Note: Descriptions are shown in the official language in which they were submitted.
CA 02498267 2009-03-16
METHOD FOR TREATING ERECTILE DYSFUNCTION
AND INCREASING LIBIDO IN MEN
FIELD OF THE INVENTION
The present invention is directed to method of treating erectile dysfunction
and
increasing libido in men.
BACKGROUND OF THE INVENTION
A. Sexual Performance, Erectile Dysfunction ("ED"), and Libido in Men
1. Sexual Performance & ED
"Sexual performance" as used herein generally refers to a man's ability to
have an
orgasm, obtain an erection, or engage in masturbation or intercourse.
"Impotence" is a type
of deficient sexual performance. Impotence or "erectile dysfunction" as used
herein is
generally refers to the inability of a man to attain an erection with
sufficient rigidity for
vaginal penetration 25% or more of the times attempted.
As many as 45 million men have some degree of erectile dysfunction. At least
10
million American men-about 9% of the adult population-are thought to have
impotence. The
rate increases with age. Thus, impotence affects about 10% of men in their
sixties, 25% of
men in their seventies, 40% of men in their eighties, and more than half of
those in their
nineties. In young couples, the incidence of impotence is about 7%. One-third
of older men
receiving medical treatment also have difficulty with erectile function.
CA 02498267 2001-08-29
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Over the past decade, the medical perspective on the causes of impotence has
shifted. Conventional wisdom used to attribute almost all cases of impotence
to
psychological factors. Investigators i ow estimate that between 70% and 80% of
impotence cases are caused primarily by medical problems. Risk factors for
impotence
include hypogonadism, atherosclerosis, hypertension, diabetes mellitus,
depression and
other emotional or psychological illnesses, pelvic surgery, kidney failure,
multiple
sclerosis, stroke, some types of epilepsy, any, alcoholism. Another risk
factor is taking any
of a variety of drugs, including cardiovascular medications, drugs that affect
the central
nervous system, certain hormonal preparations, heroin, and cocaine.
Today, 90% of all impotence cases are treated with VIAGRA' (sildenafil citrate
USP). Other drugs useful in the treatment of impotence include, but are not
limited to:
pentoxifylline (TRENTAL ), yohimbine hydrochloride (ACTIB1NE, YOCON ,
YOHIME)e), apomorphine (UPRIMAa'), alprostadil (the MUSE' system, TOPIGLAN',
CAVERJECT&), papavaerine (PAVAIB1D2), CERESPANO), and phentolamine
(V ASOMAX', REGITINE ).
These pharmaceuticals act by a variety of physiological mechanisms. For
example, the physiologic mechanism of erection of the penis involves release
of nitric
oxide ("NO") in the corpus cavernosum during sexual stimulation. NO then
activates the
enzyme guanylate cyclase, which icsudis in increased levels of cyclic
guanosine
monophosphate ("cGMP"), producing smooth muscle relaxation in the corpus
cavernosum
and allowing inflow of blood. VIAGRA' has no direct relaxant effect on
isolated human
corpus cavernosum, but enhances the effect of NO by inhibiting
phosphodiesterase type 5
("PDES"), which is responsible for degradation of cGMP in the corpus
cavernosum.
When sexual stimulation causes local release of NO, inhibition of PDES by
sildenafil
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causes increased levels of cGMP in the corpus cavemosum, resulting in smooth
muscle
relaxation and inflow of blood to the corpus cavemosum. In contrast, UPRIMAf"
is a
doparnine receptor agonist that acts on the central nervous system. Once
absorbed and
transported into the brain, UPRIMA initiates a chain of reactions that result
in increased
blood flow to the male genital organs anti an erection. In accordance with the
present
invention., testosterone plays a beneficial role physiologically, and
stimulates both sexual
motivation (i.e., libido) and sexual performance.
2. Sexual Motivation and Libido
While the terms "sexual performance" and "impotence" describe physiological
effects, the terms "sexual motivation" and "libido" describe psychological
effects.
"Libido" or "sexual motivation" as used herein is a parameter measured by the
duration,
frequency and extent of sexual daydreams, anticipation of sex, flirting, and
sexual
interaction.
As discussed above, while uocto>rs now believe that erectile dysfunction is
primarily caused by a physiological mewhanism, some cases are still
attributable to
psychological causes. Moreover, decreased libido may also be a reaction to the
experience
of impotence. Unfortunately, pharmai:cuticals such as VIAGRA treat erectile
dysfunction by the focusing on the physiological mechanics of attaining and
maintaining
an erection and do little or nothing to et Nance the sexual motivation or
libido of men
suffering from erectile dysfunction. "I'hus, there remains a need to treat
sexual
performance disorders such as impotence in a manner that overcomes both the
physiological and psychological problems associated with the disorder.
An number of clinical studies involving testosterone replacement in
hypogonadal
males have provided convincing evidence that testosterone plays a role in both
sexual
11.
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motivation libido and sexual performance. For example, researchers have
reported, that
testosterone replacement results in increased sexual fantasies, sexual arousal
and desire,
spontaneous erections during sleep and in th morning, ejaculation, sexual
activities with
and without a partner, and orgasm through coitus or masturbation. See
generally
Christiansen, Behavioral Correlates of Testosterone, TESTOSTERONE: ACTION,
DEFICIENCY, SUBSTITUTIOn 109-111 (1998).
B. Testosterone Synthesis, Metabolism, and Regulation
Testosterone, the major circulating androgen in men, is synthesized from
cholesterol. The approximately 500 million Leydig cells in the testes secrete
more than
95% of the 6-7 mg of testosterone produced per day. Two hormones produced by
the
pituitary gland, luteinizing hormone ("Li/I') and follicle stimulating hormone
("FSH"), are
required for the development and mainttnance of testicular function and
negatively
regulate testosterone production. Circulate ig testosterone is metabolized to
various 17-
keto steroids through two different lpathways. Testosterone can be metabolized
to
dihydrotestosterone ("DHT') by the enzymic 5a-reductase or to estradiol ("E:")
by an
aromatase enzyme complex.
Testosterone circulates in the blood 98% bound to protein. In men,
approximately
40% of the binding is to the high-affinity sex hormone binding globulin
("SHBG"). The
remaining 60% is bound weakly to albumin. Thus, a number of measurements for
testosterone are available from clinical laboratories. The term "free"
testosterone as used
herein refers to the fraction of testosterone: in the blood that is not bound
to protein. The
term "total testosterone" or "testosterone" as used herein means the free
testosterone plus
protein-bound testosterone. The term "bioavailable testosterone" as used
herein refers to
the non-S}IBG bound testosterone and includes that weakly bound to albumin.
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The following table from the UCLA-Harbor Medical Center summarizes the
hormone concentrations in normal adult men range:
Table 1: Hormone Levels in Normal Men
Hormone Normal Range
Testosterone 2a8 to 1043 ng/dL
Free testosterone 3 5 to 17.9 ng/dL
DHT 3 to 193 ng/dL
DHT/T Ratio C- 052 to 0.33
DHT + T 312 to 1349 ng/dL
SHBG 10.8 to 46.6 nmol/L
FSH l O to 6.9 mIU/mL
LH 1 .0 to 8.1 mlU/mL
E2 7.1 to 46.1 pg/mL
5 There is considerable variation in the half-life of testosterone reported in
the
literature, ranging from 10 to 100 minutes. Researchers do agree, however,
that
circulating testosterone has a diurnal variation in normal young men. Maximum
levels
occur at approximately 6:00 to 8:00 a.m. with levels declining throughout the
day.
Characteristic profiles have a maximum testosterone level of 720 ng/dL and a
minimum
level of 430 ng/dL. The physiological significance of this diurnal cycle, if
any, however,
is not clear.
C. Testosterone Levels and Sexual Behavior/Performance
Because increasing testosterone concentrations has been shown to alter sexual
performance and libido, researchers have investigated methods of delivering
testosterone
is to men. These methods include intramuscular injections (43%), oral
replacement (24%),
pellet implants (23%o), and transdermal patches (10%). A summary of these
methods is
shown in Table 2.
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{)
Table 2: Mode of Application and Dosage of Various Testosterone Preparations
Preparation Route Of i. p licatlon Full Substitution Dose
In Clinical Use
Testosterone crianthate Intramuscular injection 200-25.0 g every 2-3 weeks
Testosterone cypionate Intramuscular iri-cction 200 mg every 2 weeks
Testosterone undecanoatc oral 2-4 capsules at 40 mg per day
Transdenmal testosterone patch Scrotal skin I membrane per day
Transdermal testosterone patch Non-scrotal ski); I or 2 systems per day
Testosterone implants Implantation unrer the 3-6 implants of 200 mg every 6
abdominal spin months
Under Development
Testosterone cyclodextrin Sublingual 2.5-5.0 mg twice daily
Testosterone undecanoate Intramuscular ir:gection 1000 mg every 8-10 weeks
Testosterone buciclate Intramuscular irsiection 1000 mg every 12-16 weeks
Testosterone micro hexes Intramuscular injection 315 mg for I I weeks
Obsolete
17a-Methyltestosteronc Oral 25-5.0 g per day
Fluoxymestcrone Sublingual 10-25 mg per day
oral 10-20 ma per day
All of the testosterone replacement methods currently employed, however,
suffer
from one or more drawbacks. For example, subdermal pellet implants and ester
injections
are painful and require doctor visit,, Many of these methods, such as
oral/sublingual/buccal preparations, sutler from undesirable phannacokinetic
profile-
creating supra-physiologic testosterone concentrations followed a return to
baseline.
Transderm,al patches provide less than ,)ptimal pharmacokinetic
characteristics, are
embarrassing for many patients, and are associated with significant skin
irritation. Thus,
although the need for an effective testosterone replacement methodology has
existed for
decades, an alternative replacement die) ap!, that overcomes these problems
has never been
developed.
SUMMARY CIF THE INVENTION
The present invention relates to rs, transdermal hydroalcoholic testosterone
gel
formulation that overcomes the probicm, associated with other testosterone
delivery
mechanisms by providing, among other things, a desirable pharrnacokinetic
hormone
CA 02498267 2001-08-29
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profile with little or no skin imtation The gel may be used as a method of
improving
sexual performance, including treating : rectile dysfunction, and increasing
libido by
increasing testosterone levels in men. In addition, the gel may be used in
conjunction with
pharmaceuticals aimed at treating erectile: dysfunction, such as VIAGRA , to
enhance
their effectiveness.
BRIEF ]DESCRIPTION OF THE DRAWINGS
FIG. I (a) is a graph showing the 4-hour testosterone pharmacokinetic profile
for
hypogonadal men prior to receiving 5,0 g day of AndroGclL, 10.0 g/day of
AndroGelL, or
the testosterone patch (by initial treatment group).
FIG. 1(b) is a graph showing the >.4-hour testosterone pharmacokinetic profile
for
hypogonadal men on the first day of treatment with either 5.0 g/day of
AndroGel`L, 10.0
g/day of AndroGcl"~, or the testostcrocte patch (by initial treatment group).
FIG. 1(c) is a graph showing the 24-hour testosterone pharmacokinetic profile
for
hypogonadal men on day 30 of treatmen with either 5.0 ,Q, /day of AndroGel4',
10.0 g/day
of AndroGel, or the testosterone patch (b,.y initial treatment group).
.FIG. 1(d) is a graph showing the 24-hour testosterone pharmacokinetic profile
for
hypogonadal men on day 90 of treatment with either 5.0 g/day of AndroGelR',
10.0 g/day
of AndroGelV, or the testosterone patch 1 by initial treatment group).
FIG. 1(e) is a graph showing the 24-hour testosterone pharmacokinetic profile
for
hypogonadal men on day 180 of treatment with either 5.0 g/day of AndroGel ',
10.0 g/day
of AndroGel`D. or the testosterone patch (by final treatment group).
FIG. 1(f) is a graph showing the 24-hour testosterone pharmacokinetic profile
for
hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with 5.0 g/day of
AndroGel E`.
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FIG. 1(g) is a graph showing the 24-hour testosterone pharmacokinetic profile
for
hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with 10.0 g/day of
AndroGela'.
FIG. 1(h) is a graph showing the 24-hour testosterone pharmacokinetic profile
for
hypogonadal men on day 0. 1, 30, 90, and 180 of treatment with the
testosterone -patch.
FIG. 2(a) is a graph showing the :4-hour free testosterone pharmacokinetic
profile
for hypogonadal men on day I of treatment with either 5.0 g/day of AndroGel*,
10.0
g/day of AndroGelo, or the testosterone patch (by initial treatment group).
FIG. 2(b) is a graph showing the '4-hour free testosterone pharmacokinetic
profile
for hypogonadal men on day 30 of treatment with either 5.0 g/day of AndroGelo,
10.0
g/day of AndroGc1, or the testosterone patch (by initial treatment group).
FIG. 2(c) is a graph showing the 4-hour free testosterone pharmacokinctic
profile
for hypogonadal rtien on day 90 of treatment with either 5.0 g/day of
AndroGelt, 10.0
g/day of AndroGele, or the testosterone patch (by initial treatment group).
FIG. 2(d) is a graph showing the :14-hour free testosterone pharmacokinetic
profile
for hypogonadal men on day 180 of tre t.mcnt with either 5.0 g/day of
AndroGe1, 10.0
g/day of AndroGel'r', or the testosterone patch (by final treatment group).
FIG. 2(e) is a graph showing the ;'_4-hour free tcstosterone pharmacokinetic
profile
for hypogonadal men on day 0, 1, RN, 90, and 180 of treatment with 5.0 g/day
of
AndroGel4.
_4-hour free testosterone pharmacokinetic profile
FIG. 2(f) is a graph showing the 1
for hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with 10.0 g/day
of
AndroGela'.
FIG. 2(g) is a graph showing the 24-hour free tcstosterone pharmacokinetic
profile
for hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with the
testosterone patch.
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FIG. 3 is a graph showing the DUT concentrations on days 0 through 180 for
hypogonadal men receiving either 5.0 ,g/day of AndroGela', 10.0 g/day of
AndroGele, or
the testosterone patch (by initial treatment group).
FIG.4 is a graph showing the DHTrF ratio on days 0 through 180 for hypogonadal
men receiving either 5.0 g/day of AndroGca', 10.0 g/day of AndroGelD, or the
testosterone
patch (by initial treatment group).
