Note: Descriptions are shown in the official language in which they were submitted.
CA 02526433 1997-09-17
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THERAPEUTIC AGENT WITH QUANTITATIVE CONSUMPTION MARKER
AND METHOD OF MONITORING T~iERAPEUTIC AGENT CONSUMPTION
This is a division of Canadian Patent File No. 2,265,795
filed September 17, 1997.
TECHNICAL FIELD
The present invention relates generally to monitoring
patient compliance with medication prescriptions. More
particularly, the invention relates to compositions and
methods for monitoring patient compliance using
quantitative compliance markers in association with
prescribed medications.
BA~ICGRpUND OF
In the fields of human and animal medicine, psychiatry
and animal husbandry, insuring that the patient or animal
ingests the proper amount of medicine, hormone or nutrient
to produce a desired effect is a commonly encountered
problem. For example, human research has demonstrated that
patients typically ingest only half the amount of
medications prescribed by their physicians. Thus, patients
placed on prescribed medication treatment programs are
often monitored . Both sub j active and obj active methods are
used to identify bothersome symptoms and to implement
,, necessary changes during the course of treatment.
Monitoring generally continues for as long as treatment is
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provided. For example, the Hamilton Anxiety Scale can be
used to quantify the amount of anxiety remaining as
treatment proceeds for an anxiety-related condition. If
the level of residual anxiety decreases significantly, say
from the proper prescription of a benzodiazepine drug, like
diazepam, then the physician and patient can be assured
that treatment is efficacious and should be continued.
Preferably both quantitative and analytical methods
should be used to monitor the patient on a repetitive basis
to insure that the patient is indeed ingesting the
prescribed amounts of medication. Currently, the most
common method of monitoring patients for medication
compliance is clinical observation which involves
individual counseling and close personal supervision by
physicians. Physicians observe physiological signs and
symptoms such as intoxication, drug withdrawal typically
occurring for benzodiazepines, barbiturates and opioids, or
residual signs of illness such as tremor in anxiety,
sighing in depression, and nociception in pain syndromes.
Physicians also listen to patient complaints regarding
degree of pain relief and evaluate psychological changes
over time. This method however is time consuming,
expensive and highly subjective. Needless to say, it is
fraught with potential errors.
Additional compliance information can be obtained
using qualitative urine monitoring methods such as the
standard laboratory procedure called enzyme-multiplied
immunoassay (EMIT). Utilizing an arbitrary cutoff value,
these methods provide the clinician with a simple positive
or negative indication of the possible presence or absence
of a parent drug or its metabolites in a patient s urine.
The parent drug is the prescribed medication itself and the
metabolites are those chemical derivatives of the
medication which naturally occur upon the patient s body
metabolizing the medication. These tests do. not provide
CA 02526433 1997-09-17
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information concerning the time or amount of last drug use
or whether or not the prescribed dose of medication was
ingested properly, diverted or supplemented. This type of
testing fails to provide any indication as to the actual
quantity of drug ingested.
Physicians utilizing only clinical evaluation and
qualitative urine drug screening test results may develop
problems in their treatment methods. Such is often the
case in treating patients who have become bioehemically
dependent upon opioids either through prescription or
illegal use. Opioid addicts experience great difficulty
eliminating their dependency upon such drugs and typically
enter into extended rehabilitative treatment programs which
utilize prescribed methadone dosages to eliminate opioid
dependency. For example, physicians must effectively
assess the condition of patients on methadone maintenance
programs in order to adjust dosages and monitor compliance.
If a patient is continually testing positive for opioids or
complains of continuing subjective opioid withdrawal
symptoms, a physician may conclude that the currently
prescribed dose of methadone is not sufficient to curb the
body's desire for opioids and may increase the prescribed
dosage. This highly subjective monitoring method can
result in over-medication with patients being given more
methadone than they require, creating an unnecessary
reliance on methadone. Alternately, physicians sometimes
conclude, erroneously, that a patient's methadone dose is
sufficient to prevent opioid withdrawal and drug cravings
and deny the patient a further increase sufficient to stop
illicit opioid use. Such action can expose the patient to
further intravenous drug use and the associated negative
social and medical consequences which can follow such as
HIV, hepatitis, and blood poisoning.
Similar problems with treatment may arise for patients
prescribed diazepam for longstanding generalized anxiety.
