is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 4A and Example 1.
[49] FIG. 19 is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 4B and Example 2.
[50] FIG. 20A is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 5 and Example 3-1.
[51] FIG. 20B is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 5 and Example 3-2.
[52] FIG. 20C is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 5 and Example 3-3.
[53] FIG. 20D is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 5 and Example 3-4
[54] FIG. 21 is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 6 and Example 4
[55] FIG. 22 is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 7 and Example 5.
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[56] FIG. 23 is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the capsule shown in FIG. 2 and Example 6.
[57] FIG. 24 is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the capsule shown in FIG. 8 and Example 7.
[58] FIG. 25 is a diagram illustrating the dissolution rates of drugs
administered according to various embodiments of the present disclosure, and
according to the capsule shown in 9 and Example 8.
[59] FIG. 26 is a graphical representation of the percent change from
baseline in lumbar spine bone mineral density (BMD) in Women with Uterine
Fibroids who received 12 months of the System described in Example 10 and had
follow-up BMD 12 months off therapy in studies UF-1, UF-2, UF-3.
[60] FIG. 27 is a graphical representation of monthly change from
Baseline in MBL Volume in Women with Uterine Fibroids in the UF-1 study.
[61] FIG. 28 is a graphical representation of monthly change from
Baseline in MBL Volume in Women with Uterine Fibroids in the UF-2 study.
[62] FIG. 29A is a diagram illustrating the dissolution rates of elagolix
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 6 using USP apparatus 1.
[63] FIG. 29B is a diagram illustrating the dissolution rates of E2
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 6 using USP apparatus 1.
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[64] FIG. 29C is a diagram illustrating the dissolution rates of NETA
administered according to various embodiments of the present disclosure, and
according to the multi-drug tablet shown in FIG. 6 using USP apparatus 1.
DETAILED DESCRIPTION
[65] The following detailed description illustrates the disclosure by way
of example and not by way of limitation. The description enables one skilled
in
the art to make and use the disclosure, describes several embodiments,
adaptations, variations, alternatives, and use of the disclosure.
[66] Embodiments of the present disclosure relate to a drug dosage form
that enables substantially simultaneous, immediate release of more than one
drug
enclosed within a capsule upon administration by a patient, and a delivery
system
for the dosage that facilitates compliance of administration instructions by a
patient. The drug delivery system includes a first capsule and also may
include a
second capsule intended to be administered within different and non-
overlapping
time windows in the day. For example, in one embodiment, the first capsule is
intended to be administered during morning hours (e.g., before noon), and the
second capsule is intended to be administered at least 5 hours after
administration of the first capsule (e.g., during the afternoon or evening
hours).
The first capsule and the second capsule may contain different drugs, or
combinations of drugs, and may be marked with identifiers that facilitate
compliance with the administration instructions of a prescription, for
example. The
surfaces of the first capsule and the second capsule may have distinct
identifying
colors and/or surface characteristics. The first capsule and the second
capsule
may also include symbolic and/or textual markings that indicate in which time
window the respective capsule should be administered. In addition, a plurality
of
first capsules and a plurality of second capsules may be housed in a package
that
includes symbolic and/or textual markings that likewise indicate in which time
window the respective capsules should be administered. Thus, the first capsule
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and the second capsule are conspicuously and prominently marked or marked
and arranged to enable the patient to easily distinguish the capsules.
[67] In some embodiments, the system co-packages multiple capsules
and may include a single capsule containing two or more different drugs, for
example, a first tablet containing a first drug and a second tablet containing
a
second and third drug. In some examples, the first drug may be elagolix or
other
gonadotropin-releasing hormone (GnRH) releasing antagonists. Oral dosage size
is an important component for patient compliance. Larger oral dose sizes
create a
reluctance for patients to comply with dosing recommendations. In one
embodiment, the first capsule contains at least two distinct tablets, with the
first
tablet including a first drug and the second tablet including a second drug
and a
third drug different from the first drug. The first, second, and third drugs
have
different efficacies and, in the example embodiment, the second and third
drugs
are included in the capsule to at least partially counteract the undesirable
adverse
effects of the first drug on the patient. As such, the first and second
tablets are
formed separately from each other and then secured within the first capsule to
facilitate simultaneous, immediate release of the drugs in the first tablet
and the
second tablet upon dissolution of the outer shell of the capsule within the
patient.
That is, securing the distinct tablets within the capsule enables the tablets
to
dissolve simultaneously to result in a desirable bioavailability for a
patient. Thus,
the dosage form provided by the first capsule facilitates desirable
dissolution of
the drugs and bioavailability within the patient.
[68] As used herein, a bioequivalent composition or formulation is one
that is bioequivalent as defined by the U.S. Food and Drug Administration
(FDA).
[69] Furthermore, co-administration of the tablets in a capsule may
provide a presentation that is easy for a patient to swallow and simpler to
manufacture. In addition, the presentation allows the co-administration of the
first,
second, and third drugs. This co-administration allows for the desired balance
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between the therapeutic effect and safety of the first drug in the first
tablet with at
least the second drug or the third drug in the second tablet. As such, the co-
administration of the first drug in the first tablet and the second and third
drugs in
the second tablet facilitates potential reduction of the undesired effects of
the first
drug. In one example, the first drug in the first tablet may be elagolix or
another
GnRH antagonist, and the second and third drugs in the second tablet may be a
combination of estradiol (E2) and norethindrone (NETA) (e.g. ActiveIla
tablet).
Thus, the E2/NETA facilitate the add-back therapy that counters certain
undesirable impact of hormone regulation that is caused by the exogenous
introduction of a GnRH antagonist, such as elagolix, relugolix and the like.
[70] In any of the various aspects of the present disclosure, the first drug
may suitably be a GnRH antagonist, such as elagolix, and/or relugolix, the
second
drug may suitably be estradiol, and the third drug may suitably be
norethindrone
acetate. Elagolix is commonly available as elagolix sodium. For these
particular
drugs, it is important that a delivery mechanism be used that facilitates
achieving
improved and desirable dissolution of the drugs and desirable bioavailability
within
the patient. For example, it has been found that the dissolution of the drugs
is
likely increased when the drugs are administered in powder form or likely
decreased when the drugs are in an embedded multi-drug tablet form having a
first tablet embedded within a second tablet. When in powder form, the
dissolution rate of the drugs and resulting bioavailability within the patient
may be
undesirably high and therefore may not be ideal for dosing under certain
conditions. When in the embedded multi-drug tablet form, it has been found
that
the drugs in the first and second tablets do not dissolve together as a result
of the
second tablet slowing down the release of the drug in the first tablet.
[71] The total amount of elagolix contained in the first capsule or the
second capsule may suitably be the free acid equivalent of elagolix,
administered
as a sodium salt. The free acid equivalent of elagolix may be provided as 100
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milligrams (mg), 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 450 mg, or 500 mg,
and ranges constructed therefrom, such as about 100 mg to about 500 mg, about
150 mg to about 400 mg, and about 175 mg to about 325 mg. The total amount of
estradiol contained in the first capsule may suitably be 0.5 mg, 0.75 mg, 1.0
mg,
1.25 mg, or 1.5 mg, and ranges constructed therefrom, such as about 0.5 mg to
about 1.5 mg, about 0.5 mg to about 1.25 mg, about 0.75 mg to about 1.5 mg, or
about 0.75 mg to about 1.25 mg. The total amount of base equivalent of
norethindrone, available as norethindrone acetate that is contained in the
first
capsule may suitably be 0.05 mg, 0.1 mg, 0.25 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.75
mg, or 1.0 mg, and ranges constructed therefrom, such as about 0.1 mg to about
1.0 mg, about 0.25 mg to about 0.75 mg, or about 0.4 mg to about 0.6 mg.
[72] Tablets within the scope of the present disclosure comprise the
active drug and one or more excipients, including but not limited to, binders,
fillers,
disintegrants, surfactants, efficacy/bioavailability enhancing agents,
glidants, and
lubricants.
[73] Binders promote the bonding and cohesiveness of granules and
tablets and function to improve hardness. Some non-limiting examples of
binders
include: pregelatinized starch, hydroxypropyl cellulose, methyl cellulose,
hydroxypropyl methyl cellulose, copovidone, povidone, crospovidone, and
combinations. Other examples include polyethylene glycol, polyvinyl
pyrrolidone,
and polyvinyl alcohols. In some aspects, the binder is copovidone, povidone,
HMP, pregelatinized starch, and combinations thereof. In some further aspects,
the binder is copovidone.
[74] Fillers that may be used, include non-limiting examples such as
sugars and sugar alcohols, cellulosics, and other fillers. Non-limiting
examples of
suitable sugars and sugar alcohols include dextrates, dextrin, dextrose,
lactose,
maltodextrin, mannitol, isomalt, sorbitol, sucrose, sugars spheres, xylitol,
fructose,
lactitol, erythritol, maltitol, xylose, glucose, mannose, galactose, maltose,
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cellobiose, trehalose and raffinose. Non-limiting examples of cellulosics
include
microcrystalline cellulose ("MCC") and silicified MCC. Non-limiting examples
of
other fillers include calcium carbonate, calcium sulphate, calcium silicate,
chitin,
chitosan, dibasic calcium phosphate dihydrate, glyceryl palmitostearate,
hydrogenated vegetable oil, kaolin, magnesium aluminum silicate, magnesium
carbonate, magnesium oxide, polymethacrylates, potassium chloride, powdered
cellulose, pregelatinized starch, sodium chloride, starch, talc, and di- and
tri-basic
calcium phosphate. Combinations of the above-listed fillers are within the
scope
of the present disclosure.
[75] Disintegrants that may be used include, non-limiting examples such
as modified starches such as sodium carboxymethyl starch (sodium starch
glycolate); cross-linked polyvinylpyrrolidones such as crospovidone; modified
celluloses such as croscarmellose sodium; cross-linked alginic acid; gums such
as gellan gum and xanthan gum; calcium silicate; and combinations thereof.
[76] Surfactants may function to increase the concentration of the drug
in the diffusion layer formed at the interface of the drug surface and the
aqueous
medium after administration and/or increase wettability of the
drug/formulation.
Non-limiting examples of surfactants include, vitamin E d-alpha tocopheryl
polyethyleneglycol succinate, sodium dodecyl sulfate, polysorbate, poloxamer,
Tween type, and combinations thereof.
[77] Lubricants that may be used include, non-limiting examples such
magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate,
hydrogenated vegetable oils, polyethylene glycol (4000-6000), sodium lauryl
sulfate, and combinations thereof.
[78] Glidants that may be used include, non-limiting examples such
colloidal silicon dioxide (e.g., highly dispersed silica (Aerosil )), animal
or
vegetable fats, waxes, and combinations thereof.
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[79] Other excipients may be present include an acidifying agent or an
alkalizing agent. Acidifying agents may be organic acids for pH adjustment
and/or
control after administration, such as, for instance and without limitation,
fumaric
acid, citric acid, and tartaric acid.
[80] Selection of excipients and weight/weight concentrations or active to
excipient ratios thereof in tablets may be made to increase drug solubility in
an
aqueous medium (e.g., the stomach and/or intestine) and thereby improve
dissolution rate and bioavailability. Further, in the case of co-
administration of a
first tablet having a first drug and a second tablet having a second drug,
selection
of excipients and weight over weight concentrations or active to excipient
ratios
thereof may be made to both increase drug bioavailability and minimize any
interaction between the first and second tablets that could adversely affect
bioavailability of either drug.
[81] Tablets of the present disclosure may be formed utilizing
pharmaceutical operations, such as, but not limited to, screening, blending,
dry
granulation, compression, and optional film coating. In some aspects, the
excipient may be blended, the blend may be roller compacted and milled, and
the
resulting material may be tableted by compression in tableting equipment known
in the art. In some such aspects, the roller compacted, and milled material
may
be termed "intragranular" and said material may then be blended with one or
more
additional excipients described above prior to tableting. The one or more
additional excipients would be present as an "extragranular" component in the
tablet.
[82] The uncoated tablets of the present disclosure (e.g., tablet cores)
may be optionally coated with a film-coating to provide for tablets that are
predominantly tasteless and odorless and are easy to swallow. Further, film
coating prevents dust formation during packaging and ensures robustness during
transportation. Commercial coating compositions are suitable for purposes of
the
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present disclosure and include, without limitation, Opadry YS-1-7003, Opadry
YS-1-18202, and Opadry II White 85F18422.
[83] Tablets containing elagolix sodium are commercially available as
Orilissa . Manufacturing of different strengths of elagolix is described in
AbbVie
Inc's applications US201900540088 and US 20190054027, both of which are
incorporated in its entirety by reference. Other manufacturers also provide
various manufacturing of elagolix active ingredient and elagolix containing
drug
product, as described in applications W02017/221144, W02018/189213, and
W02018/224063. Tablets containing varying strengths of E2/NETA are
commercially available as ActiveIla .