FIG. 5 is a graph showing the total androgen concentrations (DHT +T) on days 0
through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel`, 10.0
g/day of
AndroGel , or the testosterone patch (by initial treatment group).
FIG. 6 is a graph showing the 1.2 concentrations on days 0 through 180 for
hypogonadal men receiving either 5.0 g/day of AndroGelo', 10.0 g/day of
AndroGel"', or
the testosterone patch (by initial treatment group).
FIG. 7 is a graph showing the SHBG concentrations on days 0 through 180 for
hypogonada] men receiving either 5.0 g/day of AndroGel , 10.0 g/day of
AndroGelo, or
the testosterone patch (by initial treatment group).
FIG. 8(a) is a graph showing the YSH concentrations on days 0 through 180 for
men having primary hypogonadism and receiving either 5.0 g/day of AndroGee,
10.0
g/day of AndroGel4O, or the testosterone patch (by initial treatment group).
FIG. 8(b) is a graph showing the FSH concentrations on days 0 through 180 for
men having secondary hypogonadism and receiving either 5.0 g/day of AndroGelo,
10.0
g/day of AndroGelo, or the testosterone patch (by initial treatment group).
FIG. 8(c) is a graph showing the FSH concentrations on days 0 through 180 for
men having age-associated hypogonadism and receiving either 5.0 g/day of
AndroGel"O,
10.0 g/day of AndroGe1, or the testosterone patch (by initial treatment
group).
\ti.
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FIG. 8(d) is a graph showing the FSH concentrations on days 0 through I$0 for
men having hypogonadism of an unknown origin and receiving either 5.0 g/day of
AndroGel , 10.0 g/day of AndroGels, oa the testosterone patch (by initial
treatment
group).
5 FIG. 9(a) is a graph showing the LII concentrations on days 0 through 180
for men
having primary hypogonadism and receiving either 5.0 g/day of AndroGel-D, 10.0
g/day of
AndroGel'o. or the testosterone patch (by inatial treatment group).
FIG. 9(b) is a graph showing the Lfi concentrations on days 0 through 180 for
men
having secondary hypogonadism and receiving either 5.0 g/day of AndroGelo,
10.0 g/day
10 of AndroGelo, or the testosterone patch (b} initial treatment group).
FIG. 9(c) is a graph showing the Lfl concentrations on days 0 through 180 for
men
having age-associated hypogonadism and receiving either 5.0 g/day of
AndroGel", 10.0
g/day of AndroGel , or the testosterone pat h (by initial treatment group).
FIG. 9(d) is a graph showing the Lft concentrations on days 0 through 180 for
men
having hypogonadism of an unknown origtrt and receiving either 5.0 g/day of
AndroGelo,
10.0 g/day of AndroGel o, or the testosterone patch (by initial treatment
group).
FIG. 10(a) is a graph showing sexual motivation scores on days 0 through 180
for
hypogonadal men receiving either 5.0 g day of AndroGel4', 7.5 g/day 10.0 g/day
of
AndroGel1', or the testosterone patch.
FIG. 10(b) is a graph showing overall sexual desire scores on days 0 through
180
for hypogonadal men receiving either 5.0 day of AndroGe16, 7.5 g/day 10.0
g/day of
AndroGels, or the testosterone patch.
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FIG. 10(c) is a graph showing sexual enjoyment (with a partner) scores on days
0
through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel*, 7.5
g/day 10.0
g/day of AndroGel'D, or the testosterone patch.
FIG. 11(a) is a graph showing sexual performance scores on days 0 through 180
for hypogonadal men receiving either 5.0 g/day of AndroGel , 7.5 g/day 10.0
g/day of
AndroGel , or the testosterone patch.
FIG. I I (b) is a graph showing crec ion satisfaction performance scores on
days 0
through 180 for hypogonadal men receiving; either 5.0 g/day of AndroGe]'', 7.5
g/day 10.0
g/day of AndroGela', or the testosterone patch.
FIG. 11(c) is a graph showing per, cnt erection scores on days 0 through 180
for
hypogonadal men receiving either 5.=) g/day of AndroGel4o, 7.5 g/day 10.0
g/day of
AndroGel'', or the testosterone patch.
D TAILFn DESCRIPTION QF THE INVENTION
While the present invention may t-e embodied in many different forms, several
specific embodiments are discussed herein with the understanding that the
present
disclosure is to be considered only as an c>;amplification of the principles
of the invention,
and it is not intended to limit the invention co the embodiments illustrated.
The present invention is directed to a pharmaceutical composition for
percutaneous
administration comprising testosterone in i, hydroalcoholic gel useful for
treating erectile
dysfunction and libido deficiencies. In a broad aspect of the invention, other
steriods in
the testosterone anabolic or catabolic pathway may be used (e.g.
androstenedione,
androstenediol, dehydroepiandrosteronc, pr cnenolone, and DHT). The gel
comprises one
or more lower alcohols, such as ethanol of isopropanol; a penetration
enhancing agent; a
.0
CA 02498267 2001-08-29
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thickener, and water. Additionally, the present invention may optionally
include salts,
emollients, stabilizers, antimicrobials, fragrances, and propellants.
A "penetration enhancer" is an agent known to accelerate the delivery of the
drug
through the skin. These agents also have t-heen referred to as accelerants,
adjuvants, and
sorption promoters, and are collectively rccrred to herein as "enhancers."
This class of
agents includes those with diverse mecharusms of action including those which
have the
function of improving the solubility and diffusibility of the drug, and those
which improve
percutaneous absorption by changing the ability of the stratum corneum to
retain moisture,
softening the skin, improving the skin s permeability, acting as penetration
assistants or
hair-follicle openers or changing the state o4'the skin such as the boundary
layer.
The penetration enhancer of the present invention is a functional derivative
of a
fatty acid, which includes isosteric modifications of fatty acids or non-
acidic derivatives of
the carboxylic functional group of a fatty acid or isosteric modifications
thereof. In one
embodiment, the functional derivative of w: fatty acid is an unsaturated
alkanoic acid in
which the -COOH group is substituted with a functional derivative thereof,
such as
alcohols. polyols, amides and substituted derivatives thereof. The term "fatty
acid" means
a fatty acid that has four (4) to twenty-four 24) carbon atoms.
Non-limiting examples of penetration enhancers include C8-C22 fatty acids such
as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such
as oleyl
alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as
ethyl oleate,
isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters
of C6-C8
diacids such as diisopropyl adipate; mnor-toglycerides of C8-C22 fatty acids
such as
glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether;
polyethylene
glycol, propylene glycol; 2-(2-ethoxyethox,, )ethanol; diethylene glycol
monomethyl ether,
CA 02498267 2001-08-29
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alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers;
polyethylene oxide dimethyl ethers; uimethyl sulfoxide, glycerol; ethyl
acetate;
acetoacetic ester, N-alkylpyrrolidone; and terpenes.
The thickeners used herein may in(. lude anionic polymers such as polyacrylic
acid
(CARBOPOL by B.F. Goodrich Specialty Polymers and Chemicals Division of
Cleveland, Ohio), carboxymethylcelluose and the like. Additional thickeners,
enhancers
and adjuvants may generally be found n Remington's The Science and Practice of
pharmacy, Meade Publishing Co., United States Pharmacopeia/National Formu~.
The composition is used in a pharmacologically effective amount." This means
that the concentration of the testosterone is such that in the composition it
results in a
therapeutic level of drug delivered over th term that the gel is to be used.
Such delivery
is dependent on a number of variables including the time period for which the
individual
dosage unit is to be used, the flux rate c i' the testosterone from the gel,
surface area of
application site, etc. The amount of estosterone necessary can be
experimentally
determined based on the flux rate of the drug through the gel, and through the
skin when
used with and without enhancers.
One such testosterone gel has only recently been made available in the United
States under the trademark AndroGeI`e by Unimed Pharmaceuticals, Inc.,
Deerfield,
Illinois, the assignee of this application. In one embodiment, the gel is
comprised of the
following substances in approximate amounts:
Table 3: Composition of AndroGel'
SUBSTANCE AMOUNT (wlw)
PER I OOg OF GEL
Testosterone 1.0
Carbo ol980 0.90
Isopropyl mvristate 0.50
0.1 N NaOH 4.72
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SUBSTANCE AMOUNT (wiw)
PER l00 OF GEL
Ethanol (95% w/w) 72.5 g*
Purified water (sf) 100 g
'' Cotrespondicig to 67 g of ethanol.
One skilled in the art will appreciate that the constituents of this
formulation may
be varied in amounts yet continue to be within the spirit and scope of the
present
invention. For example, the composition may contain about 0.1 to about 10.0 g
of
testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g
isopropyl
myristate, and about 30.0 to about 98.0 g cuianol.
A therapeutically effective amount of the gel is rubbed onto a given area of
skin by
the user. The combination of the lipopnilic testosterone with the
hydroalcoholic gel helps
drive the testosterone in to the outer layers of the skin where it is absorbed
and then slowly
released into the blood stream. As demonstrated by the data presented herein,
the
administration of the gel of the present invention has a sustained effect.
Toxicity and therapeutic efficacy o1 the testosterone can be determined by
standard
pharmaceutical procedures, e.g., for determining LD50 (the dose lethal to 50%
of the
population) and the ED50 (the dose therapeutically effective in 50% of the
population).
The dose ratio between toxic and therapeutic effects is the therapeutic index
and it can be
expressed as the ratio TLDWED;,o. Compounds which exhibit large therapeutic
induces are
preferred. While compounds that exhibit ataxic side effects may be used, care
should be
taken to design a delivery system that targeis such compounds to the site of
affected tissue
in order to minimize potential damage to uninfected cells and, thereby, reduce
side effects.
The present invention is further ilustrated by the following examples, which
should not be construed as limiting in any way. The contents of all cited
references
throughout this application are hereby expressly incorporated by reference.
The practice
CA 02498267 2001-08-29
of the present invention will employ, unless otherwise indicated, conventional
techniques
of pharmacology and pharmaceutics, which are within the skill of the art_
EXAMPLES
Example 1: Method of Im rn oving Sexual Performance and Increasing Libido in
5 H.ypogonadal Men
One embodiment of the present invention involves the transdermal application
of
AndroGel as a method of increasing sexual performance and libido in
hypogonadal men
without causing significant skin irritation.
In this example, hypogonadal men were recruited and studied in 16 centers in
the
10 United States. The patients were between 19 and 68 years and had single
morning scrum
testosterone levels at screening of less than or equal to 300 ng/dL (10.4
nmol/L ). A total
of 227 patients were enrolled: 73, 78, and 76 were randomized to receive 5.0
g/day of
AndroGel'a (delivering 50 mg/day of testosterone to the skin of which about
10% or 5 mg
is absorbed), 10.0 g/day of AndroGela (de ivering 100 mg/day of testosterone
to the skin
15 of which about 10% or 10 mg is absorbed), or the ANDRODERM' testosterone
patch ("T
patch"; delivering 50 mg/day of testosteroxra), respectively.
As shown in the following table, there were no significant group-associated
differences of the patients' characteristics at baseline.
Table 4. Baseline Characteristics of the Hypogonadal Men
Treatment Group T patch AndroGel AndroGei
(5.0 ldav (10.0 g/day)
No of subjects enrolled 76 73 78
Age (years) 51.1 51.3 51.0
Range (years) 28-67 23-67 19-68
-Height cm 179.30.9 175.8 0.8 178.610.8
Weight (k92.7 1.6 90.51 1.8 91.6 1.5
Serum testosterone (nmolIL) 6.40: 0.41 6.44 0.39 6.49 f 0.37
Causes of h ogonadism
CA 02498267 2001-08-29
'ROW
16
Treatment Group T patch AndroGel" AndroGel"
(5.0%/day) I0.0 /dav
Primary hypogonadism 34 26 34
Klinefelter's Syndrome 9 5 8
Post Orchidectomy/Anorchia 2 1 3
Primary Testicular Failure 23 20 23
Secondary hypogonadism 15 17 12
Kallman's Syndrome 2 2 0
Hypothalimic Pituitary Disorder 6 6 3
Pituitary Tumor 7 9 9
Ain 6 13 6
Not classified 21 17 26
Years diagnosed 5.8 t 1.1 4.4 0.9 5.7 t 1.24
Number previously treated with 50 (65.8%) 38 (52.1%) 46 (59.0%)
testosterone
Type of Previous Hormonal Treatment
Intramuscular injections 26 20 28
Transdermal patch 12 7 8
All others 12 11 10
Duration of treatment (years) 5.8 t 1.0 5.4:t 0.8 4.6 t 80.7
Forty-one percent (931227) of the subjects had not received prior testosterone
replacement therapy. Previously treated hypogonadal men were withdrawn from
testosterone ester injection for at least six weeks and oral or transdermal
androgens for
four weeks before the screening visit. Aside from the hypogonadism, the
subjects were in
good health as evidenced by medical history, physical examination, complete
blood count,
urinalysis, and serum biochemistry. 'if the subjects were on lipid-lowering
agents or
tranquilizers, the doses were stabilized or at least three months prior to
enrollment. Less
than 5% of the subjects were taking supplemental calcium or vitamin 1) during
the study.
The subjects had no history of chronic medical illness, alcohol or drug abuse.
They had a
normal rectal examination, a PSA level of less than 4 ng/mL, and a urine flow
rate of 12
mils or greater. Patients were excluded if ,hey had a generalized skin disease
that might
affect the testosterone absorption or prior history of skin irritability with
ANDRODERM's'
i
CA 02498267 2001-08-29
w
17
patch. Subjects weighing less than 80 ,4 or aver 140% of their ideal body
weight were also
excluded.
The randomized, multi-center, parallel study compared two doses of AndroGeIt
with the ANDRODERM testosterone patch. The study was double-blind with respect
to
the AndroGelt dose and open-labeled for the testosterone patch group. For the
first three
months of the study (days 1 to 90), the subjects were randomized to receive
5.0 g/day of
AndroGele, 10.0 g/day of AndroGel , or two non-scrotal patches. In the
following three
months (days 91 to 180), the subjects were administered one of the following
treatments:
5.0 g/day of AndroGelo, 10.0 g/day of AdroGel , 7.5 g/day of AndroGcl'o, or
two non-
scrotal patches. Patients who were applying AndroGel't had a single, pre-
application
serum testosterone measured on day 60 and, if the levels were within the
normal range of
300 to 1,000 ng/dL (10.4 to 34.7 nrnol/l. ), then they remained on their
original dose.