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Patients may not show improvement in their condition even
though this therapy is known to be highly efficient. This
medication is a member of the sedative-hypnotic family of
benzodiazepines which have been clinically shown to cause
sedation, hypnosis, decreased anxiety, muscle relaxation,
anterograde amnesia and anticonvulsant activity. A
patient, for example, may insist that he or she is
ingesting the medication as prescribed, and yet claim no
significant improvement in symptomology. The physician
suspects that the patient is not ingesting the medication
properly and perhaps is selling it, and orders a
qualitative urine drug screen to verify compliance. The
screen is reported as positive at greater than 200 ng/ml
drug concentration. Since some benzodiazepine is present
the physician assumes, incorrectly, that the patient is
compliant, but will require additional medication and
increases the daily dose. In truth, the patient is
diverting the majority of his or her dose to the illicit
market and only ingesting enough drug to test positive on
the drug screen.
Patients also commonly visit multiple physicians to
obtain similar medication for self-ingestion. These
patients desire the intoxicating effects of the medication,
but are unable to obtain sufficient quantities from a
single source. Qualitative tests like the EMIT are
generally not useful in detecting this situation since the
quantitative amount of medication concentration in the body
is not measured.
Another monitoring method sometimes used, though most
often only in research centers, is direct measurement of
parent drug concentrations or active metabolites
concentrations of the drug in plasma. This method has been
particularly useful to eliminate illicit opioid use of
patients on methadone maintenance programs. It is known
from anallytical studies using venous blood samples obtained
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from stable patients that plasma methadone concentrations
ranging from 150 - 600 ng/ml are necessary. This direct
method of testing is not very practical since it requires
the use of time consuming, expensive, and highly technical
analytical procedures such as high pressure liquid
chromatography and gas chromatography/ mass spectrometry
since active and inactive metabolites must be quantified
separately. Additionally, for many patients the obtaining
of plasma samples is invasive, offensive and difficult due
to inadequate venous access. Medical professionals must
also be concerned about their own health safety in doing
this since they are exposed to blood products from patient
groups which can have a high prevalence of hepatitis and
HIV infection. Therefore, such procedures are primarily
conducted in research centers and not generally utilized in
standard maintenance programs.
Another problem commonly encountered by pharmaceutical
companies occurs whenever they are comparing the clinical
efficacy of a potential, new medication versus a placebo.
For example, in clinical trials new medications appear to
be two to three times as effective as a placebo, i.e.,
placebo response rates can range from 20-30% while drug
response rates range from 60-80%. One explanation for why
new medications are not more effective is that many test
subjects are not taking their prescribed doses. The end
result is that many medications with undesirable side-
effects, as formulated for the study, may appear not to be
efficacious and be inappropriately dropped from research
only because subjects are not ingesting sufficient drug to
observe the desired effects. Other medications may end up
being clinically prescribed at higher doses than necessary,
increasing morbidity and mortality, because the researchers
think the subjects are taking more medication than they
actually are.
i
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Researchers have proposed several solutions to this
problem. For instance, drug compliance in a research
setting has been monitored by counting the residual pills
remaining following a course of treatment. In this regard
the use of a tablet container which incorporates a recorder
that records each opening of the container is described in
the scientific literature. However, the technique of
residual pill counting is not necessarily indicative of
pill ingestion.
Another method of drug compliance monitoring which is
disclosed in scientific literature involves adding
secondary substances to medication which presence can be
qualitatively detected in blood work and other bodily
fluids. In this regard, some researchers have added
ingredients like riboflavin to pills and looked for the
ingredient in the patient's serum, urine, or feces.
However, testing serum necessitates additional labor and
care since it requires a blood sample to be taken.
Furthermore, since ingredients like riboflavin are commonly
found in food, beverage, and multivitamins, they are
normally also present in urine independent of any
supplemented riboflavin. The normal presence of such
ingredients in the urine therefore leads to false positive
readings during testing. Additionally, no accurate
relationship has been determined between the presence of
these markers in the urine and the amount of medication
taken.
As an alternative solution, researchers have added
relatively harmless amounts of a second medication to pills
for this purpose. However, the addition of this type of
ingredient again only indicates that patients are taking
some pills. Depending on the half-life of these secondary
medications, researchers may only be able to tell if the
patient ingested the medication recently. Furthermore,
S
CA 02526433 1997-09-17
research with "second medication" type markers has focused
on serum testing for verification.
While methods now exist for determining compliance
using quantitative urine monitoring that are useful for
insuring that patients are obtaining adequate body levels
of specific drugs, as disclosed in the applications earlier
cited, these methods require the development of specific
analytical methods tailored for measuring each specific
drug and its metabolites. Often these methods are not
available in a clinically useful manner in the early
development of new drugs.