[84] Referring now to the drawings, FIG. 1 is an illustration of an
example multi-drug delivery system 100 that includes a first capsule 102 and a
second capsule 104 of drugs. First capsule 102 includes a first capsule body
106
including a first body portion 108 and a first cap portion 110, and second
capsule
104 includes a second capsule body 112 including a second body portion 114 and
a second cap portion 116. In the example embodiment, first capsule 102 is
marked with a first identifier 118, and second capsule 104 is marked with a
second identifier 120 that is different from first identifier 118 to
facilitate rendering
first capsule 102 and second capsule 104 visually distinguishable from each
other
to a patient. First capsule 102 and second capsule 104 may include any
suitable
identifier that enables multi-drug delivery system 100 to function as
described
herein. The identifier may include, but is not limited to, shading, coloring,
a
symbolic marking, and/or a textual marking.
[85] For example, in the example embodiment, a first color 122 (as
illustrated by a first pattern) is included on first capsule 102, and a second
color
124 (as illustrated by a second pattern) is included on second capsule 104.
More
specifically, first cap portion 110 is first color 122 and second cap portion
116 is
second color 124. First color 122 is different from second color 124. Thus,
first
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cap portion 110 is visually distinguishable from first body portion 108,
second
body portion 114, and second cap portion 116, and second cap portion 116 is
visually distinguishable from first body portion 108, first cap portion 110,
and
second body portion 114.
[86] First identifier 118 and second identifier 120 may also be configured
to indicate when a respective capsule is intended to be administered. For
example, in the example embodiment, first identifier 118 includes a first
textual
marking 126 and second identifier 120 includes a second textual marking 128.
First textual marking 126 is configured to indicate that first capsule 102 is
intended
for administration within a first time window in the day, and second textual
marking 128 is configured to indicate that second capsule 104 is intended for
administration within a second time window in the day that is different from
the
first time window. More specifically, first textual marking 126 ("AM")
indicates that
first capsule 102 is intended for administration before noon, and second
textual
marking 128 ("PM") indicates that second capsule 104 is intended for
administration after noon. As will be described in more detail below, first
capsule
102 and second capsule 104 may contain different types of drugs. As such,
first
textual marking 126 and second textual marking 128 facilitate quick and easy
identification of the capsules and compliance with administration
instructions.
[87] FIG. 2 is a cross-sectional views of examples of first capsule 102
that may be used in multi-drug delivery system 100 (shown in FIG. 1), and FIG.
8
is a cross-sectional view of an additional first capsule 102 that may be used
in
multi-drug delivery system 100.
[88] FIG. 3 is a cross-sectional view of an example second capsule 104
that may be used in multi-drug delivery system 100 (shown in FIG. 1). In the
example embodiment, second capsule body 112 includes a second interior 140
sized to receive at least one first tablet 132 therein. While illustrated as
housing a
single first tablet 132, it should be understood that any number of first
tablets 132
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may be included within second interior 140 that enables multi-drug delivery
system 100 to function as described herein. Second capsule body 112 includes
second body portion 114 and second cap portion 116. Second body portion 114
includes an open end 142 sized to enable insertion of first tablet 132
therethrough. After insertion of first tablet 132 into second body portion
114,
second cap portion 116 may be engaged with second body portion 114 to enclose
open end 142, and to define and seal second interior 140.
[89] First capsule body 106 (shown in FIGS. 2 and 3) and second
capsule body 112 may be fabricated from any material that enables multi-drug
delivery system 100 to function as described herein. Example capsule body
materials include, but are not limited to, gelatin (in the form of hard
gelatin
capsules or soft elastic gelatin capsules), starch, carrageenan and
hydroxypropylmethylcellulose. First capsule body 106 and second capsule body
112 can additionally be prepared with coatings that ease swallowing, provide a
taste barrier, or provide other functions.
[90] As described above, first capsule 102 and second capsule 104 may
each contain a different drug, or a different combination of drugs, such that
first
capsule 102 and second capsule 104 are intended for administration at
different
times of the day. As such, second capsule 104 only contains first tablet 132
therein, and does not contain second tablet 134 therein.
[91] FIG. 17 is a perspective view of an example package 144 that may
be used to house and transport multi-drug delivery system 100 (shown in FIG.
1).
In the example embodiment, package 144 includes a carton 146, and a blister
card 148 positioned within carton 146. Carton 146 includes a first wall 150
having
an access opening 152 defined therein. Access opening 152 is sized to provide
access to blister card 148 and, more specifically, to a plurality of
compartments
154 of blister card 148 that are each configured to house an individual first
capsule 102 or second capsule 104 therein. As such, a plurality of first
capsules
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102 and a plurality of second capsules 104 are housed within package 144. In
one embodiment, the number of first capsules 102 and the number of second
capsules 104 housed within package 144 in compartments 154 are each a
multiple of the number of days in a week (e.g., 7, 14, or 21), and each
compartment 154, or groupings of compartments 154, are labeled according to
respective days of the week. In addition, first wall 150 includes
informational
markings 156 thereon that may be either symbolic or textual markings to easily
distinguish the capsules 102 and 104 from each other. Informational markings
156 are printed on package 144 and include information related to when to
administer first capsule 102 and second capsule 104 to the patient. As such,
including compartments 154 as a multiple of the number of days in the week in
package 144, and including informational markings 156 on first wall 150,
facilitates compliance of administration instructions by a patient.
[92] The invention further provides a multi-drug capsule composition
comprising: (a) 300 mg of free acid equivalent of elagolix which is
administered
twice daily; (b) 1 mg of estradiol which is administered once daily; and (c)
0.5 mg
of norethindrone acetate which is administered once daily. Table A7, provides
the
mean peak concentration Cmax and mean Area Under the Curve AUC(t) for this
formulation when the composition is administered to healthy volunteers. The
invention further includes the mean peak concentration Cmax and the mean Area
Under the Curve, AUCT that is 80%-125% of the Cmax or AUCT provided in Table
A7. Therefore, mean peak concentration, Cmax for said elagolix is about 80% to
about 125% of 1200 45% ng/mL or about 528-2175 ng/mL The mean peak
concentration, Cmax for said estradiol is about 80% to about 125% of 0.06 52%
ng/ml or 0.023-0.114 ng/mL The mean peak concentration, Cmax for said
norethindrone acetate is about 80% to about 125% of 6.1 35% ng/m I or 3.172-
10.294 ng/mL. Moreover, the mean Area Under the Curve, AUCT for said elagolix
is about 80% to about 125% of 2826 44% ng.hr/mL or 1266.0-5086.8 ng.hr/m L.
The mean Area Under the Curve, AUCT for said estradiol is about 80% to about
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125% of 0.86 38% ng.hr/mL or 0.4266-1.4835 ng.hr/mL. The mean Area Under
the Curve, AUCT for said norethindrone acetate is about 80% to about 125% of
23.8 48% ng.hr/mL or 9.90-44.03 ng.hr/mL.
[93] The invention further provides a multi-drug capsule composition
comprising: (a) 300 mg of free acid equivalent of elagolix which is
administered
twice daily; (b) 1 mg of estradiol which is administered once daily; and (c)
0.5 mg
of norethindrone acetate which is administered once daily. Table A7, provides
the
mean peak concentration Cmax and mean Area Under the Curve AUC (t) for this
formulation when the composition is administered to healthy volunteers. The
invention further includes the mean peak concentration Cmax and the mean Area
Under the Curve, AUCT that is 80%-125% of the Cmax AUCT provided in Table
A7. Therefore, mean peak concentration, Cmax for said elagolix is about 80% to
about 125% of 1200 ng/mL or about 960-1500 ng/mL The mean peak
concentration, Cmax for said estradiol is about 80% to about 125% of 0.06 ng/m
I
or 0.048-0.075 ng/mL The mean peak concentration, Cmax for said
norethindrone acetate is about 80% to about 125% of 6.1 ng/ml or 4.88-7.625
ng/mL. Moreover, the mean Area Under the Curve, AUCT for said elagolix is
about 80% to about 125% of 2826 ng.hr/mL or 2260.8-3532.5 ng.hr/mL. The
mean Area Under the Curve, AUCT for said estradiol is about 80% to about 125%
of 0.86 ng.hr/mL or 0.688-1.075 ng.hr/mL. The mean Area Under the Curve,
AUCT for said norethindrone acetate is about 80% to about 125% of 23.8
ng.hr/mL or 19.04-29.75 ng.hr/mL.
[94] The invention further provides a multi-drug capsule composition
comprising: (a) 300 mg of free acid equivalent of elagolix which is
administered
twice daily; (b) 1 mg of estradiol which is administered once daily; and (c)
0.5 mg
of norethindrone acetate which is administered once daily. Table A7, provides
the
mean peak concentration Cmax and mean Area Under the Curve AUC (t) for this
formulation when the composition is administered to healthy volunteers. The
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invention further includes the mean peak concentration Cmax and the mean Area
Under the Curve, AUCT that is 80%-125% of the Cmax AUCT provided in Table
A7. Therefore, mean peak concentration, Cmax for said elagolix is about 80% to
about 125% of 629-1770 ng/mL or about 503-2212.5 ng/mL. The mean peak
concentration, Cmax for said estradiol is about 80% to about 125% of 0.053-
0.062
ng/ml or 0.0424-0.0775 ng/mL. The mean peak concentration, Cmax for said
norethindrone acetate is about 80% to about 125% of 5.7-6.4 ng/ml or 4.56-8.0
ng/mL. Moreover, the mean Area Under the Curve, AUCT for said elagolix is
about 80% to about 125% of 1534-4118 ng.hr/mL or 1227.2-5147.5 ng.hr/mL.
The mean Area Under the Curve, AUCT for said estradiol is about 80% to about
125% of 0.81-0.91 ng.hr/mL or 0.688-1.1375 ng.hr/mL. The mean Area Under the
Curve, AUCT for said norethindrone acetate is about 80% to about 125% of 22-
26.3 ng.hr/mL or 17.6-33.125 ng.hr/mL.
[95] In some examples, the current invention provides an oral multi-drug
capsule composition comprising: (a) 300 mg of free acid equivalent of
elagolix; (b)
1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate.
[96] When the composition is administered as depicted on Table 7 (d) to
healthy adult subjects, it results in a steady state concentration Cmax ss for
said
elagolix of about 503-2212.5 ng/mL; mean peak concentration Cmax for said
estradiol of about 0.0424-0.0775 ng/mL ng/ml; mean peak concentration Cmax for
said norethindrone acetate of about 4.56-8.0 ng/ml; a mean Area Under the
Curve, (AUCT) for said elagolix of about 1227.2-5147.5 ng.hr/mL; a mean Area
Under the Curve AUC(t) for said estradiol of about 0Ø688-1.1375 ng.hr/mL;
and
AUC(t) for said norethindrone acetate of about 17.6-33.125 ng.hr/mL. In
another
embodiment, when the composition is administered as depicted on Table 7 (d) to
healthy adult subjects, it results in a mean peak concentration Cmax for said
elagolix of about 1218.4-2185 ng/mL; Cmax for said estradiol of about 0.0424-
0.0775 ng/mL ng/ml; Cmax for said norethindrone acetate of about 4.56-8.0
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ng/ml; a mean Area Under the Curve, (AUC(t)) for said elagolix of about 3293.6-
5892.5 ng.hr/mL; AUC(t) for said estradiol of about 0Ø688-1.1375 ng.hr/mL;
and
AUC(t) for said norethindrone acetate of about 17.6-33.125 ng.hr/mL.
[97] In another embodiment, the current invention provides an oral multi-
drug capsule composition comprising: (a) 300 mg of free acid equivalent of
elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate. When
the
composition is administered based on Table A7(c) or Table A7(d), to healthy
adult
subjects, it results in a mean steady state concentration, Cmax ss for said
elagolix
of about 503-2212.5 ng/mL; mean peak concentration Cmax for said estradiol of
about 0.0424-0.0775 ng/mL; and mean peak concentration, Cmax for said
norethindrone acetate of about 4.56-8.0 ng/ml.
[98] In one example, the oral multi-drug capsule composition has a
steady state Area Under the Curve, AUCT for said elagolix of about 1227.2-
5147.5
ng.hr/mL; AUCT for said estradiol of about 0Ø688-1.1375 ng.hr/mL; and AUCT
for
said norethindrone acetate of about 17.6-33.125 ng.hr/mL.
[99] In another embodiment, the current invention provides an oral multi-
drug capsule composition comprising: (a) 300 mg of free acid equivalent of
elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate. When
the
composition is administered based on Table A7(c) or Table A7(d), to healthy
adult
subjects, it results in a mean peak concentration, Cmax for said elagolix of
about
1218.4-2185 ng/mL; mean peak concentration Cmax for said estradiol of about
0.0424-0.0775 ng/ml; and mean peak concentration, Cmax for said norethindrone
acetate of about 4.56-8.0 ng/ml.