Patients with testosterone levels less than 300 ng/dL and who were originally
assigned to
apply 5.0 g/day of AndroGell) and those with testosterone levels more than
1,000 ng/dL
who had received 10.0 g/day of AndroGta" were then reassigned to administer
7.5 g/day
of AndroGel for days 91 to 180.
Accordingly, at 90 days, dose adjustments were made in the AndroGelt groups
based on the pre-application serum testosterone levels on day 60. Twenty
subjects in the
5.0 g/day AndroGel* group had the dose increased to 7.5 g/day. Twenty patients
in the
10.0 g/day AndroGele group had the Ar droGelo dose reduced to 7.5 g/day. There
were
three patients in the testosterone patch group who were switched to 5.0 g/day
AndroGelo
because of patch intolerance. One 10.0 g/day AndroGely subject was adjusted to
receive
5.0 g/day and one 5.0 g/day AndroGel"' subject had the dose adjusted to 2.5
g/day. The
number of subjects enrolled into day 91 to 180 of the study thus consisted of
51 receiving
1L'
CA 02498267 2001-08-29
i8
5.0 g/day of AndroGelo, 40 receiving 7,5 g/day of AndroGela, 52 receiving 10.0
g/day of
AndroGel , and 52 continuing on the ANDRODERM4' patch. The treatment groups in
this example may thus be characterized in two ways, either by "initial" or by
the "final"
treatment group. Subjects returned to the study center on days 0, 30, 60, 90,
120, 150, and
180 for a clinical examination, skin irritation and adverse event assessments.
A. AndroGele and ANDRODERM`a patch
Approximately 250 g of AndroGeli" was packaged in multidose glass bottles that
delivered 2.25 g of the gel for each acttxatiun of the pump. Patients assigned
to apply 5.0
g/day of Androgel" testosterone were given one bottle of AndroGel" and one
bottle of
placebo gel (containing vehicle but no testosterone), while those assigned to
receive 10.0
g/day of AndroGel'a were dispensed two -,)ottles of the active AndroGel*. The
patients
were then instructed to apply the bottle contents to the right and left upper
arms/shoulders
and to the right and left sides of the abdomen on an alternate basis. For
example, on the
first day of the study, patients applied two actuations from one bottle, one
each to the left
and right upper arm)shoulder, and two actuations from the second bottle, one
each to the
left and right abdomen. On the following day of treatment, the applications
were reversed.
Alternate application sites continued throughout the study. After application
of the gel to
the skin, the gel dried within a few minutes. Patients washed their hands
thoroughly with
soap and water immediately after gel application.
The 7.5 g/day AndroGcl* group rel. ived their dose in an open-label fashion.
After
90 days, for the subjects titrated to the AndroGel~ 7.5 g/day dose, the
patients were
supplied with three bottles, one containing placebo and the other two
AndroGelo. The
subjects were instructed to apply one actuation from the placebo bottle and
three
1
CA 02498267 2001-08-29
W
19
actuations from a AndroGel'3' bottle to four ifferent sites of the body as
above. The sites
were rotated each day taking the same sequence as described above.
ANDRODERM testosterone patches each delivering 2.5 mg/day of testosterone
were provided to about one-third of the ;patients in the study. These patients
were
instructed to apply two testosterone patches to a clean, dry area of skin on
the back,
abdomen, upper arms, or thighs once per day. Application sites were rotated
with
approximately seven days interval between applications to the same site.
On study days when the patients =wore evaluated, the gel/patches were applied
following pre-dose evaluations. On the remaining days, the testosterone gel or
patches
were applied at approximately 8:00 a.m for 180 days.
B. Study Method and Results
1. Hormone Pharmacokinetics
On days 0, 1, 30, 90, and 1 F0, .he patients had multiple blood samples for
testosterone and free testosterone measurements at 30, 15 and 0 minutes before
and 2, 4, 8,
12, 16, and 24 hours after AndroGel or patch application. In addition,
subjects returned
on days 60, 120, and 150 for a single blood sampling prior to application of
the gel or
patch. Serum DHT, E2, FSH, LH and SWIG were measured on samples collected
before
gel application on days 0, 30, 60, 90, 12=J, 150, and 180. Sera for all
hormones were
stored frozen at -20 eC until assay. Al' samples for a patient for each
hormone were
measured in the same assay whenever possible. The hormone assays were then
measured
at the Endocrine Research Laboratory of the UCLA-Harbor Medical Center.
The following table summarizes the pharmacokinetic parameters were measured
for each patient:
CA 02498267 2001-08-29
Table 5: Pharmacokinetic Parameters
AUCo-24 area under the curve from U to 24 hours, determined using the linear
trapezoidal rule.
Cb.u or C. Baseline concentration
time-averaged concentration over the 24-hour dosing interval determined
C'"i by AUCo24/24
maximum concentration d tiring the 24-hour dosing interval
Cm;n minimum concentration during the 24-hour dosing interval
T. time at which C,r.,, Occurred
Tmin time at which Can occurred
Fluctuation extent of variation in the serum concentration over the course of
a single
Index day, calculated as (C,,.1-& ,,,,n)/C..e
Accumulation increase in the daily drug 'xposure with continued dosing,
calculated as
the ratio of the AUC at steady on a particular day over the AUC on day I
ratio _ (e.g., AUC Uy 3o/AUCcry I)
Net AUCo-24 AUCo.24 on days 30, 90, 80 - AUCo.24 on day 0
a. Testosterone Pharmacokinetics
(1) Methods
5 Serum testosterone levels were measured after extraction with ethylacetate
and
hexane by a specific radioimmunoassay ("RIA") using reagents from ICN (Costa
Mesa,
CA). The cross reactivities of the antiserum used in the testosterone RIA were
2.0% for
DHT, 2.3% for androstenedione, 0.80/c for 3-(3-andmstanediol, 0.6% for
etiocholanolone
and less than 0.01 % for all other steroids tested. Die lower limit of
quantitation ("LLQ")
10 for serum testosterone measured by this assay was 25 ngldL (0.87 nmolIL).
The mean
accuracy of the testosterone assay, determined by spiking steroid free senun
with varying
amounts of testosterone (0.9 nmol/L tc= 52 nmoVL), was 104% and ranged from
92% to
1 17%. The intra-assay and inter-assay con. tTicients of the testosterone
assay were 7.3 and
11.1 %, respectively, at the normal adult male range. In normal adult men,
testosterone
CA 02498267 2001-08-29
concentrations range from 298 to 1,043 ngidL, (10.33 to 36.17 nmoUL) as
determined at
the UCLA-Harbor Medical Center.
(2) Baseline Concentration
As shown in Table 6(a)-6(b) and FIG. l (a), at baseline, the average serum
testosterone concentrations over 24 hours (('.,,t) were similar in the groups
and below the
adult normal range. Moreover the variations of the serum concentration (based
on
maximum and minimum concentrations =luring the 24-hour period, C. and C,,,e,,,
respectively) during the day were also similar in the three groups. FIG. 1(a)
shows that
the mean testosterone levels had a the maximum level between 8 to 10 a.m.
(i.e., at 0 to 2
hours) and the minimum 8 to 12 hours later, demonstrating a mild diurnal
variation of
serum testosterone. About one-third of the patients in each group had C.,,,
within the
lower normal adult male range on day 0 (24/73 for the 5.0 g/day AndroGela
group, 2.6/78
for the 10.0 g/day AndroGelx' group, and 2 5/76 for testosterone patch group).
All except
three of the subjects met the enrollment criterion of serum testosterone less
than 300 ng/dL
(10.4 nmolfL) on admission.
Table 6(a): Baseline Pliamacokinetic Parameters
by Initial Treatment Group (Mean t SD)
5.0 g/day T-Cel 10.0 day T el T- patch
N 73 78 76
C n dL 237 *130 248 *140 237:k 139
C n dL 328* 178 333 * 194 314* 179
T ' hr 4.0 0.0-24.53 7.9 0.0-24.7 4.0 0.0-24.3)
C m n dL 175 * 104 188* 112 181 * 112
T,, = hr 8.01 0.0-24.1 8.0 0.0-24.0 8.0 (0.0-23.9)
Fluc Index (ratio) 0.627 0.47' 0.556 0.384 0.576 0.341
*Median (Range*)
CA 02498267 2001-08-29
22
Table 6(b): Baseline Testosterone Pharmacokinetic Parameters
by Final Treatment Group (Mean t SD)
Doses Received Du r tog Initial -> Extended Treatment Pbases
5.0 g/day 5.0 - 73 Vdav 10.0 -> 7.5 T,/day 10.0 g/day T-patch
T el
T T el I let
N S3 20 20 58 = 76
Cõ2 (ng/dL) 247 t 137 212 1(9 262 t 157 236:t 133 237;t 140
C,,,p, (ngidL) 333 t 180 313 t I'4 408 t 241 307:t 170 314 t 179
T,.,.,,' (hr) 4.0 (0.0-24,5) 4.0 (0.0-24.0) 19.7 (0.0-24.3) 4.0 (0.0-24.7) 4.0
(0.0-24.3)
C,,..(ng/dL) 185 t 1I I 150t8J 2061 130 182 106 181 112
Tõõõ' (hr) 8.0 (0.0-24.1) 11.9 (0Ø24.0) 8.0 (0.0-23.3) 8.0 (0.0-24.0) 8.0
(0.0-23.9)
Fluc Indcx (ratio) 0.600 t 0.471 0.699 t 0.503 0.678 t 0.580 0.514 t 0.284
0.576 t 0.341
'Median (range)
(3) Day I
FIG. 1(b) and Tables 6(c)-(d) show he pharmacokinetic profile for all three
initial
treatment groups after the first application of transdcrmal testosterone. In
general,
treatment with AndroGele and the testosterone patch produced increases in
testosterone
concentrations sufficiently large to bring ttie patients into the normal range
in just a few
hours. However, even on day 1, the pharmacokinetic profiles were markedly
different in
the AndroGel4' and patch groups. Seruln testosterone rose most rapidly in the
testosterone
patch group reaching a maximum concentration (C,,,.,,) at about 12 hours (T.).
In
contrast, serum testosterone rose steadhty t- the normal range after AndroGela
application
with C,,. levels achieved by 22 and 15 h,: urs in the 5.0 g/day AndroGelo
group and the
10.0 g/day AndroGcle' group, respectively.
Table 6(c): Testosterone Pharmacokinetic Parameters on Day I
by Initial Treatrneut Group (Meant SD)
5.0 /dav 'r-GeI 10.0 /day T el T- patch
N 73 _ 76 74
C,, n dL 398 156 514 + 227 482 + 204
C,,,,, (n /dU) 560 269 748 + 349 645 280
CA 02498267 2001-08-29
w
23
5.0 idav T-Gtl 10.0 day T el T- Patch
T, ,x* hr 22.1 f0.0-25.3; 16.0 (0.0-24.3) 11.8 (1.8-24.0)
Cõ, n dL 228+ 122 250 +143 232 +132
T,,,,,,* (hr) 1.9 0.0-24.0` 0.0 (0.0-24.2) 1.5 (0.0-24.0)
*Median (Range)
Table 6(d): Testosterone Phamacokinetic Parameters on Day I
by Final Treatment Group (Mean t SD)
Doses Received During Initial => Extended Treatment Phases
5.0 ;/day 5.0 -> 7.5 &/daa 10.0 -> 73 =/day 10.0 t/day T-patch
T MI Tad T I T -2d
N 13 20 _ 19 57 74
C , n dL1 4 1 1 1 6 0 363 t 143 554 t 243 500 t 223 482 t 204
C n /dL1 573 3 285 525 t 223 819 359 724 346 645 280
T,,* hr 22.1 (0.0-25.31 19.5 1.8-x'4.3 15.7 (3.9-24.0) 23.0 (0.0-24.3 11.8
(1.8-24.0)
C n dLl 237 3 125 204 1 : 2 265 t 154 245 140 232 t 132
T ` 1tr 1.8 (0Ø24.0 3.5 0.0-24.0) 1.9 (0.0-24.2) 0.0 (0.0-23.8) 1.3 (0.0-
24.0)
Flue Index (ratio) 0.600 0.471 0.699 t 0 $03 0.678 t 0.580 0.534 0.284 0.576
0.341
*Median (range)
(4) Days 30, 90, and 180
FIGS. 1(c) and 1(d) show the unique 24-hour pharmacokinetie profile of
AndroGel`a-treated patients on days 30 and 90. In the AndroGelo groups, serum
testosterone levels showed small and `ariable increases shortly after dosing.
The levels
then returned to a relatively constant l, ve( In contrast, in the testosterone
patch group,
patients exhibited a rise over the first 8 to 1I hours, a plateau for another
8 hours, and then
a decline to the baseline of the prior day. Further, after gel application on
both days 30
and 90, the Cõ,$ in the 10.0 g/day Andro(.=el' group was 1.4 fold higher than
in the 5.0
g/day AndroGel'a group and 1.9 fold higher than the testosterone patch group.
The
testosterone patch group also had a Cm,n substantially below the lower limit
of the normal
range. On day 30, the accumulation ratio was 0.94 for testosterone patch
group, showing
no accumulation. The accumulation ratios at 1.54 and 1.9 were significantly
higher in the
5.0 g/day AndroGelo group and 10.0 gday AndroGelt group, respectively. The
differences in accumulation ratio among the groups persisted on day 90. This
data
ti
CA 02498267 2001-08-29
24
indicates that the AndroGel1 preparations hid a longer effective half-life
than testosterone
patch.
FIG. 1(e) shows the 24-hour plarn' acokinetic profile for the treatment groups
on
day 180. In general, as Table 6(c) shows, he serum testosterone concentrations
achieved
and the pharmacokinetic parameters u ere similar to those on days 30 and 90 in
those
patients who continued on their initial randomized treatment groups. Table
6(f) shows
that the patients titrated to the 7.5 g/day itndroGele group were not
homogeneous. The
patients that were prcviously in the 10.1' g/day group tended to have higher
serum
testosterone levels than those previously receiving 5.0 g/day. On day 180, the
C.,,1 in the
patients in the 10.0 g/day group who ccont erted to 7.5 g/day on day 90 was
744 ng/dL,
which was 1.7 fold higher than the. C,=, o 450 ng/dL in the patients titrated
to 7.5 g/day
from 5.0 g/day. Despite adjusting the dose: up by 2.5 g/day in the 5.0 to 7.5
g/day group,
the C.,,1 remained lower than those remaining in the 5.0 g/day group. In the
10.0 to 7.5
g/day group, the C,,,t became similar to those achieved by patients remaining
in the 10.0
g/day group without dose titration. These results suggest that many of the
under-
responders may actually be poorly compli:=nt patients. For example, if a
patient does not
apply AndroGel" properly (e.g., prelererntially from the placebo container or
shortly
before bathing), then increasing the dose wail not provide any added benefit.