While providing useful information relative to patient
status and treatment compliance, the clinical monitoring
methods described above, i.e. clinical interviews with
patients, direct plasma drug measurement, qualitative urine
drug screening, residual tablet counting, and quantitative
urine drug screening for each drug ingested, each have
distinct drawbacks which limit their usefulness in
experiments and treatment plans. Therefore, it is seen
that a need remains for a predictable method of monitoring
patients who have been placed on potentially abusable and
dangerous maintenance medications or new experimental drugs
for compliance therewith. A need remains for a method of
monitoring drug ingestion which is not invasive to the
patient and which does not require a predetermined
mathematical relationship specific for each drug being
monitored. To help prevent continued medication misuse and
better optimize patient medication dose, it would be
advantageous for patients to have a facile bodily fluid,
such as urine, regularly and quantitatively monitored for
the presence of the medication. It would be further
desirable not to have to rely on the distinctive
pharmacokinetics of each medication in such monitoring but
on the pharmacokinetics of only a standard compliance
marker of a series of compliance markers. Such ,a
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monitoring method would help physicians both in prescribing
adequate doses of medication and in monitoring patients to
insure that they were ingesting the prescribed amounts.
Obtaining a fluid sample like urine would not be invasive
to the patient or a safety risk to the health care
provider.
Furthermore, a need remains for a composition which
includes an easily measurable quantitative compliance
marker and a therapeutic agent, in which the consumption
compliance marker readily passes through the renal system
with little or no pharmacological effect on the patient.
Accordingly, it is to the provision of such improved
methods and compositions that the present invention is
primarily directed.
SUMMARY OF INVENTION
A composition and method has been developed for
particular use in clinical drug evaluation studies for
tracking compliance of patients on prescription medications
(therapeutic agents) by using compliance markers
(quantitative consumption markers) in association with the
medications, which consumption compliance marker
concentrations can be accurately measured in the urine.
Upon a determination of the compliance marker
concentration, a correlation is made to the amount of
actual medication ingested. Only a small number of
mathematical relationships need be determined between
marker intake and urine output, rather than developing
unique relationships for each and every drug tested.
Moreover, quantitative relationships exist between the
amount ingested and the amount appearing in the urine as a
function of physical parameters such as patient weight,
lean body mass, age, urine pH, urine specific gravity
(which may be measured by a refractometer, hydrometer or
chemicalimethods), or other equivalent parameters related
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to dissolved urinary solids such as urine osmolality. This
is especially useful in clinical trials of new, potentially
useful medications.
It has now been discovered that pharmacologically
inert quantities of weakly acidic medications, specifically
benzodiazepines, provide quantitative compliance markers in
association with therapeutic agents. The measurable
benzodiazepines and their metabolites readily pass through
the renal system into the urine making benzodiazepines and
substances with similar properties especially suitable as
compliance markers. Preferably a pharmacologically inert
quantity of a benzodiazepine, referred to as a
"quantitative compliance marker," is added to each unit
dose of therapeutic agent, i.e. medication, hormone or
nutrient, which quantitative compliance marker
concentration can be measured in the urine. For the
purposes of this application, an inert substance shall
include biologically inactive substances which are non-
metabolizable and pharmacologically insignificant amounts
of therapeutic drugs and their metabolites, which can still
be detected in the urine of a patient.
The quantitative compliance marker may be added to a
medical formulation by being mixed homogeneously throughout
the formulation or solution, or as a film or coating on a
tablet or capsule containing the formulation.
Additionally, the marker may be introduced as particulates
in a suspension. If more than one medication has been
prescribed, a separate quantitative compliance marker may
be used in association with each medication. Preferably
the quantitative compliance markers have biological half-
lives of between 24 and 48 hours so that they will appear
in a urine sample long after ingestion. The quantitative
compliance markers are associated with therapeutic agents
at a predetermined proportion and preferably at a
f
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sufficiently small dosage to insure the absence of
psychotropic and physiological effects on the patient.
In the method of monitoring therapeutic agent
consumption, random samples of a patient's urine may be
analyzed for the concentration of a quantitative compliance
marker associated with a therapeutic agent. The
concentration of the quantitative compliance marker then
serves as the basis for both monitoring consumption
compliance with the prescribed therapeutic agent dosage and
to establish the proper medication dosage.