[100] In one example, the oral multi-drug capsule composition has a
mean Area Under the Curve, AUC(t) for said elagolix of about 3293.6-5892.5
ng.hr/mL; AUC(t) for said estradiol of about 0Ø688-1.1375 ng.hr/mL; and
AUC(t)
for said norethindrone acetate of about 17.6-33.125 ng.hr/mL.
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[101] In another embodiment, the current invention provides an oral
multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent
of
elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate;
further
when the composition is administered as shown in Table A7(c) and Table A7(d)
to
healthy adult subjects, it results in a mean Area Under the Curve, AUCT for
said
elagolix of about 1227.2-5147.5 ng.hr/mL; AUCT for said estradiol of about
0Ø688-1.1375 ng.hr/mL; and AUCT for said norethindrone acetate of about 17.6-
33.125 ng.hr/mL.
[102] In another example, the oral multi-drug capsule composition
results in a steady state peak concentration, Cmax ss for said elagolix of
about
503-2212.5 ng/mL; mean peak concentration, Cmax ss for said estradiol of about
0.0424-0.0775 ng/mL ng/ml; and mean peak concentration, Cmax ss for said
norethindrone acetate of about 4.56-8.0 ng/ml
[103] In another embodiment, the current invention provides an oral
multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent
of
elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate;
further
when the composition is administered as shown in Table A7(c) and Table A7(d)
to
healthy adult subjects, it results in a mean Area Under the Curve, AUC(t) for
said
elagolix of about 3293.6-5892.5 ng.hr/mL; AUC(t) for said estradiol of about
0Ø688-1.1375 ng.hr/mL; and AUC(t) for said norethindrone acetate of about
17.6-33.125 ng.hr/mL.
[104] In another example, the oral multi-drug capsule composition
results in a mean peak concentration, Cmax for said elagolix of about 1218.4-
2185 ng/mL; mean peak concentration, Cmax for said estradiol of about 0.0424-
0.0775 ng/mL ng/ml; and mean peak concentration, Cmax for said norethindrone
acetate of about 4.56-8.0 ng/ml.
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[105] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix which is administered twice daily;
1 mg
of estradiol which is administered once daily; and 0.5 mg of norethidrone
acetate
which is administered once daily; administration of the composition to healthy
subject results is shown in Table A7 (a) or Table A7 (b). For this
administration
the steady state concentration, Cmax ss for said elagolix of about 528-2175
ng/mL;
a mean peak concentration, Cmax for said estradiol of about 0.023-0.114 ng/mL;
a mean peak concentration, Cmax for said norethindrone acetate of about 3.172-
10.294 ng/ml; a mean Area Under the Curve, AUCT for said elagolix of about
1266.0-5086.8 ng.hr/ml, a mean Area Under the Curve, AUCT for said estradiol
of
about 0.4266-1.4835 ng.hr/mL; and a mean Area Under the Curve, AUCT for said
norethindrone acetate of about 9.90-44.03 ng.hr/mL.
[106] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix which is administered twice daily;
1 mg
of estradiol which is administered once daily; and 0.5 mg of norethidrone
acetate
which is administered once daily; further wherein administration of the
composition to healthy subject results in a mean steady state concentration,
Cmax ss for said elagolix of about 960-1500 ng/mL; a mean peak concentration,
Cmax ss for said estradiol of about 0.048-0.075 ng/mL; a mean peak
concentration,
Cmax ss for said norethindrone acetate of about 4.88-7.625 ng/ml; a mean Area
Under the Curve, AUCT for said elagolix of about 2260.8-3532.5 ng.hr/ml, a
mean
Area Under the Curve, AUCT for said estradiol of about 0.688-1.075 ng.hr/mL;
and
a mean Area Under the Curve, AUCT for said norethindrone acetate of about
19.04-29.75 ng.hr/mL.
[107] In one example, the oral multi-drug capsule may have a mean
Area Under the Curve, AUCT for said elagolix of about 1266.0-5086.8 ng.hr/mL;
a
mean Area Under the Curve, AUCT for said estradiol of about 0.4266-1.4835
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ng.hr/mL; and a mean Area Under the Curve, AUCT for said norethindrone
acetate of about 9.90-44.03 1.4835 ng.hr/mL.
[108] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix which is administered twice daily;
1 mg
of estradiol which is administered once daily; and 0.5 mg of norethindrone
acetate
which is administered once daily; further wherein administration of the
composition to healthy adult subjects results in a mean Area Under the Curve,
AUCT for said estradiol of about 0.4266-1.4835 ng.hr/mL; and a mean Area Under
the Curve, AUCT for said norethindrone acetate of about 9.90-44.03 ng.hr/mL.
[109] In one example, administration of the multi-drug capsule
composition to healthy adult subjects may further result in a mean steady
state
concentration, Cmaxss for said elagolix of about 528-2175 ng/mL; a mean peak
concentration, Cmaxss for said estradiol of about 0.023-0.114 ng/mL; and a
mean
peak concentration, Cmaxss for said norethindrone acetate of about 3.172-
10.294
ng/ml.
[110] In one example, an oral multi-drug capsule composition is provided
comprising: (a) 300 mg of free acid equivalent of elagolix which is
administered
twice daily; (b) 1 mg of estradiol which is administered once daily; and (c)
0.5 mg
of norethindrone acetate which is administered once daily; wherein using USP
apparatus 2 at 50 rpm, pH 6.8, and 37.5 0.5 C, at least 75% of the first drug
in
the first tablet dissolves after 60 minutes and at least 70% of the second and
third
drugs in the second tablet dissolve after 30 minutes.
[111] In one example, an oral multi-drug capsule composition is provided
comprising: (a) 200 mg of free acid equivalent of elagolix which is
administered
twice daily; (b) 1 mg of estradiol which is administered once daily; and (c)
0.5 mg
of norethindrone acetate which is administered once daily; wherein using USP
apparatus 2 at 50 rpm, pH 6.8, and 37.5 0.5 C, at least 75% of the first drug
in
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the first tablet dissolves after 60 minutes and at least 70% of the second and
third
drugs in the second tablet dissolve after 30 minutes.
[112] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone acetate; and following administration of a single dose of the
composition to healthy adult subjects results in a mean peak concentration
(Cmax) for said elagolix of about1218.4 ng/mL to about 2185 ng/mL; a mean peak
concentration (Cmax) for said estradiol of about 0.0424 ng/mL to about 0.0775
ng/mL; a mean peak concentration (Cmax) for said norethindrone acetate of
about 4.56 ng/mL to about 8.0 ng/mL; a mean Area Under the Curve (AUC(o) for
said elagolix of about 3293.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean Area
Under the Curve (AUC(o) for said estradiol of about 0.688 ng.hr/mL to about
1.1375 ng.hr/mL; and a mean Area Under the Curve (AUC(o) for said
norethindrone acetate of about 17.6 ng.hr/mL to about 33.125 ng.hr/mL.
[113] In another aspect, a multi-drug capsule composition includes 300
mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone acetate; and administration of a single dose of the composition
to
healthy adult subjects results in a mean peak concentration, Cmax for said
elagolix of about 1218.4 ng/ml to about 2185 ng/mL; a mean peak concentration,
Cmax for said estradiol of about 0.0424 ng/ml to about 0.0775 ng/ml; and a
mean
peak concentration, Cmax for said norethindrone acetate of about 4.56 ng/ml to
about 8.0 ng/ml.
[114] In one example, the multi-drug composition has a mean Area
Under the Curve, AUC(t) for said elagolix of about 3296.6 ng.hr/mL to about
5892.5 ng.hr/mL; a mean Area Under the Curve, AUC(t) for said estradiol of
about
0.688 ng.hr/mL to about 1.1375 ng.hr/mL; and a mean Area Under the Curve,
AUC(t) for said norethindrone acetate of about 17.6 ng.hr/mL to about 33.125
ng.hr/mL.
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[115] In one aspect, multi-drug capsule composition includes 300 mg of
free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone
acetate; and administration of a single dose of the composition to healthy
adult
subjects results in a mean Area Under the Curve, AUC(t) for said elagolix of
about
3293.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean Area Under the Curve, AUC(t)
for said estradiol of about 0Ø688 ng.hr/mL to about 1.1375 ng.hr/mL; and a
mean
Area Under the Curve, AUC(t) for said norethindrone acetate of about 17.6
ng.hr/mL to about 33.125 ng.hr/mL.
[116] In one example, administration of the multi-drug capsule to healthy
adult subjects results in a mean peak concentration, Cmax for said elagolix of
about 1218.4 ng/mL to about 2185 ng.hr/mL; a mean peak concentration, Cmax
for said estradiol of about 0.0424 ng.hr/mL to about 0.0775 ng/mL ng/ml; and a
mean peak concentration, Cmax for said norethindrone acetate of about 4.56
ng.hr/mL to about 8.0 ng/ml.
[117] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of
norethindrone acetate; and using USP apparatus 2 at 50 rpm, pH 6.8, and
37.5 0.5 C, at least 75% of the first drug in the first tablet dissolves after
60
minutes and at least 70% of the second and third drugs in the second tablet
dissolve after 30 minutes.
[118] The invention further provides an oral multi-drug capsule
composition that is bioequivalent to any of the multi-drug capsules described
herein.
[119] In another aspect, an oral multi-drug capsule composition includes
300 mg of free acid equivalent of elagolix; 1 mg of free acid equivalent
estradiol;
and 0.5 mg of free acid equivalent norethindrone acetate may be useful for
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reducing uterine fibroid volume prior to surgery (pre-surgery) for removal of
uterine fibroids.
[120] In another aspect, certain doses of elagolix plus estradiol and
norethindrone acetate therapy may be useful for treating pain associated with
endometriosis. For example, in one embodiment, 200 mg of free acid equivalent
of elagolix plus 1 mg free acid equivalent of estradiol, and 0.5 mg free acid
equivalent of norethindrone may be useful for treating pain associated with
endometriosis.
[121] In another aspect, a method of treating heavy menstrual bleeding
associated with uterine leiomyomas (fibroids) includes once daily oral
administration to an adult human female patient suffering from uterine
leiomyomas (fibroids) of a capsule comprising 300 mg of free acid equivalent
of
elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate, and the
method
results in a mean Cmax for the elagolix of about 1218.4 ng.hr/mL to about 2185
ng/mL; for the estradiol of about 0.0424 ng/mL to about 0.0775 ng/mL; for the
norethindrone acetate of about 4.56 ng/mL to about 8.0 ng/mL, and a mean
AUC(t) for the elagolix of about 3293.6ng.hr/mL to about 5892.5 ng.hr/mL; for
the
estradiol of about 0Ø688 ng.hr/mL to about 1.1375 ng.hr/mL; and for the
norethindrone acetate of about 17.6 ng.hr/mL to about 33.125 ng.hr/mL.
EXAMPLES
Example 1: Estradiol (E2) and norethindrone (NETA) tablet with elagolix
compression overcoat. As shown in FIG. 4A
[122] Elagolix/E2/NETA tablets 400 were prepared by coating
commercially sourced E2/NETA tablets 403 with compression coating using
elagolix granules 401 as shown in FIG. 4A. The composition of the tablets 400
is
provided in Table 1 and the granule composition is in Table 2 and the process
is
shown in FIG. 10.
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Table 1: Composition of Example 1
Component Amount per Unit
Elagolix Layer
Intragranular
Elagolix Sodium 310.5 mg a
Sodium Carbonate Monohydrate 155.3 mg
Polyethylene Glycol 3350 25.0 mg
Crospovidone 25.0 mg
Colloidal Silicon Dioxide 5.2 mg
Extragranular
Mannitol 70 mg
Colloidal Silicon Dioxide 3.0 mg
Magnesium Stearate 6.0 mg
Total Elagolix Layer 600 mg
Activella Core
ActiveIla tablet, (estradiol/norethindrone 1 Tablet (approx. 80 mg)
acetate, 1.0/0.5 mg)
Approximate total weight 680 mg
a. (300 mg of free acid elagolix is equivalent to about 310.5 mg elagolix
sodium)
Table 2: Composition of Elagolix Melt Granule
Component % w/w
Elagolix Sodium 59.67%
Sodium Carbonate Monohydrate 29.75%
Polyethylene Glycol 3350 4.80%
Crospovidone 4.80%
Colloidal Silicon Dioxide 0.97%
Total 100%
Table 3: Melt Granulation Temperature Settings.
Temperature ( C)
Barrel 1 20
Barrel 2 40
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Barrel 3 55
Barrel 4 60
Barrel 5 60
Barrel 6 60
Die 70
Example 2: Elagolix tablets containing E2/NETA tablets. As shown in FIG.
4B.