FIGS. 1(f)-(h) compare the pharmcicokinetic profiles for the 5.0 g/day
AndroGelt
group, the 10.0 AndroGel4' g/day group, and the testosterone patch group at
days 0, 1, 30,
90, and 180, In general, the mean serum testosterone levels in the
testosterone patch
group remained at the lower limit of the normal range throughout the treatment
period. In
contrast, the mean serum testosterone levers remained at about 490-570 ng/dL
for the 5.0
g/day AndroGel'e group and about 630-86C ng/dL AndroGel' for the 10.0 g/day
group.
1
CA 02498267 2001-08-29
Table 6(e): Testosterone Phamacokinetic Parameters on Day 1
by Initial Treatment Group (Mean SD)
5.0 R/dav T-Gtl 10.0 g/day T-acl T-patch
Day30 N=66 N-74 N=70
C.,, (ng/dL) 566 262 792 294 419 + 163
C,,,., (ng/dL) 876 466 1200 482 576 22
3
T,,,.,,=(hr) 7.9 (0.0-24.01 7.8 (0.0-24.3) 11.3 (0.0-24.0)
C,,,õ, (ng/dL) 361 49 505 + 233 235 122
T,*;.* (hr) 8.0 (0.0-24.1 8.0 (0.0-25.8) 2.0 (0.0-24.2)
Hut: Index (ratio) 0.857 J.33 0.895 0.434 0.823 0.289
Accum Ratio (ratio) 1.529 1.726 1.911 1.588 0.937 + 0.354
Day 90 N-r-5 N=73 N64
C,,, (ng/dL) 553 247 792 276 417 +157
C,õõ (ng/dL) 846 444 1204 570 597 +242
T,,.,"(hr) 4.0 (0.0 24.1) 7.9 (0.0-25.2) 8.1 (0.0-25.0)
C,.,,, (ng/dL) 354 147 501 193 213 105
T,,,,,* (hr) 4.0 (0.0 ~25.:) 8.0 (0.0-24.8) 2.0 (0.0-24.0)
Fluc Index (ratio) 0.851 0.402 0.859 0.399 0.937 0.442
Accum Ratio (ratio) 1.615 + 0.85 9 1.927 + 1.310 0.971 0.453
Day 180 N = 63 N = 68 N - 45
C,,, (ng/dL) 520 22" 722 242 403 163
C.., (ng/dL) 779 359 1091 437 580 240
T,,,,,,*(hr) 4.0 (0.0-24.t)) 7.9 (0.0-24.0) 10.0 (0.0-24.0)
C,,,,,, (ng/dL) 348 + 164 485 184 223 114
T-tiõ* (hr) 1 1.9 (0.1-24 0) 11.8 (0.0-27.4) 2.0 (0.0-25.7)
Fluc Index (ratio) 0.845 + 03-9 0.829 0.392 0.891 0.319
Accum Ratio (ratio) 1.523 + I.04 1.897 + 2.123 0.954 + 0.4105
*Median (Range)
Table 6(f): Testosterone Pbamacoicinetic Parameters on Days 30, 90,180
5 by Final Treatment Group (Mean SD)
Dozes Received I`lurint Initial -> Extended Treatment Phases
5.0 c/day 5.0 -K-j- 7.5 81dm v 10.0 -> 7.5 t/dav 10.0 t/day T-patch
T-gel T-get T -gel T el
Day30 N-47 N- 19 N- 19 N-55 N-70
C,,, (ng/dL) 604 t 288 472,t 148 946 t 399 739 t 230 419 t 163
C. (ng/dL) 941 t 509 716 t 294 1409 t 556 1 128 436 576t 223
7.8 (0.0-24.3) 11.3 (0.0-24.0)
T..,' (hr) 7.9 (0.0-24.0) 8.0 (0.0-24.0 8.0 (0.0-74.11
C,,. (ng/dL) 387 t 159 2%:t 97 600 339 471 175 235 t 122
T.,.' (hr) 8. t (0.0-24.1) 1.7 (0.-14.1 11.4 (0.0-24.1) 8.0 (0.0-25.8) 2.0
(0.0-24.2)
Fluc index (ratio) 0.861 0.341 0.846 10.3 1 0.927 0.409 0.884 t 0.445
0.823 3 0.289
Accum Ratio (ratio) 1.543 t 0.747 1.494:t 0.69 2.053 t 1.393 1.864 t 1.657
0.937 t 0.354
Day90 N45 N-20 N-18 N-55 N-64
C.,, (ng/dL) 596 t 266 455 164 859:t 298 771 t 268 417 t 157
C,,. (ng/dL) 931 t 455 654 359 1398 733 1141 498 597 242
T,,,,.' (hr) 3.8 (0.0-24.1) 7.7 (0.0 24.0 7.9 (0.0-24.0) 7.9 (0.0-25.2) 8.1
(0.0-25.0)
C.õ, (ng1dL) 384 t 147 296 125 532 t 181 492 1197 213 t 105
T~' (hr) 7.9 (0.0-25.3) 0.0 (0.024.0 12.0 (0.0-24.1) 4.0 (0.0-24.8) 2.0 (0.0-
24.0)
Fluc Indcx (ratio) 0.860 10.39 1 0.771 t 0,42'0.959 t 0.490 0.826 3 0.363
0.937 t 0.442
Accum Ratio (ratio) 1.593 0.813 1.737 1.14 `. 1.752:t 0.700 1.952 1.380
0.971 3 0.453
CA 02498267 2001-08-29
w
26
Doses Received During Initial -> Extetded Treatment Phases
5.0 g/day 5.0 -> 7.5 g?day 10.0 -> 7.3 g/day 10.0 g/day T-patent
T=tel T-gel T -gel T el
Day180 N-44 N-18 N-19 N-48 N-41
C,,, (ng/dL) 5551225 4501219 744 1320 713 t 209 408 t 165
C,,,Q (ng/dL) 803 t 347 680 t 369 1110 t 468 1083 t 434 578 t 245
T.0 (hr) 5.8 (0 0-24.0) 2.0 (0.0-24.0) 7.8 (0.0-24.0) 7.7 (0.0-24.0) 10.6 (0.0-
24.0)
Cm. (ng/dL) 371 t 165 302 t I t0 505 t 233 485 t 156 1 222 t 116
T,,,.= (hr) 11.9 (0Ø24.0) 9.9 (0.0-24.0) 12.0 (0.0-24.0) 8.0 (0Ø27.4) 2.0
(0.0-25.7)
Fluc Index (ratio) 0.853 t 0.402 0.833 10,335 0.824 t 0.298 0.818 t 0.421
0.866 t 0.311
Accum Ratio (ratio) 1.541 t 0.917 NA NA 2.061 t 2.445 0.969 0.415
"Median (range)
(5) Dose P -oportionality for AndroGel D
Table 6(g) shows the increase in i.UC0..24 on days 30, 90, and 180 from the
pretreatment baseline (net AUCv_24) as calculated using an arithmetic mean. In
order to
assess dose-proportionality, the biocquwvak nce assessment was performed on
the log-
transformed AUCs using "treatment" as the only factor. The AUCs were compared
after
subtracting away the AUC contribution :Tom the endogenous secretion of
testosterone (the
AUC on day 0) and adjusting for the two-fo,d difference in applied doses. The
AUC ratio
on day 30 was 0.95 (90% C.I.: 0.75-1.19) aid on day 90 was 0.92 (90% C.L: 0.73-
1.17).
When the day 30 and day 90 data was comb; ned, the AUC ratio was 0.93 (90%
C.I.: 0.79-
1.10).
The data shows dose proportioaali,,v for AndroGelà treatment. The geometric
mean for the increase in AUC0.24 from day 1 to day 30 or day 90 was twice as
great for the
10.0 giday group as for the 5.0 g/day group. A 125 ng/dL mean increase in
serum
is testosterone Caõs level was produced by each 2.5 g/day of AndroGe1 . In
other words, the
data shows that 0.1 g/day of AndroGel1 produced[, on the average, a 5 ng/dL
increase in
serum testosterone concentration. This lose proportionality aids dosing
adjustment by the
physician. Because AndroGel is pr;wi4.ed in 2.5 g packets (containing 25 mg
of
testosterone), each 2.5 g packet will product., on average, a 125 ng/dL
increase in the Can
for serum total testosterone.
CA 02498267 2001-08-29
Table 6(g): Net AUCa24 (nmol11 h!L) on Days 30, 90, and 180
after Transdermal Testosterone Application
T Patch T gel 5.0 day T gel 10.0 day
Da 30 154 f 18 268 - 28 446 - 30
Da 90 157 20 26.t 29 461 28
Da 180 160 f 25 250 32 401 27
The increase in AUC .24 from pret; eatrnent baseline achieved by the 10.0
g/day and
the 5.0 g/day groups were approximately 2.^j and 1.7 fold higher than that
resulting from
application of the testosterone patch. These figures also indicate that an
ANDRODERMt*
patch, which produces an approximately 18 0 ng/dL increase in C,,,B, is
equivalent to
approximately 3.5 g/day of AndroGelt.
b. Pharmacokinetics of Serum Free Testosterone
Concentration
(1) Methods
Serum free testosterone was measured by RIA of the dialysate, after an
overnight
equilibrium dialysis, using the same RIA reagents as the testosterone assay.
The LLQ of
serum free testosterone, using the equilibrium dialysis method, was estimated
to be 22
pmol/L. When steroid free serum was spike: with increasing doses of
testosterone in the
adult male range, increasing amounts of free testosterone were recovered with
a
coefficient of variation that ranged from. 11.0-18.5%. The intra- and
interassay
coefficients of free testosterone were 15% and 16.8% for adult normal male
values,
respectively. As estimated by the UCLA -Harbor Medical Center, free
testosterone
concentrations range from 3.48-17.9 rig/di". (121-620 pmol/L) in normal adult
men.
(2) Pharrmacoklnetlc Results
In general, as shown in Table 7, the pharmacokinetic parameters of serum free
testosterone mirrored that of serum total testosterone as described above. At
baseline (day
0), the mean serum free testosterone concentrations (Cõ.a) were similar in all
three groups '
CA 02498267 2001-08-29
which were at the lower limit of the adult male range. The maximum serum free
testosterone concentration occurred betweer 8 and 10 a.m., and the minimum
about 8 to
16 hours later. This data is consistent with the mild diurnal variation of
serum
testosterone.
FIG. 2(a) shows the 24-hour phannacokinetic profiles for the three treatment
groups on day 1. After application of the testosterone patch, the serum free
testosterone
levels peaked at 12 hours about 4 hours earlier than those achieved by the
AndroGel'
groups The serum free testosterone levels then declined in the testosterone
patch group
whereas in the AndroGel5 groups, the se runt free testosterone levels
continued to rise.
FIGS. 2(b) and 2(c) show the pharm.acokinetic profiles of free testosterone in
the
AndroGel's'-treated groups resembled the unique testosterone profiles on days
30 and 90.
After AndroGel' application, the mean serum free testosterone levels in the
three groups
were within normal range. Similar to the total testosterone results, the free
testosterone
C1 achieved by the 10.0 g/day group was 1 4 fold higher than the 5.0 g/day
group and 1.7
fold higher than the testosterone patch grot.p. Moreover, the accumulation
ratio for the
testosterone patch was significantly less thane that of the 5.0 g/day
AndroGel'' group and
the 10.0 g/day AndroGelr group.
FIG. 2(d) shows the free tcstosterow. concentrations by final treatment groups
on
day 180. In general, the free testosterone concentrations exhibited a similar
pattern as
serum testosterone. The 24-hour pharrnacokinetic parameters were similar to
those on
days 30 and 90 in those subjects who reme,ned in the three original randomized
groups.
Again, in the subjects titrated to receive '.5 g/day of AndroGela', the group
was not
homogenous. The free testosterone Cava in t:te patients with doses adjusted
upwards from
5.0 to 7.5 g/day remained 29% lower than those of subjects remaining in the
5.0 g/day
~1
CA 02498267 2001-08-29
9
group. The free testosterone C,,,a in the patients whose doses were decreased
from 10.0 to
7.5 g/day was 11 % higher than those in remaining in the 10.0 g/day group.
FIGS. 2(c)-(g) show the free testosterone concentrations in the three groups
of
subjects throughout the 180-day treatment period. Again, the free testosterone
levels
followed that of testosterone. The mean free testosterone levels in all three
groups were
within the normal range with the 10.0 rr/day group maintaining higher free
testosterone
levels than both the 5.0 g/day and the testosicrone patch groups.