[123] The Elagolix/E2/NETA tablets were prepared according to the
process shown in FIG. 10. The tablets 410 of Example 2 were prepared by first
loading of the final blend and subsequently placing the ActiveIla tablets 403
on
the surface of the powder bed followed by compression manually. The
composition of the tablets 410 is provided in Table 4 and the tablet 410 is
shown
in FIG. 4B.
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Table 4: Composition of Example 2 Tablet.
Component Amount per Tablet
Elagolix Blend
Intragranular
Elagolix Sodium 310.5 mg
Sodium Carbonate Monohydrate 155.3 mg
Polyethylene Glycol 3350 25.0 mg
Crospovidone 25.0 mg
Colloidal Silicon Dioxide 5.2 mg
Extragranular
Mannitol 70 mg
Colloidal Silicon Dioxide 3.0 mg
Magnesium Stearate 6.0 mg
Total Elagolix Layer 600 mg
Activella
Activella tablet, (estradiol/norethindrone acetate, 1 Tablet (approx.80
1.0/0.5 mg) mg)
Approximate total weight 680 mg
Example 3: Elagolix and E2/NETA bilayer tablets. As shown in FIG. 5.
[124] The bilayer tablets 500 consisting of elagolix 501 and E2/NETA
layers 503 as shown in FIG. 3 were prepared using following examples:
Example 3-1
[125] Elagolix/E2/NETA tablets 500 were prepared according to the
process shown in FIG. 11A.
[126] (The composition of the tablets is provided in
[127] Table 6.
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Table 5: Extrusion Melt Granulation Temperature Settings.
Temperature ( C)
Barrel 1 20
Barrel 2 40
Barrel 3 55
Barrel 4 90
Barrel 5 110
Barrel 6 70
Die 70
Table 6: Composition of Example 3-1 Tablet.
Component Amount per Unit
Elagolix Layer
Intragranular
Elagolix Sodium 207.0 mg a
Sodium Carbonate Monohydrate 103.5 mg
Polyethylene Glycol 3350 16.7 mg
Crospovidone 16.7 mg
Colloidal Silicon Dioxide 3.5 mg
Extragranular
Colloidal Silicon Dioxide 2.0 mg
Magnesium Stearate 3.3 mg
Total Elagolix Layer 352.7 mg
E2/NETA Layer
Estradiol hem ihydrate 1.0 mg
Norethindrone Acetate 0.5 mg
Lactose Monohydrate, 316 69.2 mg
Polysorbate 80 0.3 mg
Magnesium Stearate 0.4 mg
Total E2/NETA Layer 71.4 mg
Total weight 424.1 mg
a. (200 mg of free acid elagolix is equivalent to about 207.0 mg elagolix
sodium)
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Example 3-2
[128] Elagolix/E2/NETA tablets 500, were prepared according to the
process shown in FIG. 11B.
[129] The composition of the tablets 500 is provided in Table 7.
Table 7: Composition of Example 3-2 Tablet.
Component Amount per Unit
Elagolix Layer
Intragranular
Elagolix Sodium 207.0 mg
Sodium Carbonate Monohydrate 103.5 mg
Polyethylene Glycol 3350 16.7 mg
Crospovidone 16.7 mg
Colloidal Silicon Dioxide 3.5 mg
Extragranular
Colloidal Silicon Dioxide 2.0 mg
Magnesium Stearate 3.3 mg
Total Elagolix Layer 352.7 mg
E2/NETA Layer
Estradiol hem ihydrate 1.0 mg
Norethindrone Acetate 0.5 mg
Lactose Monohydrate, 316 67.4 mg
Povidone K-29/32 2.1 mg
Magnesium Stearate 0.4 mg
Total E2/NETA Layer 71.4 mg
Total weight 424.1 mg
Example 3-3
[130] Elagolix/E2/NETA tablets 500 were prepared according to the
process shown in FIG. 11C.
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[131] The composition of the tablets 500 is provided in Table 8.
Table 8: Composition of Example 3-3 Tablet.
Component Amount per Unit
Elagolix Layer
Intragranular
Elagolix Sodium 207.0 mg
Sodium Carbonate Monohydrate 103.5 mg
Polyethylene Glycol 3350 16.7 mg
Crospovidone 16.7 mg
Colloidal Silicon Dioxide 3.5 mg
Extragranular
Colloidal Silicon Dioxide 2.0 mg
Magnesium Stearate 3.3 mg
Total Elagolix Layer 352.7 mg
E2/NETA Layer
Estradiol hem ihydrate 1.0 mg
Norethindrone Acetate 0.5 mg
Lactose Monohydrate, 316 65.9 mg
Crospovidone XL-10 3.6 mg
Magnesium Stearate 0.4 mg
Total E2/NETA Layer 71.4 mg
Total weight 424.1 mg
Example 3-4
[132] Elagolix/E2/NETA tablets were prepared according to the process
shown in FIG. 11D.
[133] The composition of the tablets is provided in Table 9.
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Table 8: Composition of Example 3-4 Tablet.
Component Amount per Unit
Elagolix Layer
Intragranular
Elagolix Sodium 207.0 mg
Sodium Carbonate Monohydrate 103.5 mg
Polyethylene Glycol 3350 16.7 mg
Crospovidone 16.7 mg
Colloidal Silicon Dioxide 3.5 mg
Extragranular
Colloidal Silicon Dioxide 2.0 mg
Magnesium Stearate 3.3 mg
Total Elagolix Layer 352.7 mg
E2/NETA Layer
Estradiol hem ihydrate 1.0 mg
Norethindrone Acetate 0.5 mg
Lactose Monohydrate, 316 69.5 mg
Magnesium Stearate 0.4 mg
Total E2/NETA Layer 71.4 mg
Total weight 424.1 mg
Example 4: Elagolix tablets with E2/NETA overcoat. As shown in FIG. 6.
[134] Elagolix/E2/NETA tablets were prepared by coating elagolix tablets
601 using layering of E2/NETA formulation as shown in FIG. 4. elagolix tablets
601 were first compressed using the final blend described in Example 3-1 on a
tablet press with the target tablet weight of 352.7 mg. The tablets were
prepared
using the process shown in FIG. 12. The composition of the tablets 600 is
provided in Table 9.
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Table 9: Composition of Example 4 Tablet.
Component Amount per Unit
Elagolix Tablet
Intragranular
Elagolix Sodium 207.0 mg
Sodium Carbonate Monohydrate 103.5 mg
Polyethylene Glycol 3350 16.7 mg
Crospovidone 16.7 mg
Colloidal Silicon Dioxide 3.5 mg
Extragranular
Colloidal Silicon Dioxide 2.0 mg
Magnesium Stearate 3.3 mg
Total Elagolix Tablet 352.7 mg
E2/NETA Layer
Estradiol hem ihydrate 1.0 mg
Norethindrone Acetate 0.5 mg
Polysorbate 80 0.3 mg
Povidone K-29/32 10.0 mg
Total E2/NETA Layer 11.8 mg
Total weight 364.5 mg
Example 5: Elagolix and E2/NETA bilayer tablets. As shown in FIG. 7.
[135] Bilayer tablets consist of one layer of elagolix formulation 701 and
a rapidly disintegrating layer 705 with embedded E2/NETA tablets 703, as shown
in FIG. 7, were prepared for dissolution test. The compositions of each layer
are
provided in Table 10 and prepared according to the process shown in FIG. 13.
[136] Additionally, the barrel temperature setup is shown in Table 11.
[137] The rapidly disintegrating layer 705 contains commercially sourced
excipient composite of Prosolv EASYtab (JRS Pharma) and one commercially
sourced E2/NETA tablet 703 (Breckenridge Pharmaceutical Inc.). The bilayer
tablet 700 was prepared individually by sequential filling into the die of
tooling
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A2310: (1) 80 mg EASYtab, (2) one E2/NETA tablet, (3) 80 mg EASYtab and (3)
529 mg Elagolix granules, followed by compression into the final tablet.
Table 10: Composition of Example 5 Tablet.
Component Amount per Unit
Elagolix layer
Intragranular
Elagolix 310.5 mg
Anhydrous sodium carbonate 155.3 mg
PEG 3350 25 mg
Crospovidone 25 mg
Silicon dioxide 5.2 mg
Extragranular
Silicon dioxide 3 mg
Magnesium stearate 0.92 mg
Total Elagolix Tablet 529 mg
E2/NETA layer
E2/NETA tablet, (estradiol/norethindrone acetate, 1 tablet (approx.
1.0/0.5 mg) 80 mg)
Prosolv Easytab 160 mg
Total E2/NETA Layer 240 mg
Approximate total weight 769 mg
Table 11: Extruder temperature setup for melt granules used in Example 5.
Temperature ( C)
Barrel 1 20
Barrel 2 80
Barrel 3 110
Barrel 4 130
Barrel 5 130
Barrel 6 130
Die 120
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Calender Roller 25
Conveyer Belt 15
Liquid Dose - Line 80
Example 6: Elagolix and E2/NETA Capsules. As shown in FIG. 2
[138] The capsule of example 6, as shown in FIG. 2, provides a
presentation that is easy for a patient to swallow and simpler to manufacture.
The
capsule was prepared according to the process shown in FIG. 14. This
formulation allows for desirable co-administration of Elagolix/E2/NETA, which
in
turn provides the desired balance between the therapeutic and safety effect of
elagolix E2 and NETA. Exogenous addition of a GnRH antagonist, such as
elagolix regulates the hormones that may create certain adverse effects. These
adverse effects may be effectively counterbalanced by administration by
appropriate dosage and formulation of E2/NETA which is provided with elagolix
such that the patient is not negatively impacted by competitive antagonism of
the
elagolix administration. The composition of this capsule is shown in Table 12.
The use of the preformed E2/NETA tablet 134 in the capsule of example 6 avoids
further handling of the estradiol (E2) hormone.
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Table 12: Composition of Example 6 Capsules.
Component Amount per Unit
Elagolix Tablet
Intragranular
Elagolix Sodium 310.5 mg
Sodium Carbonate Monohydrate 155.3 mg
Polyethylene Glycol 3350 25.0 mg
Crospovidone 25.0 mg
Colloidal Silicon Dioxide 5.2 mg
Extragranular
Colloidal Silicon Dioxide 3.0 mg
Magnesium Stearate 6.0 mg
Total Elagolix Layer 529.0 mg
Activella Tablet
ActiveIla tablet, (estradiol/norethindrone acetate, 1 Tablet (approx. 80
1.0/0.5 mg) mg)
Capsule, Gelatin, No. 0, Light Gray Opaque 1 Capsule
Example 7: Elagolix tablets in capsules. As shown in FIG. 8.
[139] The elagolix granules were manufactured as described before (see
Example 1). Furthermore, the capsules were prepared according to the process
shown in FIG. 15.
Table 13: Composition of Example 7 Elagolix Tablets.
Component Amount per Unit
Intragranular
Elagolix Sodium 77.9 mg a
Sodium Carbonate Monohydrate 38.8 mg
Polyethylene Glycol 3350 6.3 mg
Crospovidone 6.3 mg
Colloidal Silicon Dioxide 1.3 mg
Extragranular
Colloidal Silicon Dioxide 0.8 mg
Magnesium Stearate 1.3 mg
Total Elagolix Tablet 132.5 mg
a. (75 mg of free acid elagolix is equivalent to about 77.9 mg elagolix
sodium)
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Example 8: Elagolix Melt Granules and E2/NETA Tablet in capsules. As
shown in FIG. 9.
[140] The capsules 900 containing elagolix melt granules 901 and
E2/NETA tablets 903 were prepared according to the process shown in FIG. 16.
Example 6 and one E2/NETA tablet (Activella ) 903 into a size 00 capsule 901,
as
shown in FIG. 9, for dissolution test. The capsule 900 may include air, or any
other suitable filler in interior space 910. In some examples, the elagolix
melt
granules 901 and E2/NETA tablets 903 may be mixed/placed together in the
capsule 900.
Example 9A: Dissolution test of Examples 1-8
[141] Gelling properties of amorphous elagolix creates unpredictability in
a formulation that contains both elagolix and E2/NETA. It is unclear how the
elagolix in the presence of an anti-gelling agent such as sodium carbonate
will
interact with E2/NETA.
[142] In vitro dissolution of elagolix dosage forms for examples 1-8 were
tested using USP apparatus 2 at 50 rpm in a 900 m L of 0.05M pH 6.8 phosphate
buffer at 37.5 0.5 C and shown in Table 15-25. The filtrate was analyzed by
HPLC. Elagolix, E2 and NETA were determined by a multiple wavelength detector
at 310, 220 or 241 nm, respectively.
Table 15: Dissolution Data for Example 1 (mean SD). As shown in FIG. 4A.