Table 7: Free Testosterone Pharmacokinetic Parameters
by Final Treatment (Meant SD)
Doses Received Dunn` initial ->Extended Treatment Phases
5.0 C/day 5.0 -> 7.5 %/daw 10.0 -> 7S g/dav 10/0 g/day T-patch
T el T el T el T el
Day0 N-53 N-2(= N-20 N-58 N-76
Cavg (ng/dL) 4.52:k 3.35 4.27 t 3.45 4.64 t 3.10 4.20 3.33 4.82 t 3.64
Cmax (ng/dL) 5.98 14.25 6.06 t 5.05 6.91 4.66 5.84 4.36 6.5
Tmax= (hr) 4.0 (0.0-24.5) 2.0 (0.0-24.0) 13.5 (0.0-24.2) 2.1 (0.0-24.1) 3.8
(0.0-24.0)
Cmin(ng/dL) 3.23 2.74 3.10 2.02 3.14 2.14 3.121 2.68 3.56 2.88
Tmin' (hr) 8.0 (0.0-24.2) 9.9 (0.0-1 o.0) 4.0 (0.0-23.3) 9.0(0.0-24.0) 7.9
(0.0-24.0)
Fluc Index (ratio) 0.604 0.342 0.674 0 512 0.756 t 0.597 0.634 0.420
0.614 0.362
DayI N-53 N-2(} N-19 N-57 N-74
Cavg (ng/dL) 7.50 4.83 6.80 4 82 9.94 t 5.04 8.93 t 6.09 9.04 t 4.81
Cmax (ng/dL) 10.86 7.45 10.10 79 15.36 7.31 13.20 8.61 12.02 6.14
Tmax0 (hr) 16.0 (0.0-23.3) 13.9 (0.0-.:'4.3') 15.7 (2.0-24.0) 23.5 11.6-24.31
12.0 (1.8-24.0)
Cmin (ng/dL) 4.30 3.33 3.69.t 3.24 3.88 t 2.73 4.40 3.94 4.67 t 3.52
Tmin' (hr) 0.0 (0.0-24,1) 1.8 (0.0-24.0) 0.0 (0.0-24.2) 0.0 (0.0-23.9) 0.0
(0.0-24.0)
Day30 N+47 N-14) N-19 N-55 N-70
Cavg(ng/dL) 11.1216.22 7.81 3"M 16.18 8.18 13.37 17.13 8.1214.15
Cmax (ng/dL) 16.93 10.47 11.62 t C.34 25.141 10.80 19.36 9.75 11.48 5.78
Tmax= (hr) 8.0 (0.0-27.8) 8.0 (0.0-26.3) 8.0 (0.0-24.3) 8.0 (0.0-24.3) 8.0
(0.0-24.0)
Cmin IngidL) 6.99 13.92 4.78 3 10 9.99 7.19 8.25 5.22 4.31 t 3.20
Tmin= (hr) 4.0 (0.0-24.1) 3.5 (0Ø24.1) 1 1.4 (0Ø24.1) 7.8 (0.0-25.8) 2.0
(0.0-24.8)
Fluc index (ratio) 0.853 10.331 0.872 0 510 1.051 0.449 0.861 0.412
0.929 0.311
Accum Ratio (ratio) 1.635 t 0.820 1.479 0 925 2.065 1.523 1.953 1.626
0.980 0.387
Day90 N45 N-2( N-18 N-55 N-64
Cavg (ng/dL) 12.12 17.78 8.06 t 3 78 17.65 8.62 13.11 5.97 8.50 t 5.04
Cmax (ng/dL) 18.75 12.90 10.76 4.48 25.29 12.42 18.61 18.20 12.04 6.81
Tmax= (hr) 4.0 (0Ø24.0) 9.7 (0.0-24.0) 8.0 (0.0-24.0) 8.0 (0.0-25.2) 11.6
(0.0-25.0)
Cmin (ng/dL) 7.65 t 4.74 4.75 2 86 10.56 6.07 8.40 4.57 4.38 3.70
TminO (hr) 8.0 (0,0-24.0) 1.9 (0.0-24.0) 5.9 (0.0-24.1) 4.0 (0.0-24.8) 2.0
(0.0-24.1)
Fluc Index (ratio) 0.913 * 0.492 0.815 * 0 292 0.970:t 0.401 0.812 0.335
0.968 t 0.402
AcCum Ratio (ratio) 1.755 t 0.993 1.916 1 816 1.943;t 0.742 2.075 2 1.866
1.054 0.498
CA 02498267 2001-08-29
mr
Sit
Doses Received During Initial ->Extended Treatment Phases
5.0 glday 5.0 -> 7.5 g/day 10.0 -> 7.5 glday 10/0 g/day r-paaA
T- el T- gel T el T el
Dav_ 180 N-44 N-18 N-19 N-48 N-41
Cavg(ng/dL) 11.01 2524 7.80t4.62 14.14 7.73 12.77 7.25 4.90
Cmax (ng/dL) 16.21 :t 7.32 11.36 3 6.3-6 22.56:t 12.62 18.58 t 9.31 10.17
5.90
Tmax= (hr) 7.9 (0.0-24.0) 2.0 (0.0-23.1)) 7.8 (0.0-24.0) 8.0 (0Ø24.0) 11.1
(0Ø24.0)
Cmin (ng/dL) 7.18 13.96 5.32:t 4.06 9.54 16.45 8.23 4.01 3.90 4.20
Tmin= (hr) 9.9 (0.0-24.2) 7.9 (0.0-24.0) 8.0 (0.0-23.2) 11.8 (0Ø27.4) 2.5
(0.0-25.7)
Flue Index (ratio) 0,897 3 0.502 0.838 10.378 0.950 0.501 0.81 S 0.397
0.967 0.370
Accum Ratio (ratio) 1.712:t 1.071 NA NA 2.134 t 1,989 1.001 t 0.580
`Median (Range)
(:. Serum DHT Concentrations
Serum DHT was measured by RIA after potassium permanganate treatment of the
sample followed by extraction. The methods and reagents of the DHT assay were
provided by DSL (Webster, TX). The crass eactivities of the antiserum used in
the RIA
for DHT were 6.5% for 3-(I-androstanediol, 1.2% for 3-a-androstanediol, 0.4%
for 3-a-
androstanediol glucuronide, and 0.4% for testosterone (after potassium
permanganate
treatment and extraction), and less than ().01 % for other steroids tested.
This low cross-
reactivity against testosterone was further col=firmed by spiking steroid free
serum with 35
nmol/L (1,000 pg/dL) of testosterone and tak..ng the samples through the DHT
assay. The
results even on spiking with over 35 nmol/L )f testosterone was measured as
less than 0.1
nmol/L of DHT. The LLQ of serum DH7' in the assay was 0.43 nmol/L. The mean
accuracy (recovery) of the DHT assay determined by spiking steroid free serum
with
varying amounts of DHT from 0.43 nmol!L o 9 nmoi/L was 101 % and ranged from
83 to
114%. The intra-assay and inter-assay c oefticients of variation for the DHT
assay were
7.8 and 16.6%, respectively, for the norma adult male range. The normal adult
male
range of DHT was 30.7-193.2 ng/dL (1.06 t4:i 6.66 nmol/L ) as determined by
the UCLA-
Harbor Medical Center.
As shown in Table 8, the pretreatment mean serum DHT concentrations were
between 36 and 42 ng/dL, which were near the lower limit of the normal range
in all three
CA 02498267 2001-08-29
M _
:31
initial treatment groups. None of the patients had DHT concentrations above
the upper
limit of the normal range on the pretreat;-nenl day, although almost half (103
patients) had
concentrations less than the lower limit.
FIG. 3 shows that after treatment, the differences between the mean DHT
concentrations associated with the different treatment groups were
statistically significant,
with patients receiving AndroGelo having a higher mean DHT concentration than
the
patients using the patch and showing louse-dependence in the mean serum DHT
concentrations. Specifically, after testosterone patch application mean serum
DHT levels
rose to about 1.3 fold above the baseline. In contrast, serum DHT increased to
3.6 and 4.8
fold above baseline after application of 5.0 g/day and 10.0 g/day of
AndroGel'd`,
respectively.
Table S: DHT Concentrations (ng/dL)
on Each of the Observation Days
By Initial Treatment (Mean SD)
Dav 0 Dav 30 DDav 90 Dav 120 Dow 130 Div 190
5.0,/dav N-73 N-69 N70 N-67 N-65 N-63 N-65
T -gel .16.0 19.9 117.6 74.9 122.4 994 1 130.1 99.2 121.8 89.2 141.7 110.3
143.7
I0.0 */day N-78 N-78 N-74 N-75 N-61 N-67 N-71
T d 42.0 29.4 200.4 127.8 222.0 126.6 207.7 111.0 187.3 97.3 199.1
102.4 206.1 1 105.9
N-76 N-73 N-68 N-66 N-49 N-46 N-49
T-Patch 37.4 2 21 4 50,3134-6 49.3 272 43.6 126.9 53.0 52.8 54.0 42.5 52.1
34.3
Acrocs RX 0.6041 0.0001 0.0001 0.0001 00001 0.0001 0.0001
The increase in DHT concentrations are likely attributed to the concentration
and
location of 5a-rcductase in the skin- For rxarrlple; the large amounts of 5a-
reductase in
the scrotal skin presumably causes an increase in DHT concentrations in the
TESTODERM`' patch. In contrast, the ANDRODERM" and TESTODERM TTS"'
patches create little change in DTH levels Because the surface area of the
patch is small
and little 5a-reductase is located in none + otal skin. AndroGelo presumably
causes an
increase in DHT levels because the gel is applied to a relatively large skin
area and thus
exposes testosterone to greater amounts of the enzyme.
CA 02498267 2001-08-29
32
To date, elevated DHT levels have not been reported to have any adverse
clinical
effects. Moreover, there is evidence w su};gest that increased DHT levels may
inhibit
prostate cancer.
d. DHT/T Ratio
The UCLA-Harbor Medical Center reports a DHT/T ratio of 0.052-0.328 for
normal adult men. In this example, the mean ratios for all three treatments
were within the
normal range on day 0. As shown in FIG, 4 and Table 9, there were treatment
and
concentration-dependent increases observed over the 180-day period.
Specifically, the
AndroGcl'e treatment groups showed the largest increase in DHT/T ratio.
However, the
mean ratios for all of the treatment groups remained within the normal range
on all
observation days.
Table 9: DHT/T Ratio
on Each of the Observation Days
By Initial Treatment (Mean SD)
Day 0 1 Dow 30 Dav f0 Dav 90 Day 120 Dow 150 Dav 180
5.0g/day N-73 N-68 N-7G N-67 N-65 N-62 N-64
T-0- 0.199 0 23010.104 0.25610 ! 32 0148 0266 0.319 0.290 0.345 0.273 0.160
10.0//dav N-78 N-77 N-74 N-74 N-68 N-67 N-71
T d 0.206 0.163 C.266 0.124 0.313 0.160 0.30010.131 0.309 0.32510.142 0.291
0.124
T-Patch N76 N73 N64 N-65 N-49 N-46 N-46
0.20410.135 0.192 0.182 0.175 0102 0.175 0.092 0.18630.134 0.22330.147
0.21210.160
wcrou RX 0.7922 0.0001 0,0001 Q.0001 0.0001 0.0001 0.0002
e. Total Androgen (DHT + T)
The UCLA-Harbor Medical Center ! gas determined that the normal total androgen
concentration is 372 to 1,350 ng/dL. As shown in FIG. 5 and Table 10, the mean
pre-dose
total androgen concentrations for all three Treatments were below the lower
limit of the
normal range on pretreatment day 0. The total androgen concentrations for both
AndroGel'e groups were within the normal range on all treatment observation
days. In
contrast, the mean concentrations for patienrs receiving the testosterone
patch was barely
CA 02498267 2001-08-29
3
within the normal range on day 60 and 120, but were below the lower normal
limit on
days 30, 90, 150, and 180.
Table 10: Total Androgen (DHT+T) (ng/dL)
on Each of the Observation Days
By Initial Treatment (Mean t SD)
Dav 0 Dav 30 Dav 60 Div 90 Div 120 Dav 150 Div 1110
S.0Wdav N-73 N-68 N'70 N-67 N-65 N-62 N-64
T d 2811 150 6591398 617 2 429 690 2 431 3741331 631 384 6941412
10.9Wday N-78 N-77 N-74 N-74 N-68. N-67 N-71
T d 3071 180 974 t 532 1052,t W. 921 t 420 827 t 361 305:t 383 944 t 432
T=Patch N-76 N-73 N-68.. N-65 N-49 N-46 N-46
1 2821 159 369 t 206 392 229 ' 330 t 173 379:1:250 364 220 355 3202
Across RX 0.7395 0.0001 0.0001 0.0001 0.0001 00001 0.0001
f. E2 Concentrations
Serum E2 levels were measured by a direct assay without extraction with
reagents
from ICN (Costa Mesa, CA). The infra.-assay and inter-assay coefficients of
variation of
E2 were 6.5 and 7.1% respectively. ncc UCLA-Harbor Medical Center reported an
average E2 concentration ranging from 7.1 >a 46.1 pg/mL (63 to 169 pmol/L) for
normal
adult malt range. The LLQ of the E2 wa.s 18 pmolIL. The cross reactivities of
the E2
antibody were 6.9% for estrone, 0.4% for equilenin, and less than 0.01% for
all other
steroids tested. The accuracy of the E2 assay was assessed by spiking steroid
free serum
with increasing amount of E2 (18 to 275 prr.oUL). The mean recovery of E2
compared to
the amount added was 99.1% and ranged from 95 to 101%.
FIG. 6 depicts the E2 concentrations throughout the 180-day study. The
pretreatment mean E2 concentrations fur ail three treatment groups were 23-24
pg/mL.
During the study, the E2 levels increased by an average 9.2% in the
testosterone patch
during the treatment period, 30.9% in the '.0 g/day AndroGelei group, and
45.5% in the
10.0 g/day AndroGelei group. All of the mean concentrations fell within the
normal range.
CA 02498267 2001-08-29
w
34
Table 11; Estradlol Concentration (pglmL)
on Each of the Observation Days
By Initial Treatment (Mean SD)
Dav O Div 30 Dav 60 Div 90 Div 120 Dav ISO DOW 180
S.6 'day T=;ad N-73 4 - 69 N 68 N-67 N - 64 N -65 N - 65
23.0 9.2 29.2 11.0 28.1 1411_ 31.4 11.9 28.2 t9.9 30.8 12.5 32.3 13.8
0 8/di 1-P1 N- 78 N- 78 N -_i4 N-75 N - 71 H-66 N - 71
24.5 9.5 33.7 11.5 36.513.:1 37.8 13.3 34.6 10.4 35.01 36.3
T-Patch N-76 N-72 N-68 N-66 N-SO N-49 N-49
23.8 8.2 25.8 9.8 24.8 x 8.0 25.7 t 9.8 25.719.4 27.0 9.2 26.9 9.3
Across RX 0.6259 0.0001 0.(101 0.0001 0.0001 0.0009 0.0006
5 E2 is believed to be important for the --naintenance of normal bone. In
addition, E2
has a positive effect on serum lipid profiles.
g. Serum SHBG Concentrations
Serum SHBG levels were measured with a luoroimmunornetric assay ("FIA")
obtained from Delfia (Wallac, Gaithersberg, MD). The infra- and interassay
coefficients
10 were 5% and 12% respectively. The LLQ as 0.5 nmol/L. The UCLA-Harbor
Medical
Center determined that the adult normal male range for the SHBG assay is 0.8
to 46.6
nmol/L.
As shown in FIG. 7 and Table 12, the serum SHBG levels were similar and within
the normal adult male range in the three reatment groups at baseline. None of
the
treatment groups showed major changes from these the baseline on any of the
treatment
visit days. After testosterone replacement serum SHBG levels showed a small
decrease in
all three groups. The most marked change occurred in the 10.0 g/day AndroGele
group.
Table 12: SHBG Concentration (nmol/L)
on Each of the Observation Days
By Initial Treatment (Mean SD)
Div 0 Div 30 Day 60 Dav 90 Day 120 Dav 150 Dav 1 O
S.Of/day N-73 N-G9 N69 N-67 N=66 N-6S N-65
T d 26.2 24.9 14.0 25.9 14.4 25.5 14.7 25.2 14.1 24.9 12.9 24.2 13.6
10.08/day N-78 N-78 N-75T N-75 N-72 N-68 N=71
T-Zd 26.6 3 17.8 24.9 14.5 25.2 15.5 23.6 14.7 25.5 1 165 _23_8t12.3
24.01 14.5
T-Patch N-76 N-72 N6i y N-66 N-SO N-49 N-49
30.2 22.6 28.4 21.3 28.23'_'3.8 a 28.0 23.6 26.7 16.0 26.7 16.4 25.8 15.1
Across RX 0.3565 0.3434 05931 { 0.3459 0.8578 0.5280 0.7668
CA 02498267 2001-08-29
h. Gonadotroplos
Serum FSH and LH were measured by highly sensitive and specific solid-phase
FIA assays with reagents provided by Delfi4 (Wallac, Gaithersburg, MD). The
intra-assay
coefficient of variations for LH and FSH f aroim tunometric assays were 4.3
and 5.2%,
5' respectively; and the interassay variation!, for LH and FSH were 11.0% and
12.0%,
respectively. For both LH and FSH assays, the LLQ was determined to be 0.2
IUIL. All
samples obtained from the same subject were measured in the same assay. The
UCLA-
Harbor Medical Center reports that the adult normal male range for LH is 1.0-
8.1 UIL and
for FSH is 1.0-6.4UIL.
10 (1) FSH
Table 13(a)-(d) shows the concentrations of FSH throughout the 180-day
treatment
depending on the cause of hypogonadism: {1) primary, (2) secondary, (3) age-
associated,
or (4) unknown.
Patients with primary hypogonadism show an intact feedback mechanism in that
15 the low serum testosterone concentrations are associated with high FSH and
LH
concentrations. However, because of testicular or other failures, the high LH
concentrations are not effective at stimulating testosterone production.
Secondary hypogonadism involves an idiopathic gonadotropin or LH-releasing
hormone deficiency. Because patients with secondary hypogonadism do not
demonstrate
an intact feedback pathway, the lower testosterone concentrations are not
associated with
increased LH or FSH levels. Thus, these me ri have low testosterone serum
levels but have
gonadotropins in the normal to low range..
Hypogonadism may be age-related. ; 4cn experience a slow but continuous
decline
in average serum testosterone after approximately age 20 to 30 years. These
untreated
CA 02498267 2001-08-29
S
a6
testosterone deficiencies in older men may Icad to a variety of physiological
changes. The
net result is geriatric hypogonadism, or what is commonly referred to as "male
menopause."
As discussed above, patients with pi mary hypogonadism have an intact feedback
inhibition pathway, but the testes do not sect to testosterone. As a result,
increasing serum
testosterone levels should lead to a decrease in the serum FSH concentrations.
In this
example, a total of 94 patients were identified as having primary
hypogonadism. For these
patients, the mean FSH concentrations in the three treatment groups on day 0
were 21-26
mlU/mL, above the upper limit of the nor; ial range. As shown in FIG. 8(a) and
Table
13(a), the mean FSH concentrations cecrtased during treatment in all three
treatment
regimens. However, only the 10.0 g,;day AndroGcl* group reduced the mean
concentrations to within the normal range during the first 90 days of
treatment. Treatment
with the 10.0 g/day AndroGel4' group required approximately 120 days to reach
steady
state. The mean FSH concentration in patients applying 5.0 g/day of AndroGela
showed
an initial decline that was completed by daa 30 and another declining phase at
day 120 and
continuing until the end of treatment. Mean FSH concentrations in the patients
receiving
the testosterone patch appeared to reached toady state after 30 days but were
significantly
higher than the normal range.
Table 13(a): FSH Concentrations (mIU/mL) on Each of
the Observation Days b) Initial Treatment Group for
Patients Having Primary Hypogonadism (Mean SD)
N 5 g/day ''1 10 day N T- atcb
Day 0 26 21.6 21.0 3 20.9 15.9 34 25.5 25.5
Day 30 23 10.6 15.0 "4 10.6 14.1 31 21.4 24.6
Day 60 24 10.8+16.9 2 7.2 4:12.6 31 21.7 f 23.4
Da 90 24 10.4 19.7 1 5.7 10.1 30 19.5 20.0
Day 120 24 8.1 15.2 m'8 4.6 10.2 21 25.3 28.4
Dav 150 22 6.7 15.0 9 5.3::L 11.0 21 18.6 f 24.0
Dav 180 24 6.2 11.3 8 5.3f 11.2 22 24.5 27.4
CA 02498267 2001-08-29
37
Patients with secondary hypogonadism have a deficient testosterone negative
feedback system. As shown in FIG. 8(b), of 44 patients identified as having
secondary
hypogonadism, the mean FSH concen:rat:uns decreased during treatment, although
the
decrease over time was not statistically significant for the testosterone
patch. The patients
in the 5.0 g/day AndroGel' group showed a decrease in the mean FSH
concentration by
about 35% by day 30, with no further decrease evident by day 60. Beyond day
90, the
mean FSH concentration in the patients appeared to slowly return toward the
pretreatment
value. By day 30, all of the 10.0 g/day AndroGel6 group had FSH concentrations
less
than the lower limit.
Table 13(b): FSH Concentrations (m1U/mL) on Each of
the Observation Days by Initial Treatment Group for
Patients Having Seconda} Hypogonadism (Meant SD)
N S g/day N 10 day N T- patch
Day 0 17 4.216.6 2 2.1 1.9 15 5.1 9.0
Day 30 16 2.8 5.9 ;2 0.2 0.1 14 4.2 8.0
Day 60 17 2.8 6.1 '2 0.2 0.1 13 4.2 7.4
Day 90 15 2.915.6 2 0.2 0.1 14 4.9 9.0
Day 120 14 3.0 6.1 2 0.1+0.1 12 6.1110.7
Dav 150 14 3.5 7.5 2 0.2 0.2 11 4.6 6.5
Dav 180 14 3.7 8.6 '.2 0.1 0.1 12 4.9 7.4
Twenty-five patients were dia3no:sed with age-associated hypogonadism. As
shown in FIG. 8(c), the 5.0 g/day AndroGela group had a mean pretreatment FSH
concentration above the normal range. The mean concentration for this group
was within
the normal range by day 30 and had decreased more than 50% on days 90 and 180.
The
decrease in FSH mean concentration in the 10.0 g/day AndroGel1e group showed a
more
rapid response. The concentrations in all six patients decreased to below the
lower normal
limit by day 30 and remained there for the duration of the study. The six
patients who
CA 02498267 2001-08-29
3$
received the testosterone patch exhibited no consistent pattern in the mean
FSH level;
however, there was an overall trend towards lower FHS levels with continued
treatment.
Table 13(c): FSH Concentrations (m1U/mL) on Each of
the Observation Days by Initial Treatment Group for
Patients Having Age-Related Hypogonadism (Mean t
SD)
N 5 /da N 10 day N T- patch
[Day
Da 0 13 8.0 9.1 6 5.2 1.9 6 4.7 1.7
Da 30 12 4.6 7.4 6 0.4 0.3 6 3.7 2.0
60 12 3.9 6.6 6 -0.3 0.4 4.3 3.3
Da 90 11 3.8 7.1 6 0.4 0.7 4 3.5 1.9
Day 120 11 4.2 8.3 6 0.4 0.7 4 4.2 3.3
Da 150 11 4.3 8.1~ S 0.2 0.2 4 3.4 2.7
Dav 180 11 4.0 7.1 6 0.2 0.2 4 2.7 2.1
Sixty-four patients in the stud) sL: jTered from unclassified hypogonadism. As
shown in FIG. 8(d), the patients showed a marked and comparatively rapid FSH
concentration decrease in all three groups, with the greatest decrease being
in the 10.0
g/day AndroGelz' group. The 10.0 g. da,; AndroGelo group produced nearly a 90%
decrease in the mean FSH concentration b,a day 30 and maintained the effect to
day 180.
The 5.0 g/day AndroGels' group produced ~ibout a 75% drop in mean FSH
concentration
by day 30 and stayed at that level for the remainder of treatment. The 21
patients
receiving the testosterone patch had a 500/, decrease in the mean FSH
concentration by
day 30, a trend that continued to day 90 wh:n the concentration was about one-
third of its
pretreatment value.
Table 13(d): Concentrations (mlU/mL) for FSH on Each
of the Observation Days b,% Initial Treatment Group for
Patients Having Unknown-Related Hypogonadism
(Mesa SD)
N 5 2/day 10 day N T- arch
Da 0 17 4.0 1.8 _ !6 4.1 1.6 21 3.7 1.4
Da 30 17 1.1 1.0 -16 0.5:t 0.5 21 1.8 0.8
Day 60 16 1.1 1.1 16 0.3 0.3 18 1.6 1.0
Dav 90 17 1.1 1.1:_ 5 0.4 0.7 18 1.2 0.9
CA 02498267 2001-08-29
low
:9
N 5 lda N 10 day N T- Patch
Day 120 16 1.2 1.4 26 0.4 0.6 12 1.4 1.0
Day 150 17 1.4 1.4 23 0.3 0.5 13 1.4 1.2
Day 180 16 1.0 0.9 -.4 0.4 0.4 11 1.3 0.9
This data shows that feedback tnhiition of FSH secretion functioned to some
extent in all four subpopulations. The primary hypogonadal population showed a
dose-
dependency in both the extent and rate of the., decline in FSH levels. The
sensitivity of the
feedback process appeared to be reduced it, the secondary and age-associated
groups in
that only 'the highest testosterone doses had a significant and prolonged
impact on FSH
secretion. In contrast, the feedback inhibition pathway in the patients in the
unclassified
group was quite responsive at even the lowest dose of exogenous testosterone.
(2) LB
The response of LH to testosterone u as also examined separately for the same
four
subpopulations. Table 14(a)-(d) shows the LH concentrations throughout the
treatment
period.
As shown in FIG. 9(a) and Table 14(a), the LH concentrations prior to
treatment
were about 175% of the upper limit of the i ormal range in primary hypogonadal
patients.
The mean LH concentrations decreased Jun ig treatment in all groups. However,
only the
AndroGela groups decreased the mean L.H c ncentrations enough to fall within
the normal
range. As with FSH, the primary hypogon;idal men receiving AndroGelo showed
dose-
dependence in both the rate and extent o thy: LH response.
Table 14(a): Concentrations for LH (mlU/mL) on Each
of the Observation Days for Patients Having Primary
Hypogonadism (Summary of Meant SD)
N 5 davN 10 day N T- patch
Da 0 26 12.2+12.1 3-1 13.9:k 14.9 33 13.3 14.3
Day 30 23 5.6 7.6 1 34 5.9 8.1 31 10.9 12.9
Day 60 24 6.8 9.0 13 -4 4.8 10.0 31 10.8* 11.8
Day 90 24 5.9 9.5 t 31 4.2 11.0 30 10.0 11.7
CA 02498267 2001-08-29
N 5 /day N 10 ldav N T- Patch
Da 120 24 6.4 11.9 2R 3.8 10.4 21 11.5 11.5
Da 150 22 4.4 8.5 29 4.0 11.3 21 7.4 6.0
Day 180 24 4.816.8 2 4.0 11.9 22 11.2 10.5
The: secondary hypogonadal men A,,-re less sensitive to exogenous
testosterone.
For the 44 patients identified as having secondary hypogonadism, the
pretreatment mean
concentrations were all within the lower limit normal range. The mean LH
concentrations
5 decreased during treatment with all three regimens as shown in FIG. 9(b) and
Table 14(b).
Table 14(b): Concentrations for LH (mlU/mL) on Each
of the Observation Days for Patients Having Secondary
Hypogonadism (Summary of Mean SD)
N 5 day N 10 day N T- patch
Da 0 17 1.8 2.6 2 1.4 1.8 15 1.6 3.1
Dav30 16 1.1 2.2 ,2 0.2 0.2 14 0.4 0.4
Day 60 17 1.4 3.8 2 0.2 0.2 13 0.6 0.5
Dav 90 15 1.2 2.4 .2 0.2 0.2 14 0.7 1.0
Day 120 14 1.6 4.0 2 0.2 0.2 12 0.8 0.8
Day 150 14 1.613.5 2 0.2 0.2 11 1.2 2.0
Dav 180 14 1.5 3.7 2 0.2 0.2 12 1.4 2.1
10 None of the 25 patients suf eri;ig from age-associated hypogonadism had
pretreatment LH concentrations outside of the normal range as shown in FIG.
9(c) and
Table 14(c). The overall time and treatment effects were significant for the
AndroGelo
patients but not those patients using the testosterone patch.
Table 14(c): Concentrations for LH (mlU/mL) on Each
15 of the Observation Days for Patients Having Age-Related
Hypogonadism "Summary of Meant SD)
N 5 da , N 10 day N T- patch
Da 0 13 3.2 1.1 6 2.4 1.8 6 2.9 0.6
Day 30 12 1.1 1.0 6 0.1 0.0 6 1.8 1.1
Day 60 12 0.8 0.7 6 0.2 0.3 5 3.4 2.8
Dav 90 11 0.9 1.' 6 0.1 0.0 4 2.3 1.4
Da 120 11 1.0 t 1.= 6 0.1+0.0 4 2.2::k 1.4
Dav 150 11 1.3 1. 5 0.1 0.0 4 1.9 1.2
Day 180 11 1.812.1 6 0.1 0.0 4 1.4 1.0
CA 02498267 2001-08-29
41
Of the 64 patients suffering from an unclassified hypogonadism, none of the
patients had a pretreatment LH concentration above the upper limit. Fifteen
percent,
however, had pretreatment concentrations below the normal limit. The
unclassified
patients showed comparatively rapid LH concentration decreases in all
treatment groups as
shown in FIG. 9(d) and Table 14(d).