Description 15 min 30 min 45 min 60 min
Elagolix Release 58 (75) 89 (8.1) 100 (3.5) 103 (2.0)
E2 Release 4(6.4) 67(172) 85(1.5) 93(06)
NETA Release 4(7.5) 77 (21.0) 99(15) 101 (1.5)
Table 16: Dissolution Data of Example 2 (mean SD). As shown in FIG. 4B.
Description 15 min 30 min 45 min 60 min
Elagolix Release 47 (5.3) 79 (8.7) 96 (4.0) 100 (0.0)
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E2 Release 47(186) 78 (9.1) 89 (4.5)
89(0.6)
N ETA Release 54(226) 90 (10.0) 98(40)
96 (0.6)
Table 17: Dissolution Data of Example 3-1 (mean SD). As shown in FIG. 5.
Description 15 min 30 min 45 min
60 min
Elagolix Release 61(66) 92 (5.3) 101 (0.5)
102 (0.5)
E2 Release 91(4.2) 93(1.7) 94 (1 2)
95(1.1)
N ETA Release 94(4.7) 96(0.8) 97(1.1)
96(1.0)
Table 18: Dissolution Data for Example 3-2 (mean SD). As shown in FIG.
5.
Description 15 min 30 min 45 min 60 min 90 min
103
Elagolix Release 54(9.6) 86 (8.4) 100 (2.8) 102 (0.5)
(0.6)
E2 Release 39(97) 79(5.1) 88(2.8) 90(10)
90(1.1)
N ETA Release 41(9.7) 82(6.2) 91(2.1) 93(1.0)
93(0.7)
Table 19: Dissolution Data of Example 3-3 (mean SD). As shown in FIG. 5.
Description 15 min 30 min 45 min 60 min 90 min
100
Elagolix Release 62(2.0) 92 (1.9) 99(0.6) 100 (0.6)
(0.5)
E2 Release 72(2.4) 76(1.6) 79(2.1) 80(2.1)
82(1.9)
N ETA Release 92 (2.3) 93 (1.3) 93 (1.5) 93 (1.4) 93 (1.2)
Table 20: Dissolution Data for Example 3-4 (mean SD). As shown in FIG.
5.
Description 15 min 30 min 45 min 60 min 90 min
101
Elagolix Release 60(8.9) 90(7.2) 100 (1.3) 101 (0.4)
(0.5)
E2 Release 80 (5,3) 84 (2.4) 86 (1.2) 88 (1,5)
89 (2.6)
N ETA Release 93 (4.4) 96 (1.3) 96 (1.0) 96 (0.9) 96 (0.9)
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Table 21: Dissolution Data for Example 4 (mean SD). As shown in FIG. 6.
Description 15 min 30 min 45 min 60 min
90 min
104
Elagolix Release 57(7.1) 91(6.1) 102 (2.2) 104 (0.9)
(0.9)
E2 Release 98 (3.5) 98 (3.7) 98 (3.8) 98 (3.6)
98 (3.6)
100
NETA Release 100 (3.6) 100 (3.5) 100 (3.6) 100 (3.5)
Table 22: Dissolution Results of Example 5 (mean SD). As shown in FIG. 7
Description 15 min
30 min 45 min 60 min 90 min
Elagolix Release 31(4) 55 (5) 73 (4) 85 (5) 97 (5)
E2 Release 22(13) 43(18) 60(12) 70(6) 78(2)
NETA Release 16(13) 41(23) 56(11) 60(1) 63(5)
Table 23: Dissolution Data of Example 6 (mean SD). As shown in FIG. 2
Description 15 min
30 min 45 min 60 min 90 min
Elagolix Release 11(3.9) 43 (6.9) 73 (6.7) 91(4.2) 102 (1)
E2 Release 78(173)
95(1.4) 96(14) 97(1.1) 97(1.2)
NETA Release 79
(18,1) 96(1.3) 97(1.7) 98(1.2) 98(1.5)
Table 24: Elagolix Dissolution Data of Example 7 (mean SD). As shown in
FIG. 8
Description 15 min 30 min 45 min 60 min
4 mini-tablets in HG capsule 14(1.4) 68(4.2) 97(7.1)
101 (0.7)
4 mini-tablets in HPMC capsule 5(2.8) 26(3.5) 52 (21) 71(1.4)
4 mini-tablets 85(0.7)
103 (0.7) 103 (0.7) 103 (0,7)
Table 25: Dissolution Data of Example 8 (mean SD). As shown in FIG. 9
Description 15 min 30 min 45 min 60 min 90 min
Elagolix Release 23 (5.6) 76 (4.9) 96 (4.7) 99 (2,7) 99 (2.3)
E2 Release 6(14.3) 66 (29.9) 93(2.2) 93(2.9) 95(1.0)
NETA Release 6(15.1)
71 (31.0) 99(1.6) 100 (1.5) 101 (1,0)
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Example 9B: Dissolution test of Example 6
[143] In vitro dissolution of elagolix dosage form for example 6 was
tested using USP apparatus 1 at 100 rpm with 900 mL of 0.05 M sodium phosphate
buffer, pH 6.8 maintained at 37 C. The dissolution release shown was measured
and
the release at various time intervals is shown in Table 26 and FIGS. 29A
(Elagolix
release), 29B (E2 release), and 29C (NETA release). The filtrate was analyzed
by
HPLC. Elagolix, E2 and NETA were determined by a multiple wavelength detector
at
310, 220 or 241 nm, respectively.
Table 26: Dissolution Data of Example 6 (mean SD). As shown in FIGS.
29A, 29B, and 29C n=6.
Description 10 min 15 min 30 min 45 min 60 min 90 min
Elagolix 49
NA 9(34) 87(5.7) 100(11) 101 (0.9)
Release (8.2)
100
E2 Release 34 (24.9) NA 100 (1.8) NA NA
(2.1)
NETA NA 99
35 (24, i) 99 (1.8) NA NA
Release (1.9)
Example 10: Dosage Forms and Administration
[144] The drug delivery system 100 includes a morning capsule 102
labelled "AM" 126. Capsule 102 is white and yellow and includes additional
identifying labelling "EL300." Capsule 102 includes about 300 mg elagolix,
about
1 mg estradiol, and about 0.5 mg norethindrone acetate. Capsule 104 is
labelled
"PM" is white and light blue, and also is labelled "EL300." In some examples,
capsule 104 may include about 300 mg elagolix. Each capsule 102, 104 should
be administered orally daily at approximately the same time each day (e.g. 102
taken in the morning and capsule 104 taken in the evening). In one embodiment,
each of the capsules may be taken with or without food and the capsules may be
administered daily for about 48 months. In another embodiment, each of the
capsules may be taken with or without food and the capsules may be
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administered daily for about 60 months. In another embodiment, each of the
capsules may be taken with or without food and the capsules may be
administered daily for about 72 months. In another embodiment, each of the
capsules may be taken with or without food and the capsules may be
administered daily for about 6 months, for about 12 months, for about 12-24
months, for about 24-36 months, for about 36-48 months, for about 48-60
months,
or for about 60-72 months. Duration of treatment may be extended based on
assessment of bone mineral density loss or any other adverse effect, for
example,
if a woman is treated for a duration of 24 months, and continues to have a
positive
benefit-risk profile, the duration of treatment may be extended to 36 months
or
longer. The bone mineral density loss may be assessed using any suitable
methods, including radiographic techniques e.g. DXA scan for continued
treatment. If a patient has missed a dose, the patient should be instructed to
take
the missed dose within 4 hours of the time the dose was supposed to be taken
and them the next dose may be taken and the usual time. If, however, more than
4 hours have passed since the missed dose would have usually been taken, the
patient should not take the missed dose and take the next dose at the usual
time.
Only one morning and one evening capsule should be taken per day.
Example 11: Adverse Reactions Clinical Trials Experience
[145] The safety of system of Example 10 was evaluated in two
randomized, double-blind, placebo-controlled studies [UF-1 (NCT02654054) and
UF-2 (NCT02691494)] in which 790 premenopausal women received elagolix,
elagolix 300 mg twice daily, or placebo for 6 months. Elagolix 300 mg twice
daily
was included as a reference arm to characterize the impact of
estradiol/norethindrone acetate (E2/NETA) on safety and efficacy. Women who
completed the 6-month treatment period in either UF-1 or UF-2 and met
eligibility
criteria entered an uncontrolled blinded 6-month extension study [UF-EXTEND
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(NCT02925494)] for a total treatment duration of up to 12 months receiving
either
elagolix or elagolix 300 mg twice daily.
Common Adverse Reactions
[146] The most commonly reported adverse reaction for women treated
with the system of Example 10 (incidence of at least 10%) in UF-1 and UF-2 was
hot flush and/or night sweats (see Table Al). In UF-1 and UF-2,
discontinuation
from therapy due to any adverse event occurred in 9.6% (n=38) of women treated
with elagolix and 6.6% (n=13) in those who received placebo. Adverse reactions
reported in 5% of women receiving the system of Example 10 and at a greater
frequency than placebo is shown in Table Al.
Table Al: Adverse Reactions Occurring in at Least 5% of Women with Uterine
Fibroids Receiving the System of Example 10 in Studies UF-1 and UF-2 and at a
Greater incidence Than Placebo
Adverse Reaction System of Example Placebo Elagolix 300 mg
N= 196 Twice Daily
N=395 N=199
Hot Flush 22% 9% 56%
Headache 9% 7% 15%
Fatigue 6% 4% 2%
Metrorrhagia 5% 1% 1%
[147] In Studies UF-1 and UF-2, discontinuation from therapy due to any
adverse reaction occurred in 9.6% (n=38) of women treated with the System of
Example 10 and 6.6% (n=13) in those who received placebo.
Less Common Adverse Reactions
[148] In Studies UF-1 and UF-2, adverse reactions reported in 3% and
<5% in the System of Example 10 group and greater incidence than the placebo
group included: libido decreased, arthralgia, hypertension, alopecia, mood
swings, abdominal distension, menorrhagia, influenza, upper respiratory tract
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infection, vomiting, and weight increased. The most commonly reported adverse
reactions in the extension trial (Study UF-EXTEND) were similar to those in
the
placebo-controlled trials.
Bone Loss
[149] The effect of the System of Example 10 on BMD was assessed by
dual-energy X-ray absorptiometry (DXA). In Studies UF-1 and UF-2, there was a
greater decrease in BMD in women treated with the System of Example 10
compared to placebo. The mean change from baseline in lumbar spine BMD at
Month 6 and Month 12 for women who received the system of Example 10
compared to women who received placebo was -0.6% and -1.5%, respectively,
and are presented in Table A2.
Table A2: Percent Change from Baseline in Lumbar Spine BMD at Month 6 in
UF-1 and UF-2
Studies UF-1 and UF-2
Treatment Month 6
Placebo System of Example 10
Number of Subjects 150 305
Percent Change -0.1 -0.7
from Baseline
Treatment -0.6
Difference, % (-1.0, -0.1)
(95% CI)
[150] In the extension study, UF-EXTEND, continued bone loss was
observed with 12 months of continuous treatment with the System of Example 10.
The proportion of women who experienced a greater than 8% BMD decrease in
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lumbar spine, total hip or femoral neck at treatment month 6 in Studies UF-1
and
UF-2 and at treatment month 12 in Study UF-EXTEND are presented in Table A3.
Table A3: Percent of Subjects with Greater than 8% BMD Decrease in Women
with Uterine Fibroids in Studies UF-1, UF-2, and UF-EXTEND
Studies UF-1 and UF-2 Study UF-EXTEND
Treatment Month 6 Treatment Month 12
BMD System of Placebo Elagolix System of Elagolix
Location Example 10 300 mg Example 10 300 mg
BID BID
Lumbar 0% 0% 2.9% 1.7% 14.8%
Spine
Total Hip 0% 0% 0.7% 0% 4.9%
Femoral 1.6% 0.7% 1.4% 1.7% 12.3%
neck
[151] To assess for recovery, the change in lumbar spine BMD over time
was analyzed for women who received continuous treatment with the System of
Example 10 for up to 12 months and who were then followed after cessation of
therapy for an additional 12 months (Figure 19). Twelve months after cessation
of
the System of Example 10, continued bone loss was observed at the spine, total
hip, and femoral neck in 24%, 32%, and 38% of women, respectively. Of these
women, all but one woman had 3`)/c, decline in BMD at the lumbar spine, and
all
had 5`)/c, decline at either hip site. Full recovery of bone loss was observed
in
31%, 36% and 24% of women who lost bone following 12 months of treatment
with System of Example 10 at the spine, total hip, and femoral neck,
respectively.
The remaining women had partial recovery, and the time to maximum recovery in
these women is unknown.
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[152] Overall, the presence of E2/NETA in the current 300 mg BID
elagolix formulation (System of Example 10) reduces the BMD loss as compared
to 300 mg BID of elagolix alone without E2/NETA.
Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders
[153] In the placebo-controlled trials (Studies UF-1 and UF2), the System
of Example 10 was associated with adverse mood changes. Depression,
depressed mood, and/or tearfulness were reported in 3% of women receiving the
System of Example 10 compared with 1% in the placebo group.
Hepatic Transaminase Elevations
[154] In Studies UF-1 and UF-2, asymptomatic elevations of serum ALT
to at least 3- times the upper limit of the reference (ULN) range occurred in
1.1%
(4/379) of women receiving System of Example 10, 2.2% (4/184) receiving
elagolix 300 mg twice daily, and none receiving placebo. . Elevations in ALT,
up
to 8-times the ULN were reported. Concurrent elevations in bilirubin were not
reported.
Changes in Lipid Parameters
[155] Increases in total cholesterol, low-density lipoprotein cholesterol
(LDL-C), serum triglycerides, and apolipoprotein B were noted during the
System
of Example 10 treatment in UF-1 and UF-2. In UF-1 and UF-2, 16.7% and 0% of
subjects women with mildly elevated LDL-C (130-159 mg/dL) at baseline had an
increase in LDL-C concentrations to 190 mg/dL or higher during treatment with
System of Example 10 and placebo, respectively, none receiving placebo had
such increase in LDL-C. In UF-1 and UF-2, 1.5% and 5.6% of subjects with
mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an
increase
in serum triglycerides to higher than 500 mg/dL during treatment with System
of
Example 10 and placebo, respectively. The highest measured serum triglyceride
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concentration during treatment with System of Example 10 was 852 mg/dL. In
women receiving System of Example 10, lipid changes were reversible and
elevated lipid levels returned to near Baseline baseline levels within 3
months
after cessation of treatment. No cases of pancreatitis were reported in the
clinical
trials.
[156] After cessation of six months of therapy with the System of
Example 10, resumption of menses was reported by 39.0%, 687.8% and 732.9%
of women within 1, 2, and 6 months respectively for UF-1 and 39.0%, 84.75%
and 91.52% within 1,2, and 6 months respectively for UF-2. After 12 months of
therapy with the System of Example 10 (UF-1 or UF2 then UF-EXTEND), During
the second 6 months of treatment in UF-EXTEND, the incidence of amenorrhea
ranged from 60.0% to 71.6% monthly for the System of Example 10 and
resumption of menses was reported by 40.8X%, 79.3X% and 89.7X% of women
within 1, 2, and 6 months after stopping treatment, respectively. Whether the
subject who did not resume having menses transitioned to a peri-
postmenopausal status is unknown.
Endometrial Effects
[157] In UF-1, UF-2 and UF-EXTEND, endometrial biopsies were
performed at Month 6. There were no abnormal biopsy findings, including no
endometrial hyperplasia or cancer, in women treated with the System of Example
10. Based ultrasound, the System of Example 10 treatment in UF-1 and UF-2
resulted in a decrease from baseline to Month 6 in mean endometrial thickness
(-
1.65 mm).
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Example 12: Drug Interactions
Potential for the System of Example 10 to Affect Other Drugs
[158] Elagolix is a weak to moderate inducer of cytochrome P450 (CYP)
3A). Coadministration with the System of Example 10 may decrease plasma
concentrations of drugs that are substrates of CYP3A. Elagolix is a weak
inhibitor
of CYP2C19. Co-administration with the System of Example 10 may increase
plasma concentrations of drugs that are substrates of CYP2C19 (e.g.,
omeprazole and esomeprazole) ([see Table A5)]
[159] Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp).
Co-administration with the System of Example 10 may increase plasma
concentrations of drugs that are substrates of P-gp (e.g., digoxin) ([see
Table
A5]).
Drug Interactions- Examples and Clinical Management
[160] The effect of co-administration of The System of Example 10 on
concentrations of concomitant drugs and the effect of concomitant drugs on the
System of Example 10 the clinical recommendations for these drug interactions
are summarized in Table AS.
Table A5: Drug Interactions: Effects of The System of Example 10 on Other
Drugs
Concomitant Drug Effect on Plasma Clinical Recommendations
Class: Exposure of Elagolix
Drug Name Or Concomitant Drug
Cardiac glycosides digoxin Increased monitoring of
digoxin
digoxin concentrations and potential
sign and symptoms of clinical
toxicity when initiating or
discontinuing the system of
example 10 in patients who are
taking digoxin.
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Benzodiazepines midazolam Consider increasing the
dose of
oral midazolam midazolam by no more than 2
folds and individualize
midazolam therapy based on
the patient's response.
Statins rosuvastatin Monitor lipid levels and
adjust
rosuvastatin the dose of rosuvastatin,
if
necessary.
Proton pump omeprazole No dose adjustment needed
for
inhibitors omeprazole 40 mg once daily
omeprazole when co-administered with
the
system of example 10. When
the System of Example 10 is
used concomitantly with higher
doses of omeprazole, consider
dosage reduction of
omeprazole.
The direction of the arrow indicates the direction of the change in the area
under the
curve (AUC) (T= increase, = decrease).
Example 13: Use in Specific Populations
[161] Exposure to the System of Example 10 early in pregnancy may
increase the risk of early pregnancy loss. Use of the System of Example 10 is
contraindicated in pregnant women. The System of Example 10 should be
discontinued if pregnancy occurs during treatment. When pregnant rats and
rabbits were orally dosed with elagolix during the period of organogenesis,
post
implantation loss was observed in pregnant rats at doses 12 times the maximum
recommended human dose (MRHD). Spontaneous abortion and total litter loss
were observed in rabbits at doses 4 and 7 times the MRHD. There were no
structural abnormalities in the fetuses at exposures up to 25 and 7 times the
MRHD for the rat and rabbit, respectively.
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Human Data
[162] There was one pregnancy reported out of the 453 women who
received the System of Example 10 in the Phase 3 uterine fibroids clinical
trials.
The pregnancy resulted in a spontaneous abortion and the estimated fetal
exposure to the System of Example 10occurred during the first 18 days of
pregnancy.
Animal Data
[163] Embryofetal development studies were conducted in the rat and
rabbit. Elagolix was administered by oral gavage to pregnant rats (25
animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20
animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of
organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the
rabbit).
In rats, maternal toxicity was present at all doses and included six deaths
and
decreases in body weight gain and food consumption. Increased post
implantation
losses were present in the mid dose group, which was 12 times the MRHD based
on AUC. In rabbits, three spontaneous abortions and a single total litter loss
were
observed at the highest, maternally toxic dose, which was 7 times the MRHD
based on AUC. A single total litter loss occurred at a lower non-maternally
toxic
dose of 150 mg/kg/day, which was 4 times the MRHD. No fetal malformations
were present at any dose level tested in either species even in the presence
of
maternal toxicity.
[164] At the highest doses tested, the exposure margins were 25 and 7
times the MRHD for the rat and rabbit, respectively. However, because elagolix
binds poorly to the rat gonadotropin releasing hormone (GnRH) receptor (-1000
fold less than to the human GnRH receptor), the rat study is unlikely to
identify
pharmacologically mediated effects of elagolix on embryofetal development. The
rat study is still expected to provide information on potential non-target-
related
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effects of elagolix. In a pre- and postnatal development study in rats,
elagolix
was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per
dose
group) from gestation day 6 to lactation day 20. There was no evidence of
maternal toxicity. At the highest dose, two dams had total litter loss, and
one
failed to deliver. Pup survival was decreased from birth to postnatal day 4.
Pups
had lower birth weights and lower body weight gains were observed throughout
the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on
startle
response were associated with lower pup weights at 300 mg/kg/day. Post-
weaning growth, development and behavioral endpoints were unaffected.
Maternal plasma concentrations in rats on lactation day 21 at 100 and 300
mg/kg/day (47 and 125 ng/m L) were 0.04-fold and 0.1-fold the maximal elagolix
concentration (Cmax) in humans at the MRHD. Because the exposures achieved
in rats were much lower than the human MRHD, this study is not predictive of
potentially higher lactational exposure in humans.
Lactation
Risk Summary
[165] the System of Example 10 is not recommended during lactation.
There is limited information on the presence of the System of Example 10 in
human milk, the effects on the breastfed child, or the effects on milk
production.
Data
[166] There is no information on the presence of elagolix or its
metabolites in human milk, the effects on the breastfed child, or the effects
on
milk production. Estrogen administration to nursing women has been shown to
decrease the quantity and quality of the breast milk. Detectable amounts of
estrogen and progestin have been identified in the breast milk of women
receiving estrogen and progestin combinations. There are no adequate animal
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data on excretion of elagolix in milk. The developmental and health benefits
of
breastfeeding should be considered along with the mother's clinical need for
the
System of Example 10 and any potential adverse effects on the breastfed infant
from the System of Example 10 or from the underlying maternal condition.
Example 14: Clinical Pharmacology
Mechanism of Action
[167] the System of Example 10 combines elagolix, a GnRH receptor
antagonist, and estradiol/norethindrone acetate (E2/NETA), an exogenous
combination of estrogen and progestin. Elagolix inhibits endogenous GnRH
signaling by binding competitively to GnRH receptors in the pituitary gland.
Estrogens such as E2 act through binding to nuclear receptors in estrogen-
responsive tissues. Progestins such as NETA enhance cellular differentiation
and
generally oppose the actions of estrogens by decreasing estrogen receptor
levels, increasing local metabolism of estrogens to less active metabolites,
or
inducing gene products that blunt cellular responses to estrogen. Progestins
exert their effects in target cells by binding to specific progesterone
receptors that
interact with progesterone response elements in target genes.
Pharmacodynamics
[168] Effect on Gonadotropin and Ovarian Hormones. Administration of
elagolix results in dose-dependent suppression of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH), leading to decreased blood concentrations
of
the ovarian sex hormones, estradiol and progesterone. The E2/NETA component
supplements endogenous estrogen and progesterone. In Phase 3 trials in
women with uterine fibroids administered the System of Example 10 for 6
months, LH and FSH was approximately 0.40 to 0.70 mIU/mL and 1.8 to 2.5
mIU/mL respectively, resulting in median concentrations of estradiol of
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approximately 42 to 51 pg/mL, and progesterone of approximately 0.37 to 0.38
nM.
[169] In a multiple-ascending dose study in premenopausal healthy
female subjects, elagolix 150 mg QD or 100, 200, 300, or 400 mg BID or placebo
was administered for 21 days. Dose-dependent suppression of sex hormones
was achieved rapidly within hours after administration of the first dose on
day 1
and continued through day 21, with maximum E2 suppression achieved with
elagolix doses of 200 mg BID or higher. At elagolix doses 100 mg BID, P
concentrations remained at anovulatory levels throughout 21 days of dosing.
Dose-dependent suppression of FSH and LH was also observed, with maximal
or near-maximal suppression achieved at elagolix doses of 300 mg BID and 200
mg BID, respectively. LH and FSH were suppressed compared to placebo,
however, LH suppression was more pronounced than that of FSH in all groups
except the 150 mg QD group. When elagolix administration was stopped, LH
and FSH levels rose within 24 hours after the last dose, and E2 levels began
to
rise 24 hours after the last dose was administered. The effects of different
doses
and dosing regimens of elagolix alone or with the hormonal add-back therapy
dose of Activella (E2/norethindrone acetate, 1/0.5 mg) on ovulation, ovarian
activity and ovarian reserve were evaluated in an open-label study in healthy
adult premenopausal females.
[170] During the 3-month treatment phase, with three-times-a-week
hormone sampling, suppression of gonadotropins and ovarian hormones were
observed in a dose-dependent manner. Mean E2 levels were observed at the
150 mg QD dose were approximately 40 to 50 pg/mL, consistent with partial E2
suppression. On the other hand, and consistent with the previous study, near
maximal suppression was observed with the 200 mg BID and 300 mg BID
regimens, with mean E2 levels of approximately 20 to 40 pg/mL. However, when
said dose of Activella was administered with elagolix 300 mg BID regimen, mean
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E2 levels appeared to increase to slightly above the levels observed with the
150
mg QD regimen due to exogenous E2 administration.
Effect on Ovulation
[171] In a 3-menstrual cycle study of the System of Example 10 in
healthy women, approximately 10% ovulated.
Cardiac Electrophysiology
[172] The effect of elagolix on the QTc interval was evaluated in a
randomized, placebo- and positive-controlled, open-label, single-dose,
crossover
thorough QTc study in 48 healthy adult premenopausal women. Elagolix
concentrations in women given a single dose of 1200 mg was 9-times higher
than the concentration in women given elagolix 300 mg twice daily. There was
no
clinically relevant prolongation of the QTc interval.
Pharmacokinetics
[173] The pharmacokinetic properties of the System of Example 10in
healthy subjects are summarized in Table A6. The steady-state pharmacokinetic
parameters under fasting conditions are summarized in Table A7.