Table 14(d): Coin centratioas for LH (mIUfmL) on Each
of the Observation Days for Patients Having Unknown-
Related Hypogonadism Summary of Meant SD)
N 5 /da N 10 day N T- Patch
Day 0 17 1.81 1.2 6 2.5 1 1.5 21 2.5 1.5
Da 30 17 0.3 0.3 -26 0.3 0.3 21 1.3 1.3
Day 60 17 0.4 0.56 0.3 0.3 18 1.211.4
Da 90 17 0.5 0.5 :'6 0.3 0.4 18 1.0 1.4
Day 120 17 0.4 0.4 6 0.410.5 12 1.2 1.1
Day 150 17 0.8 1.1 :3 0.3 0.4 13 1.1 1.1
Day 180 15 0.3+0.4 5 0.4 0.4 1 11 1.5 1.3
(3) Surnnmury: LH and FSH
Patients receiving AndroGel* or the testosterone patch achieve "hormonal
steady
state" only after long-term treatment. Specifically, data involving FSH and LH
show that
these hormones do not achieve steady-state until many weeks after treatment.
Because
testosterone concentrations are negatively inhibited by FSH and LG,
testosterone levels do
not achieve true steady state until these other hormones also achieve steady
state.
However, because these hormones regulate Manly endogenous testosterone (which
is small
to begin with in hypogonadal men) in an intact feedback mechanism (which may
not be
present depending on the cause of hypogonadism), the level of FSH and/or LH
may have
little effect on the actual testosterone levels achieved. The net result is
that the patients do
not achieve a "hormonal steady state" for testosterone even though the C.,
C.,,;.,, and C..
for testosterone remains relative constant after a few days of treatment.
CA 02498267 2001-08-29
42
2. Libido and Sexual Performance
Libido and sexual function were assessed by questionnaires the patients
answered
daily for seven consecutive days before clinic visits on day 0 and on days 30,
60, 90, 120,
150, and 180 days during gel and patch application. The subjects recorded
whether they
had sexual day dreams, anticipation of s!x, flirting, sexual interaction
(e.g., sexual
motivation parameters) and orgasm, erection, masturbation, ejaculation,
intercourse (e.g.,
sexual performance parameters) on each of he seven days. The value was
recorded as 0
(none) or 1 (any) for analyses and the number of days the subjects noted a
parameter was
summed for the seven-day period. The aver age of the four sexual motivation
parameters
was taken as the sexual motivation mean score and that of the five sexual
performance
parameters as the sexual performance mean score (0 to 7).
The subjects also assessed their level of sexual desire, sexual enjoyment, and
satisfaction of erection using a seven-point I..tkcrt-type scale (0 to 7) and
the percent of full
erection from 0 to 100%. The subjects rated their mood using a 0 to 7 score.
Weekly
average scores were calculated. The details of this questionnaire had been
described
previously and are fully incorporated by reference. See Wang et al.,
Testosterone
Replacement Therapy Improves Mood in Hypogonadal Men - A Clinical Research
Center
Study, 81 J. CLINICAL ENDOCRINOLOGY & METABOLISM 3578-3583 (1996).
a. Libido
As shown in FIG. 10(a), at basehae, sexual motivation was the same in all
treatment groups. After transdermal tcsto.terone treatment, overall sexual
motivation
showed significant improvement. The change in the summary score from baseline,
however, was not different among the three ti eatment groups.
CA 02498267 2001-08-29
43
Libido was also assessed from responses on a linear scale of: (1) overall
sexual
desire, (2) enjoyment of sexual activity without a partner, and (3) enjoyment
of sexual
activity with a partner. As shown in FIG. 10(b) and Table 15, as a group,
overall sexual
desire increased after transdermal testosterone treatment without inter-group
difference.
Sexual enjoyment with and without a partner (FIG. 10(c) and Tables 14 and 15)
also
increased as a group.
Table 1S: Overall Sexual Desire
Changes From Day 0 to Day 180
by Initial Treatment Group (Meant SD)
Initial Treatment N Day 6 N 11a} 180 N Change From Within-Group
Group Dav 0 to Day 180 value
5.0 uJday T-eel 69 2.1 1.6 63 3. = 1.6 60 1.4:t 1.9 0.0001
10.0 9/a T- el 77 20 1.4 68 3.;) 1.6 67 1.5:t 1.9 0.0001
T-Patch 72 2.0 1.6 47 3.: 3 1.9 45 1.6 2.1 0.0001
Actoss-Groups 0.8955 2.247 0.8579
p-value
Table 16: Level of Sexual Enjoyment Without a Partner
Changes From Day 0 to Day 180
by Initial Treatment Group (Meant SD)
Initial Treatment N Day 0 N `lay 180 N Change From Within-Group
Group Day 0 to Day 180 value
5.0g/davTeel 60 1.5 1.9 51 9 1.9 44 0.8 1.4 0.0051
10.0 erdav T-ee1 63 1.2 1.4 53 2 t 1.9 48 1.1 t 1.6 0.0001
T-Patch 66 1.4 1.8 44 2 2.3 40 1.0 1.9 0.0026
Across-Groups 0.6506 1.7461 0.6126
value
Table-17: Level of Sexual Enjoyment With a Partner
Change from Day 0 to Day 180
by Initial Treatment Group (Mean SD)
Initial Treatment N Day 0 N ino 180 N Change From Within-Group
Group Day 0 to Day 180 value
5.0 day T- el 64 2.1 12.1 55 6 2.2 48 0.4 2.2 0.0148
10.0 g/dav 1- el 66 1.81 1.7 58 '3-012 2 52 1.012.3 0.0053
T-Patch 61 1.5 1 1.7 40 2 2.4 35 0.7 2.3 0.1170
Across-Groups 0.2914 1.1738 0.3911
value
(IV
N-)
CA 02498267 2001-08-29
44
b. Sexual Performance
FIG. 11(a) shows that while all treatment groups had the same baseline sexual
performance rating, the rating improved with transdermal testosterone
treatment in all
groups. In addition, as a group, the suajects' self-assessment of satisfaction
of erection
(FIG. 11(b) and Table 18) and percent full erection (FIG. 11(c) and Table 19)
were also
increased with testosterone replacement without significant differences
between groups.
The improvement in sexual function was ncà related to the dose or the delivery
method of
testosterone. Nor was the improvement rcluted to the serum testosterone levels
achieved
by the various testosterone preparations Tie data suggest that once a
threshold (serum
testosterone level probably at the low normal range) is achieved,
normalization of sexual
function occurs. Increasing serum testosterone levels higher to the upper
normal range
does not further improve sexual motivation or performance.
Table 18: Satisfaction with Duration of Erection
Change from lay 0 to Day 180
by Initial Treatment Group (Mean SD)
Initial Treatment N Day 0 N t.ay 180 N Change From Within-Group
-----.group Dav = to Div 185 value
5.0 da T-aei 55 2.5 2.1 57 4 3:t 1.8 44 1.9:t 2.0 0.0001
10/0 da T-gel 64 2-9:t 1.9 58 5 1 1.7 53 1.5 t 2.0 0.0001
T-Patch a5 3.4 t 2.1 34 5 t 2.0 20 1.3 2.1 0.0524
Across-Groups 0.1117 3.7093 0.5090
value
Table 19: Percentage of Full Erection
Change from Pay 0 to Day 180
by Initial Treatnet t Group (Mean SD)
Initial Treatment N Day 0 N I ay 190 N Change From Within-Groep
Grow Dav = to Dav 196 value
43 18.7 t 22.1 0.0001
5.0 alda T- el 53 53,1 24.1 57 6" ; t 22.5
10.0 04T-eel 62 59.6 t 22.1 59 7: 0 t 20.2 52 10.4 t 23.4 0.0001
T-Patch 47 56.5 t 24.7 33 6( 7 t 26.7 19 12.7 20.3 0.0064
Across-Groups T E 0.3360 .4360 F 0.1947
value
Example 2= Method of Increasing Libido in Eugonadal Men
CA 02498267 2001-08-29
Having aDiiminished Libido
As discussed above, transderma application of testosterone using AndroGelm to
hypogonadal men results in improved libido and sexual performance. Researchers
have
5 found that eugonadal men having a diminished libido have a significant
increase in sexual
interest after receiving testosterone injections. See O'Carrol & Bancroft,
Testosterone
Therapy for Low Sexual Interest and Erecrde Dysfunction in Men: A Controlled
Study,
Brit. J. Psychiatry 145:146-151 (1984). Thos, the present example is directed
to a method
of treating a diminished libido in ei;gonnadal men by transderrnal application
of a
10 hydroalcoholic testosterone gel to such men, In one embodiment, AndroGel
is applied
to the body in accordance with the pprot: col summarized in Example 1. Libido
is
measured as in Example 1. Men receiving AndroGel are expected to show a
increase in
their libido.
Example 3: Method of In reasivig Libido in . gonadal Men
15 Having Normal Libido
As discussed above, transdennw application of testosterone using AndroGels' to
hypogonadal men results in improved libido= and sexual performance. Studies
have shown
that supra-physiological doses of testosterone administered to cugonadal men
having a
20 normal libido resulted in a significant increase in libido. See Anderson et
al., The Effect of
Exogenous Tstoserone on Sexuality and Mood of Normal Men, J. CLINICAL
ENDOCRINOLOGY & METABOLISM 75:1504-1507 (1992); Bagatel et al., Metabolic &
Behavioral Effects of High-Dose, Exogenous Testosterone in Healthy Men, J.
CLINICAL
METABOLISM & ENDOCRINOLOGY 79:561-5t-,7 (1994). Thus, this example is directed
to a
25 method of increasing the libido of normal c gonadal men by application of a
transdermal
hydroalcoholic testosterone gel. In one embodiment, AndroGelt is applied to
the body in
CA 02498267 2001-08-29
= =
46
accordance with the protocol summarized in Example 1. Libido is measured as in
Example 1. Men receiving AndroGel are expected to show a increase in their
libido.
Example 4; Method of Improving Sexual Perf rmance in Eugonadal Men
Having Erectile Dysfunction
In a prophetic example, 10 etugonadal males age 18 and older having erectile
dysfunction will be randomized to receive: (a) 5.0 g/day of AndroGel
(delivering 50
mg/day of testosterone to the skin of which about 10% or 5 mg is absorbed) for
30 days or
(b) 10.0 g/day of AndroGcl (delivering 100 mg/day of testosterone to the skin
of which
about 10% or 10 mg is absorbed) for 3 days ; or (c) nothing. The effectiveness
of
AndroGel in improving sexual performance and treating erecile dysfunction
will be
evaluated using several assessment instruments. The primary measure will be a
sexual
function questionnaire, the International Index of Erectile Function ("IIEF"
). Two of the
questions from the IIEF will serve as primary study endpoints; categorical
responses shall
be elicited to questions about (1) the ability to achieve erections sufficient
for sexual
intercourse and (2) the maintenance of erections after penetration. The
possible
categorical responses to these questions will be (0) no attempted intercourse,
(1) never or
almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost
always or
always. Also collected as part of the LIEF will be information about other
aspects of sexual
function, including information on erectile function, orgasm, desire,
satisfaction with
intercourse, and overall sexual satisfaction. Sexual function data shall also
be recorded by
patients in a daily diary. In addition, patients shall be asked a global
efficacy question and
an optional partner questionnaire was administered. In addition, the
improvement in
erectile dysfunction shall be assessed by an objective measurement of hardness
and
CA 02498267 2001-08-29
47
duration of erections (RigiScanl) with AndroGel treatment compared with
placebo.
Applicant expects that all test parameters will show improvement over the
placebo.
Example 5: Method of Improving Sexual Performance in Eugonadal Men
Having Nord Erections
In a prophetic example, 10 eugonaual males age 18 and older having normal
erections (i.e. not diagnosed with erectile dysfunction) will be randomized to
receive: (a)
5.0 g/day of AndroGel (delivering 50 mg/day of testosterone to the skin of
which about
10% or 5 mg is absorbed) for 30 days or (b) 10.0 g/day of AndroGel
(delivering 100
mg/day of testosterone to the skin of which about 10% or 10 mg is absorbed)
for 30 days ;
or (c) nothing- The effectiveness of AndroGel will be evaluated using several
assessment instrument as discussed in Example 4. Applicant expects that all
test
parameters will show an increase in sexual performance over the placebo.
Accordingly,
Applicant expects that AndroGel can be applied to normal men in order to
increase the
is sexual performance above their normal baseline.
Example 6yNMethod of Treating Men Having Erectile Dysfunction in
Conjunction with other Pharmaceuticals
As discussed above, transdermal application of testosterone using AndroGel`D
to
hypogonadal men results in improved libido and sexual performance. This
example is
directed use of AndroGel in combination with pharmaceuticals useful for
treating erectile
dysfunction. Such pharmaceuticals include any agent that is effective to
inhibit the
activity of a phosphodiesterase. Suitable phosphodiesterase inhibitors
include, but are not
limited to, inhibitors of the type III phosphodiesterase (cAMP-specific-cGMP
inhibitable
form), the type IV phospodiesterase (high affinity-high specificity cAMP form)
and the
type V phosphodiesterase (the cGMP specific form). Additional inhibitors that
may be
CA 02498267 2001-08-29
49
used in conjunction with the present invention are cGMP-specific
phosphodiesterase
inhibitors other than type V inhibitors.
Examples of type III phospodiesterase inhibitors that may be administered
include,
but are not limited to, bypyridines such as m irinone and amirinone.
imidazolones such as
piroximone and enoximone, dihydropyridazinones such as imazodan, 5-methyl-
imazodan,
indolidan and ICI 1118233, quinolinone compounds such as cilostamide,
cilostazol and
vesnarinone, and other molecules such as betnoradan, anergrelide, siguazodan,
trequinsin,
pimobendan, SKF-94120, SKF-95654, lixazinone and isomazole.
Examples of type IV phosphodiesterase inhibitors suitable herein include, but
are
not limited to, rolipram and rolipram derivatives such as R020-1724,
nitraquazone and
nitraquazone derivatives such as CP-77059 and RS-25344-00, xanthine
derivatives such as
denbufylline and ICI63197, and other compounds such as EMD54622, LAS-31025 and
etazolate.