Table A6: Pharmacokinetic Properties of the System of Example 10 in Healthy
Subjects
Absorption
Elagolix Estradiola Norethindrone
Tmax (h) b' 1.5 (1.0 ¨ 4.0) 2.0 (0.0 - 10.0) 1.0 (0.5 - 2.0)
High-fat AUC: 125%, AUC: no change, AUC: 123%,
meal' (relative to Cmax: 136% Cmax: 123% Cmax: 150%
fasting)
Distribution
% Bound to 80 98 97
human plasma
proteins
Blood-to-plasma 0.6 NA NA
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ratio
Metabolism
Metabolism CYP3A (major) CYP3A (partial) CYP3A (partial)
Minor pathways Other pathways
include: include: sulfation
CYP2D6, and
CYP2C8, and glucuronidation
uridine
glucuronosyl
transferases
(UGTs)
Elimination
Major route of Hepatic Hepatic Hepatic
elimination metabolism metabolism metabolism
Terminal phase
elimination
2.9 + 0.8 14.5 6.6 9.2 4.0
half-life (t112) (h)c,
% of dose <3 NA NA
excreted in urine
% of dose 90 NA NA
excreted in
feces
NA=not available
aBaseline adjusted unconjugated estradiol
bMedian and range
Tollowing administration of a single dose under fasting conditions
dHigh-fat meal is approximately 826 kcal, 52% fat.
eMean SD
Table A7 (a): Mean (%CV) Pharmacokinetic Parameters of the System of
Example 10
Pharmacokinetic Elagolix 300 mg Estradiolb 1 mg Norethindroneb
Parameter Twice Dailya N = 163 0.5 mg
(Units) N = 8 N = 163
Cmax (n g/m L) 1200 (45) 0.06 (52) 6.1 (35)
AUCT (ng=hr/mL) 2826 (44) 0.86 (38) 23.8 (48)
aData obtained at steady state (Day 21); AUCT represents the area under the
plasma
concentration-time curve from 0 to 12 hours post dose.
bData obtained following single dose administration; AUCT represents AUC from
0 to 24 hours
post dose; Estradiol: baseline adjusted unconjugated estradiol.
CV: Coefficient of variation
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Cmax: plasma peak concentration
Table A7 (b): Mean ( SD) Pharmacokinetic Parameters of the System of
Example 10 with 90% confidence intervals around the mean Cmax or AUC ratios
of 0.8-1.25.
Pharmacokinetic
Elagolix 300 mg Estradiola 1 mg Norethindronea
Parameter
(Units) Twice Daily N = 163 0.5 mg
N = 8 N = 163
Cmax (ng/mL) 1200 544 0.06 0.03 6.1 2.1
AUCT (ng=hr/mL) 2826 1231 0.86 0.33 23.8 11.4
Table A7 (c): 95% confidence intervals around the mean for Cmax and AUC of
elagolix, E2 and NETA of the System of Example 10, as well as the 80-125% of
the geometric mean.
Cmax ng/ml AUC ng.hr/m1
80-125% of
80-125% of
mean and the mean and
95% Cl geometric 95% Cl the
geometric
mean
mean
Elagolix (300 mg 1200 (629,
869 - 1359 2826 (1534,
2075 - 3242*
BID steady state) 1770) 4118)*
Elagolix (300 mg 1640 (1523,
1200 - 1875 4420 (4117,
3536 - 5525"
single dose) 1748) 4714)"
E2 (1 mg single 0.058 (0.053 0.042 - 0.86 (0.81,
0.63- 991"
dose) -0.062) 0.065 0.91)"
Norethindrone
(0.5 mg single 6.1 (5.7, 6.4) 4.6 - 7.1 23.8 (22.0,
17.0 - 26.5"
26.5)"
dose)
*AUC(tau); AUC during the dosing interval (i.e. 12 hours for BID)
"AUC(t); AUC from '0' to time of the last measured concentration
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Table A7 (d): depicting 80%-125% of mean Cmax and mean AUCT for System of
Example 10.
Cmax ng/ml AUCT ng.hr/m1
80-125%
mean and of the mean
and 95% 80-125% of
95% CI mean CI the
mean
Elagolix (300 mg 1200 (629,
503-2212.5 2826 (1534, 1227.2-
BID steady state 1770) 4118)* 5147.5*
Elagolix (300 mg 1640 (1523, 1218.4- 4420 (4117, 3293.6-
single dose) 1748) 2185 4714)" 5892.5"
E2 (1 mg single 0.058 (0.053 0.0424- 0.86 (0.81, 0.688-
dose -0.062) 0.0775 0.91)" 1.1375"
NETA (0.5 mg
6.1 (5.7, 6.4) 4.56 ¨ 8.0 23.8 (22.0' 17.6-
33.125"
single dose) 26.5)"
*AUC(tau); AUC during the dosing interval (i.e. 12 hours for BID)
"AUC(t); AUC from '0' to time of the last measured concentration
Specific Populations
Renal Impairment
[174] Elagolix exposures (Cmax and AUC) were not altered by renal
impairment. The elagolix mean plasma exposures were similar for women with
moderate to severe or end stage renal disease (including women on dialysis)
compared to women with normal renal function. The effect of renal impairment
on
the pharmacokinetics of E2/NETA has not been studied.
Patients with Hepatic Impairment
[175] Elagolix exposures (Cmax and AUC) were similar between women
with normal hepatic function and women with mild hepatic impairment. Elagolix
exposures in women with moderate and severe hepatic impairment were
approximately 3- fold and 7-fold, respectively, higher than exposures from
women
with normal hepatic function. The effect of hepatic impairment on the
pharmacokinetics of E2/NETA has not been studied.
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Racial or /Ethnic Groups
[176] No clinically meaningful difference in the pharmacokinetics of
elagolix between White and Black subjects or between Hispanics and others was
observed. There is no clinically meaningful difference in the pharmacokinetics
of
elagolix between Japanese and Han Chinese subjects. The effect of
race/ethnicity
on the pharmacokinetics of E2/NETA has not been studied.
Body weight/Body Mass Index
[177] Body weight or body mass index does not affect the
pharmacokinetics of elagolix. The effect of body weight/body mass index on the
pharmacokinetics of E2/NETA has not been studied.
Drug Interaction Studies
[178] Drug interaction studies were performed with elagolix and other
drugs likely to be co-administered and with drugs commonly used as probes for
pharmacokinetic interactions. Tables 8 and 9 summarize the pharmacokinetic
effects when elagolix was co-administered with these drugs.
Table A8: Drug Interactions: Change in Pharmacokinetics of Elagolix in the
Presence of Co-administered Drugs
Co-
Co-administered Elagolix Ratio % (90%
administered
Drug Regimen Regimen CI)*
Drug
Ketoconazole 400 mg once 150 mg 11 Cmax AUC
daily singles' dose 177 220
(148- (198 -
212) 244)
Rifampin 600 mg single 150 mg 12 437 558
dose single dose'
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(362 - (488 -
528) 637)
600 mg once 200 165
daily (166- (145 -
241) 189)
CI: Confidence interval
8' The elagolix dose in these studies was 0.5 times the approved dose in
system of Example
10) (0.25 times the total approved daily dosage of elagolix in the system of
Example 10)
*ratios for Cmax and AUC compare co-administration of the medication with
elagolix vs. administration of elagolix alone.
[179] No clinically significant changes in elagolix exposures were
observed when elagolix 300 mg was co-administered with rosuvastatin (20 mg
once daily), sertraline (25 mg once daily) or fluconazole (200 mg single
dose). The
effect of co-administered rosuvastatin, sertraline or fluconazole on E2/NETA
has
not been studied.
Table A9: Drug Interactions: Change in Pharmacokinetics of Co-administered
Drug in the Presence of Elagolix
Co- Co-administered Elagolix N Ratio % (90% CI)*
administered Drug Regimen Regimen
Drug
Digoxin 0.5 mg single 200 mg 11 Cmax AUC
dose twice daily 171 126
x 10 days (153- (117 -
191) 135)
Rosuvastatin 20 mg once daily 300 mg 10 99 60
twice daily (73 - (50 - 71)
x 7 days 135)
Midazolam 2 mg single dose 300 mg 20 56 46
twice daily (51 - (41 - 50)
x 11 days 0.62)
150 mg 11 81 65
once daily (74 - 89) (58 - 72)
x 13 days
Omeprazole 40 mg single dose 300 mg 20 195 178
twice (150- (139 -
daily 253) 227)
x 9 days
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CI: Confidence interval
*ratios for Cmax and AUC compare co-administration of the medication with
elagolix vs. administration of the medication alone.
a metabolite of norgestimate
[180] No clinically significant changes in sertraline, fluconazole,
bupropion, or transdermal patch E2/NETA 0.51/4.8 mg exposures were observed
when co-administered with elagolix 300 mg twice daily.
Pharmacogenomics
[181] Disposition Hepatic uptakedate of elagolix involves the OATP 1B1
transporter protein. Higher plasma concentrations of elagolix have been
observed
in groups of patients who have two reduced function alleles of the gene that
encodes OATP 1B1 (SLCO1B1 521T>C) (these patients are likely to have
reduced hepatic uptake of elagolix; and thus, higher plasma elagolix
concentrations). The frequency of this SLCO1B1 521 C/C genotype is generally
less than 5% in most racial/ethnic groups. WomenPatients with this genotype
are
expected to have approximately 2-fold higher elagolix mean concentrations
compared to women with normal transporter function (i.e., SLCO1B1 521T/T
genotype). Adverse effects of elagolix have not been fully evaluated in
subjects
who have two reduced function alleles of the gene that encodes OATP 1B1
(SLCO1B1 521T>C). In one embodiment, for clinical management of patients who
have two reduced function alleles of the gene that encodes OATP 1B1 (SLCO1B1
521T>C), the dose of elagolix may be reduced to about 50% of the original dose
in order to achieve once daily mean concentration of elagolix. Therefore, for
clinical management of patients who have two reduced function alleles of the
gene that encodes OATP 161, the elagolix dose may be reduced to half the
original dose, the dosing interval may be reduced from twice a day to once a
day,
or the dosing may be reduced from daily dosing to every other day dosing.
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Example 15: Nonclinical Toxicology
Elagolix
[182] Two-year carcinogenicity studies conducted in mice (50, 150, or
500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered
elagolix
by the dietary route revealed no increase in tumors in mice at up to 11.9-fold
the
MRHD based on AUC. In the rat, there was an increase in thyroid (male and
female) and liver (males only) tumors at the high dose (7.7 to 8.1-fold the
MRHD).
The rat tumors were likely species-specific and of negligible relevance to
humans.
Elagolix was not genotoxic or mutagenic in a battery of tests, including the
in vitro
bacterial reverse mutation assay, the in vitro mammalian cell forward mutation
assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells,
and the in vivo mouse micronucleus assay. In a fertility study conducted in
the rat,
there was no effect of elagolix on fertility at any dose (50, 150, or 300
mg/kg/day).
Based on AUC, the exposure multiple for the MRHD in women compared to the
highest dose of 300 mg/kg/day in female rats is approximately 2.9-fold.
However,
because elagolix has low affinity for the GnRH receptor in the rat and because
effects on fertility are most likely to be mediated via the GnRH receptor,
these
data have low relevance to humans.
E2/NETA
[183] Long-term continuous administration of natural and synthetic
estrogens in certain animal species increases the frequency of carcinomas of
the
breast, uterus, cervix, vagina, testis, and liver.
Example 16: Clinical Studies
[184] The efficacy of the System of Example 10in the management of
heavy menstrual bleeding (HMB) associated with uterine fibroids was
demonstrated in two, randomized, double-blind, placebo-controlled studies [UF-
1
(NCT02654054) and UF-2 (NCT02691494)] in which 790 premenopausal women
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who had at least two menstrual cycles with greater than 80 mL of menstrual
blood
loss (MBL), as assessed by alkaline hematin (AH) method (an objective,
validated
measure to quantify MBL volume on sanitary products), received the System of
Example 10 or placebo for 6 months. Each study also included an elagolix 300
mg
twice daily reference arm to characterize the impact of E2/NETA on efficacy
and
safety. In UF-1 and UF-2 , the median age was 43 years (ranging from 25 to 53
years); 68% of the women were Black or African American, 29% were White, and
3% were other races; 16% of women had uterine fibroids and coexisting
adenomyosis at baseline as evaluated by transvaginal and transabdominal
ultrasound (TVU/ TAU) and/or MRI; MBL at baseline ranged from 83.8 mL to
1207.1 mL; uterine volume by TVU/TAU ranged from 71.6 cm3 to 3347.9 cm3;
and primary fibroid volume by TVU/TAU ranged from 1 cm3 to 1081.5 cm3.
Menstrual Blood Loss
[185] The primary endpoint in both studies was the proportion of women
who achieved successful treatment defined as attaining both, 1) MBL volume
less
than 80 mL at the Final Month and 2) 50% or greater reduction in MBL volume
from Baseline to the Final Month. MBL at baseline was defined as the mean of
total MBL volume from at least 2 screening menstrual cycles that are >80 mL.
Final month is defined as the last 28 days before and including the last
treatment
visit date or the last dose date. A higher proportion of women treated with
the
System of Example 10 achieved successful treatment compared to placebo (see
Table A10).
Table A10: Proportion of Women Achieving Successful Treatment in Studies
UF-1 and UF-2
UF-1 UF-2
System of Placebo System of Placebo
Example Example 10
N=206 N=102 N=189 N=94
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Women with MBL
volume < 80 mL at and
50% reduction in
69% 9% 77% 11`)/0
MBL volume from
Baseline to the Final
Month
Difference from 60% (51,
66% (57, 75)
placebo 69)
Cl: confidence interval
Changes in MBL Volume
[186] Compared with placebo, the System of Example 10 reduced mean
MBL volume from Baseline at Month 1 through Month 6 (see Figures 20 and 21).
In Study UF-1, mean baseline MBL was 238.0 mL for the System of Example 10,
and 255.3 mL for placebo. In Study UF-2, mean baseline MBL was 2298.5 mL for
the System of Example 10, and 254.3 mL for placebo. Women taking the System
of Example 10 had a significant mean reduction of MBL volume from baseline to
final month in both studies UF-1 and UF-2 compared to women taking placebo
(Study UF-1; -176.7 mL for the System of Example 10 and 0.81 mL for placebo;
Study UF-2 -168.89 mL for the System of Example 10and -4.3 mL for placebo).
Suppression of Bleeding
[187] In Studies UF-1 and UF-2, a greater proportion (57% and 61%,
respectively) of women receiving the System of Example 10 experienced
suppression of bleeding, defined as no bleeding (but spotting allowed), at
final
month, compared to 4% and 5% of women receiving placebo, respectively.
Hemoglobin (Hgb)
[188] Over 90% of women with baseline Hgb 10.5 g/dL took
supplemental iron. In Studies UF-1 and UF-2, a greater proportion of women
treated with the System of Example 10 who were anemic with baseline Hgb
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10.5 g/dL achieved an increase 2 g/dL in Hgb from baseline to month 6
compared to women treated with placebo (see Table Al 1).
Table All: Proportion of Women with Baseline Hgb 0.5 g/dL and Increase 2
g/dL in Hgb at Month 6
U F-1 UF-2
System of Placebo The System Placebo
Example 10 n=32 of Example n=24
n=52 10
n=48
(%) at Month 6 62% 16% 50% 21%
Between-Group
Cl: confidence interval
Example B1
[189] PBPK Model Based Virtual Bioequivalence Assessment of Different
Elagolix Formulations
[190] Elagolix is approved at doses of 150 mg once daily and 200 mg
twice daily for the management of moderate to severe pain associated with
endometriosis, with roller compacted (RC2) tablets being used as the
commercial
formulation. A combination product of elagolix 200 mg and estradiol (E2) 1
mg/norethindrone acetate (NETA) 0.5 mg is being evaluated in endometriosis
Phase 3 trials. The phase 3 investigational product consisted of elagolix 200
mg
tablet co-administered with E2/NETA tablet, while the proposed commercial
product consists of elagolix 200 mg melt granulated (MG) tablet and E2/NETA
tablet as a fixed-dose combination (FDC) morning capsule and elagolix 200 mg
MG evening capsule. Dissolution tests performed using USP I (basket) apparatus
showed dissimilar in vitro dissolution profiles for the Phase 3 and the to-be-
marketed (TBM) capsules, thus requiring the evaluation of bioequivalence (BE)
with respect to in vivo exposures. Physiologically based pharmacokinetic
(PBPK)
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modeling was used along with in vitro dissolution data for various
formulations to
conduct virtual BE simulations in order to demonstrate simulated bioequivalent
exposures without conducting clinical BE studies.
Methods
[191] A previously developed PBPK model (Simcyp V17) for elagolix
which was verified with clinical PK and drug-drug interaction (DDI) data,
served as
the base model. (See Chiney et al., 2019, Clinical Pharmacokinetics). The PBPK
model was updated by incorporating in vitro dissolution data of the elagolix
formulations using the mechanistic ADAM (Advanced Dissolution & Absorption
Model) module which captures drug dissolution and absorption in the different
regions of the GI tract. Dissolution testing using USP-I apparatus at 100 RPM
in
900 mL of 0.05M Sodium Phosphate, pH 6.8 was conducted for the relevant
formulations. The PBPK model with in vitro data incorporated was externally
validated using clinical data from two clinical bioequivalence studies, where
the
elagolix capsules at 300 mg dose were evaluated against the reference RC2
tablet
for a different indication. Model predicted exposures (Cmax and AUC) in a
virtual
healthy, female population were compared to clinical observations for each
formulation from the BE studies. Model predicted exposure ratios for Cmax and
AUC of the test capsule formulations to the reference (RC2) tablet were also
compared to clinical observations. The clinically validated PBPK model was
used
to simulate virtual bioequivalence trials in a cross-over fashion to compare
elagolix
200 mg capsules to 200 mg RC2 tablets. The virtual BE trials were conducted
100
times with different virtual subjects to evaluate the effect of inter-occasion
or inter-
trial variability on bioequivalence of the formulations.
Results
[192] PBPK model predicted exposures for the 300 mg tablet (RC2) and
300 mg capsules formulations compared well with clinical observations from BE
studies
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with less than 25% predictions errors. Model predictions of relative BE ratios
comparing
test to reference formulations also compared well with clinical data from the
BE studies.
These BE study results were not used in model calibration or verification and
thus were
used as external validation of the PBPK model predictions. This provided
confidence in
using the PBPK model to predict exposures for clinically untested formulations
using
their in vitro dissolution data as inputs. Based on results of the virtual BE
trials
simulations, both capsule formulations at the 200 mg dose met the
bioequivalence
criteria of 0.80 ¨ 1.25 when compared to the reference RC2 formulation. Both
Cmax
and AUC ratios of the test to reference formulations were bioequivalent with
the
geometric mean of Cmax and AUC ratios predicted to be 0.9 and 0.95
respectively. The
90% prediction intervals of the exposure ratios were also within the BE
criteria. The
results from multiple trial simulations using different virtual subjects also
confirmed that
the geometric means and 90% confidence intervals of the exposure ratios for
all virtual
trials met the BE criteria.
Conclusions
[193] This novel work combined in vitro and clinical data for different
formulations using PBPK modeling to conduct virtual BE simulations in lieu of
clinical
trials. The results of the virtual BE simulations from the clinically
validated PBPK model
were used to justify that the TBM formulations of elagolix are likely to
result in exposures
similar to that of the formulations tested clinically and justifying the
request for an in vivo
bioequivalence waiver. This analysis also showed that permeability and not
solubility
was the determining factor for the absorption of elagolix, which results in
bioequivalent
in vivo exposures despite dissimilar in vitro dissolution profiles. This work
demonstrated
the value of combining in vitro and in silico data in the development and
evaluation of
new formulations.
Example B2
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[194] Clinical Pharmacology Challenges in Assessing Bioequivalence for
Elagolix Fixed Dose Combination Products
[195] Elagolix is being developed for the management of heavy menstrual
bleeding (HMB) associated with uterine fibroids (UF). The investigational drug
product being studied in the UF phase 3 trials is elagolix 300 mg twice daily
roller
compaction 2 (RC2) tablets co-administered with estradiol/norethindrone
acetate
(E2/NETA) 1 mg/0.5 mg once daily tablet. For patient compliance and
convenience, the proposed to-be-marketed (TBM) formulations are a fixed dose
combination (FDC) capsule consisting of elagolix/E2/NETA 300/1/0.5 mg for the
morning dose, and an elagolix 300 mg capsule for the evening dose. The two
formulations exhibited dissimilar for in vitro dissolution profiles,
indicating potential
different release characteristics in vivo. The purpose of the studies was to
assess
(1) BE of the TBM elagolix FDC morning capsule formulation compared to
elagolix
RC2 tablet co-administered with E2/NETA tablet in postmenopausal healthy
women; (2) BE of the TBM elagolix evening capsule formulation compared to
elagolix RC2 tablet in premenopausal healthy women; and (3) the effect of food
(high-fat meal) on bioavailability of elagolix capsules.
Method
[196] The present research included two separate large phase 1 BE
studies. The first one is a randomized, single-center, single dose, four
sequence,
two/three-period, crossover, phase 1 BE study. This study was conducted in
healthy pre-menopausal women (N= 57) to assess BE between elagolix 300 mg
capsule (test product; T) and elagolix 300 mg RC2 tablet (reference product;
R),
as well as the food effect on bioavailability of the elagolix capsule. Serial
blood
samples for assay of elagolix were collected prior to dosing and up to 24
hours
after dosing on study days.
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[197] A separate randomized, multi-center, single dose, four sequence,
two/three-period, crossover, phase 1 BE study was conducted in healthy post-
menopausal women (N= 167) to assess BE between elagolix/E2/NETA 300/1/0.5
mg FDC capsule (T) and elagolix 300 mg RC2 tablet co-administrated with
E2/NETA 1 /0.5 mg tablet (R). The food effect on bioavailability of elagolix
FDC
capsules was also evaluated. Serial blood samples for assay of elagolix, total
estrone, and norethindrone were collected prior to dosing and up to 72 hours
after
dosing on study days.
[198] For both BE studies, a non-compartmental analysis (NCA) was
performed using the SAS software (Certara, Princeton, NJ, USA). The geometric
mean ratio (GMR) (90% confidence interval [CI]) of T/R for maximum observed
plasma concentration (Cmax) and the area under the plasma concentration-time
curve from time zero to infinity (AUCO-inf) were calculated for BE assessment.
The
food effect was evaluated by assessing relative bioavailability (90%
confidence
interval) of the elagolix capsules (both elagolix capsule and FDC capsule)
under
fasting and fed conditions.
Results
[199] For the elagolix alone study, the GMR (90% CI) of T/R for elagolix
Cmax and AUCO-inf under fasting condition were 0.87 (0.81 ¨0.94) and 0.97
(0.93
¨ 1.01), respectively, indicating elagolix 300 mg capsule is bioequivalent to
elagolix
300 mg RC2 tablet. Following administration of elagolix 300 mg capsule after a
high-fat breakfast, the elagolix Cmax and AUCO-inf were 40% and 28% lower,
respectively. Tmax was delayed by approximately 1 hour compared to fasting
conditions. The effect of food on elagolix relative bioavailability was not
clinically
relevant based on exposure-response analyses.
[200] For the elagolix FDC study, the GMR (90% CI) of T/R for Cmax of
elagolix, baseline-adjusted total estrone, and norethindrone were 0.91 (0.87 -
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0.95), 1.02(0.96 - 1.08), 1.12(1.08 - 1.15), respectively, while the GMR (90%
CI)
of T/R for AUCO-inf of elagolix, baseline-adjusted total estrone, and
norethindrone
were 0.97 (0.95 - 1.00), 0.93 (0.87 - 1.00), 0.96 (0.94 - 0.98), respectively,
under
the fasting condition. The additional hormones analytes also achieved BE
criteria.
These findings indicated that elagolix/E2/NETA 300/1/0.5 mg FDC capsule is
bioequivalent to elagolix 300 mg RC2 tablet co-administrated with 1 /0.5 mg
E2/NETA tablet. Following administration of elagolix/E2/NETA 300/1/0.5 mg FDC
capsule after a high-fat breakfast, the elagolix Cmax and AUCO-inf were 36%
and
25% lower, respectively, when compared to exposures under fasting conditions.
Conclusion
[201] The BE studies' results demonstrated that the TBM elagolix FDC
(elagolix/E2/NETA 300/1/0.5 mg) morning capsule and elagolix 300 mg evening
capsule formulations are bioequivalent to the UF Phase 3 clinical trials
formulation
(co-administered elagolix 300 mg tablet and E2/NETA 1/0.5 mg tablet) despite
the
dissimilarity in their in vitro dissolution profiles. The effect of food (high
fat meal)
on the components of the TBM product was similar to that observed previously
with OrilissaTM commercial tablets for elagolix, and as expected for E2/NETA
(activella USP I). Thus, the morning FDC 300/1/0.5 mg and evening elagolix
300
mg capsules can be taken with or without food.
[202] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be taken as
limitations upon the scope of the invention, which is defined solely by the
appended claims and their equivalents.
[203] Various changes and modifications to the disclosed embodiments
will be apparent to those skilled in the art. Such changes and modifications,
including without limitation those relating to the chemical structures,
substituents,
derivatives, intermediates, syntheses, compositions, formulations, or methods
of
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use of the invention, may be made without departing from the spirit and scope
thereof.
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