Examples of type V phosphodiesterase inhibitors include, but are not limited
to,
zaprinast, MY5445, dipyridamole, and sildenafil. Other type V
phosphodiesterase
inhibitors are disclosed in PCT Publication Nos. WO 94/28902 and WO 96/16644.
In the
preferred embodiment, an inhibitor of ph sphodiesterase type 5 ("PDE5"), such
as
VIAGRAO (sildenafil citrate USP) is used.
The compounds described in PCTPublication No. WO 94/28902 are
pyrazolopyrimidinones. Examples of the inhibitor compounds include 5-(2-ethoxy-
5-
morpholinoacetylphenyl)-I-methyl-3-n-propel-1,6-dihydro-7H-p yrazolo[4,3-
d]pyrimidin-
7-one, 5-(5-morpholinoacetyl-2-n-propoxyptienyl)-I-methyl-3-n-propyl-l,6-
dihydro-7 -H-
pyrazolo[4,3-d)pyrimidin-7-one, 5-[2-ethox;,>-5-(4-methyl-l-
piperazinylsulfonyl)-
phenyl] 1-methyl-3-n-propyl- 1,6-dihydro-711-pyrazolo[4,3-d]pyrimidin-7-one, 5-
[2-
r
CA 02498267 2001-08-29
w
4 x
ailyloxy-5-(4-methyl-I -piperazinylsulfonyl)-phenyl]-I -methyl-3-n-propyl-l,6-
dihydro-
7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethooxy-5-[4-(2-propyl)-1-
pipcrazinylsulfonyl)-
phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H--pyrazolo[4,3-d]pyrimidin-7-one, 5-
[2-
ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsu lfonyl)phenyl]-1-methyl-3 -n-
propyl-1,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-[4-(2-hydroxyethyl)-1-
piperazinylsulfonyl]-2==n-propoxyphenyl] 1-r-iethy 1-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-d]pyrimidin-7-one, 5[2-ethoxy- -(4-methyl-l-
piperazinylcarbonyl)phenyl]-
1-methyl-3--n-propyl-1,6-dihydro-7H-pyrazo o[4,3-d]pyrimidin-7-one, and 5-[2-
ethoxy-5-
(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-nt-propyl- l ,6-dihyd ro-7H-
pyrazolo[4.3-
d]pyrimidin-7-one.
The phosphodiesterase inhibitors described in PCT Publication No. WO 96/16644
include griseolic acid derivatives, 2-phenylpirinone derivatives,
phenylpyridone
derivatives, fused and condensed pyrimidineu, pyrimidopyrimidine derivatives,
purine
compounds, quinazoline compounds, phenylpyrimidinone derivative,
imidazoquinoxalinone derivatives or aza analogues thereof, phenylpyridone
derivatives,
and others. Specific examples of the phosphodiesterase inhibitors disclosed in
WO
96/16644 include 1,3-dimethyl-5-benzylpyrizolo[4,3-d]pyrimidine-7-one, 2-(2-
propoxyphenyl)-6-purinone, 6-(2-propox yphenyl)-1,2-dihydro-2-oxypyridine-3-
carboxamide, 2-(2-propoxyphenyl)-pyrido [2.3-d]pyrimid-4(3H)-one, 7=methylthio-
4-oxo-
2-(2-propoxyphenyl)-.3,4-dihydro-pyrimido(4,5-d]pyrimidi ne, 6-hydroxy-2-(2-
propoxyphenyl)pyrim idine-4-carboxamide, I -ethyl-3-
methylirnidazo[1,5a]quinoxalin-
4(5H)-one, 4-phenylmethylamino-6-chloro-:-(1-imidazoloyl)quinazoline, 5-ethyl-
8-[3-(N-
cyclohexyl-N-methylc:arbamoyl)-propylox y j -4,5-dihydro-4-oxo-pyrido[3,2-e]-
pyrrolo[ 1,2-
a]pyrazine, 5'-methyl-3'-(phenylmethyl)- spiro[cyclopentane-1,7'(8'H)-(3'H)-
CA 02498267 2001-08-29
V
5(l
imidazo[2,Ib]purin]4'(5'H)-one, 1-[6-chloro-4-(3,4-methylenedioxybenzyl)-
aminoquinazolin-2-yl)piperidine-4-carboxylic acid, (6R, 9S)-2-(4-
trifluoromethyl-
phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydr ocyclopent[4,5]-midazo[2,1-
b]-purin-
4-one, I t-butyl-3-phenylmethyl-6-(4-pyridyl hpyrazolo[3,4-d]-pyrimid-4-one, 1-
cyc lopentyl-3-methyl-6-(4-pyridyl)-4,5-d ihydro-I H-pyrazolo[3,4-d]pyrimid-4-
one, 2-
butyl- I -(2-chlorobenzyl)6-ethoxy-carbonylbenzimidaole, and 2-(4-
carboxypiperidino)-4-
(3,4-methylenedioxy-benzyl)amino-6-nitroquinazoi ine, and 2-phenyl-8-
ethoxycycloheptimidazole.
Still other type V phosphodiesterase inhibitors useful in conjunction with the
to present invention include: IC-351 (ICOS 4; 4-promo-5-(pyridylmethylamino)-6-
(3-(4-
chlorophenyl)propoxy]-3(2H)pyridazi none; 1-(4-[(1,3-benzodioxol-5-
ylrnethyl)arniono]-
6-chloro-2-quinazolinyl]-4-piper idine-carboxylic acid, monosodium salt; (+)-
cis-
5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethg l)-phenymmethyl-5-meth yl-
cyclopent-
4,5]imidazo[2,1-b]purin-4(3H)one; f'ura2loci lin; cis-2-hcxyl-5-methyl-
3,4,5,6a,7,8,9,9a-
octahydrocyclopent[4,5]imidazo[2,1- b]purir-4-one; 3-acetyl-l-(2-chlorobenzyl)-
2-
propylindole-6-carboxylate; 4-bromo-5-(3-pvridylmethylamino)-6-(3-(4-
chlorophenyl)propoxy)-3-(2H)pyridazinone. 1-methyl-5-(5-morpholinoacetyl-2-n-
propoxyphenyl)-3-n-propyl-1,6-dihydro-7 H -pyrazolo(4,3-d)pyrimidin-7-one; 1-
[4-[(1,3-
benzodioxol-5-ylmethyl)amino]-6-chloro-2-aluinazolinyl]-4-piperi
dinecarboxylic acid,
monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No.
5051
(Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940);
Pharmaprojects
No. 5069 (Schcring Plough); GF-196960 (Gnaxo Wellcome); and Sch-51866.
CA 02498267 2001-08-29
V _
51
Other phosphodiesterase inhibitors that may be used in the method of this
invention include nonspecific phosphodiesterase inhibitors such as
theophylline, IBMX,
pentoxifylline and papavcrine, and direct vasodilators such as hydralazine.
The active agents may be administered, if desired, in the form of salts,
esters,
arnides, prodrugs, derivatives, and the like, provided the salt, ester, amide,
prodrug or
derivative is suitable pharmacologically, i.e., effective in the present
method. Salts, esters,
amides, prodrugs and other derivatives of the active agents may be prepared
using
standard procedures known to those skilled isnt the art of synthetic organic
chemistry and
described, for example, by J. March, Advanced Organic Chemistry: Reactions.
Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For
example,
acid addition salts are prepared from the free base using conventional
methodology, and
involves reaction with a suitable acid. Generally, the base form of the drug
is dissolved in
a polar organic solvent such as methanol or ethanol and the acid is added
thereto. The
resulting salt either precipitates or may be biought out of solution by
addition of a less
polar solvent. Suitable acids for preparing acid addition salts include both
organic acids,
e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
malic acid,
malonic acid, succinic acid, maleic acid, funiaric acid, tartaric acid, citric
acid, benzoic
acid, cinnamic acid, mandelic acid, inethanesulfonic acid, ethanesulfonic
acid, p-
totuenesulfonic acid, salicylic acid, and ilie like, as well as inorganic
acids, e.g.,
hydrochloric acid, hydrobromic acid, sulfuritlv acid, nitric acid, phosphoric
acid, and the
like. An acid addition salt may be reconverted to the free base by treatment
with a suitable
base. Particularly preferred acid addition salts of the active agents herein
are halide salts,
such as may be prepared using hydrochloric or hydrobromic acids. Conversely,
preparation of basic salts of acid moieties which may be present on a
phosphodiesterase
CA 02498267 2001-08-29
c -r
inhibitor molecule are prepared in a similar manner using a pharmaceutically
acceptable
base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,
calcium
hydroxide, trimethylamine, or the like. Particularly preferred basic salts
herem are alkali
metal salts, e.g., the sodium salt, and copper salts. Preparation of esters'
involves
functionalization of hydroxyl and/or carboxyl groups which may be present
within the
molecular structure of the drug. The esters are typically acyl-substituted
derivatives of free
alcohol groups, i.e., moieties which are derived from carboxylic acids of the
formula
RCOOH where R is alkyl, and preferably is lower alkyl. Esters can be
reconverted to the
free acids, if desired, by using conventional hydrogenolysis or hydrolysis
procedures.
Amides and prodrugs may also be prepared using techniques known to those
skilled in the
art or described in the pertinent literature. For example, amides may be
prepared from
esters, using suitable amine reactants, or they may be prepared from an
anhydride or an
acid chloride by reaction with ammonia of a lower alkyl amine. Prodrugs are
typically
prepared by covalent attachment of a moiety, which results in a compound that
is
therapeutically inactive until modified by an individual's metabolic system.
Other compounds useful for treating erectile dysfunction may also be used.
These
include: (a) pentoxifylline (TRENTAir. "); (b) yohimbine hydrocholoride
(ACTIBINE ,
YOCON , YOHIMEX'"); (c) apomorphir e (UPRIMA ); (d) alprostadil (the MUSE'
system, TOPIGLAN", CAVERJEC'1 ); (e i papavaerine (PAVABID'a, CERESPAN); (t)
phentolamine (VASOMAX', REGITINL' , and combinations, salts, derivatives and
enantiomers of all of the above.
A testosterone containing gel, such as AndroGel is administered to increase
and
enhance the therapeutic effectiveness of such drugs, in either hypogonadal or
cugonadal
men having erectile dysfunction. While pharmaceuticals such as VIAGRA work
CA 02498267 2001-08-29
w
`r 3
principally by various physiological mechanisms of erection initiation and
maintenance,
the testosterone gel used in accordance with the present invention plays a
beneficial role
physiologically, and stimulates both sexual motivation (i.e., libido) and
sexual
performance. Testosterone controls the expression of the nitric oxide synthase
gene. See
Reilly et al., Androgenic Regulation off"' Ni? Availability in Rat Penile
Erection, 18 J.
ANDROLOGY 110 (1997); Park et at., Effects of Androgens on the Expression of
Nitric
Oxide Svnrhase mRNAs in Rat Corpous Ca vernosum, 83 BJU INT'L. 327 (1999).
Thus,
testosterone and other androgens clearly play a role in erectile dysfunction.
See Lugg et
al., The Role of Nitric Oxide in Erectile Function, 16 J. ANDROLOGY 2 (1995);
Penson et
al., Androgen and Pituitary Control of Pen: ' Nitric Oxide Synthase and
Erectile Function
Its the Rat, 55 BIOLOGY OF REPRODUCTION X76 (1996); Traish et al., Effects of
Castration
and Androgen Replacement on Erectile function in a Rabbit Model, 140
ENDOCRINOLOGY
1861 (1999). Moreover, testosterone replacement restores nitric oxide
activity. See Baba
et al. Delayed Testosterone Replacement Resrores Nitric Oxide Synthase
Containing Nerve
Fibres and the Erectile Response in Rat Penis, BJU INT'L 953 (2000); Garban et
al..
Restoration of Normal Adult Penile ?recrile Response in Aged Rats by Long-Term
Treatment with Androgens, 53 BIOLOGY cr- REPRODUCTION 1365 (1995); Marin et
al.,
Androgen-dependent Nitric Oxide Relea. a in Rat Penis Correlates with Levels
of
Constitutive Nitric Oxide Synthase lsoenzYmes, 61 BIOLOGY OF REPRODUCTION 1012
(1999).
As disclosed herein, adequate blood levels of testosterone are important to
erection. In one embodiment, AndroGel(K is applied to the body in accordance
with the
protocol summarized in Example 1. The pharmaceutical(s) for erectile
dysfunction is
taken in accordance with the prescription requirements. For example, VIAGRA
is
CA 02498267 2009-03-16
54
generally taken 20-40 minutes before sexual intercourse in 50 mg doses. This
combination
of therapy is particularly useful in hypogonadal men who need increased
testosterone levels
in order to optimize the effects of VIAGRA and the sexual experience as a
whole. In
essence, a synergistic effect is obtained. AndroGel is preferably applied to
the body for a
sufficient number of days so that the steady-state levels of testosterone are
achieved.
In a prophetic example, 10 males age 18 and older will be randomized to
receive: (a)
5.0 g/day of AndroGel (delivering 50 mg/day of testosterone to the skin of
which about
10% or 5 mg is absorbed) for 30 days plus 50 mg of sildenafil citrate 1 hour
before
intercourse after at least 1 day of AndroGel therapy; or (b) 10.0 g/day of
AndroGel
(delivering 100 mg/day of testosterone to the skin of which about 10% or 10 mg
is absorbed)
for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after
at least 1 day of
AndroGel therapy; or (c) 5.0 g/day of AndroGel (delivering 50 mg/day of
testosterone)
for 30 days and nothing before intercourse. Libido, erections and sexual
performance will
be studied as in the previous Examples. Applicant expects that all test
parameters will show
improvement and synergy with the combination.
In another embodiment, the combination therapy comes in the form of kits
containing both the testosterone gel and pharmaceutical for erectile
dysfunction in amounts
sufficient for the proper dosing of the drugs. The kits also contain a set of
instructions for
the patient.
Although the invention has been described with respect to specific embodiments
and
examples, it should be appreciated that other embodiments utilizing the
concept of the
present invention are possible without departing from the scope of the
CA 02498267 2001-08-29
S 5
invention. The present invention is defined by the claimed elements, and any
ahd all
modifications, variations, or equivalents that fall within the true spirit and
scope of the
underlying principles.