In the method of monitoring therapeutic agent
consumption, if appropriate, it is first determined whether
the urine sample is adulterated as by comparing urine pH,
specific gravity, and creatinine level with that of a
normal urine sample and the specific values previously
determined for the patient. If found to be unadulterated,
and probably from the patient being monitored, the raw
urine compliance marker concentration is measured along
with the urine specific gravity or urine osmolality.
Once the actual concentration of the compliance marker
in the sample is determined (the raw urine compliance
marker concentration), adjustments are made to account for
the affects of variations in certain urinary parameters
upon this concentration, by adjusting for the compounding
effects of urine specific gravity. This is accomplished by
accounting for the difference between the measured specific
gravity and a reference specific gravity. An adjustment is
also made to reflect a normalization to a constant patient
body weight such as 70 kg or 154 lbs. This final adjusted
compliance marker concentration is defined as the
normalized urine compliance marker concentration. In the
alternative, the normalized urine compliance marker
concentration may be calculated as a function of the urine
osmolality, the measured raw urine compliance marker
s.
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concentration and the patient body weight normalized to a
constant value.
The normalized urine compliance marker concentration
value is then used to determine whether the patient is
compliant by comparing the value of the normalized
compliance marker concentration to an expected value, for
the purpose of determining whether there is any significant
statistical variance between the two values. By obtaining
multiple urine samples from the patient, once or twice a
l0 week, it is possible to establish an expected baseline
normalized compliance marker concentration against which a
current or future value can be statistically compared. An
expected baseline compliance marker concentration for a
patient is the mean normalized compliance marker
concentration from historical values obtained from the
patient. This method of monitoring compliance is dependent
upon the assumption that the patient is initially compliant
in order to get the expected value. In the alternative,
expected ranges of normalized compliance marker
concentrations for specific compliance marker dosages, may
be used for comparison. These ranges are based on a
patient database independent of the subject patient.
A corresponding value for the actual medication dose
ingested is then calculated by multiplying the prescribed
medication dose with the calculated normalized urine
compliance marker concentration, and dividing the product
by the expected normalized urine compliance marker
concentration.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is a graph of reverse urine creatinine
excretion factor (RUCEF) versus urine volume production
rate factor (UVPRF) showing their substantially linear
relationship.
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Fig. 2 is a graph of urine volume production rate
factor (UVPRF) versus specific gravity factor (SGF) showing
their substantially linear relationships.
Fig. 3 is a graph of urine production rate versus
urine specific gravity factor (SGF) using independent data
and showing their substantially linear relationship.
Fig. 4 is a graph of urine production rate versus
specific gravity ratio (1.030/urine SG).
Fig. 5 is a graph of urine creatinine concentration
versus urine production rate showing the inverse
relationship between urine creatinine and urine production
rate, forming a hyperbola.
Fig. 6 is a graph of urine volume production rate
factor versus urine specific gravity factor, showing a
slope of one and a zero intercept and demonstrating their
substantially linear relationship.
Fig. 7 is a graph of normalized urine compliance
marker concentration versus daily compliance marker dose
demonstrating their substantially linear relationship.
DETAILED DESCRIPTION
Specifics of Composition
A specified amount of the quantitative compliance
marker benzodiazepine is added to each unit dose of
therapeutic agent, i.e. medication, hormone or nutrient,
which marker can be measured in the urine. For the
purposes of this application, an inert substance includes
biologically inactive substances which are non-
metabolizable, and pharmacologically insignificant amounts
of therapeutic drugs and their metabolites, which can still
be detected in the urine of a patient. Preferably the
inert substances are not normally found in urine and are
not normally ingested as food or drink or as a medicine.
Also the inert substances are preferably weak acids so that
they are'unaffected by urine pH and pass through the renal
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system without resorption. Additionally, there are
mathematical relationships between weak acids with pK
(dissociation constants) values less than 4, and their
individual active and inactive metabolites.
Benzodiazepines, such as the alprazolam XanaxT~$nd the
diazepam ValiumT,M which are normally prescribed as
therapeutic agents for treatment of anxiety related
conditions, are especially suited as markers because their
urinary excretion is not dependent upon urine pH, as are
weak bases, because they are completely ionized at the
typical urine pH range of 4.5-8.5. This insures complete
clearance after glomerular filtration in the kidneys, since
these drugs are not absorbed or secreted in great
quantities by the renal tubules of the kidneys. For
instance, Valium could serve as a marker at a dosage range
of 1-lOmg a day, depending on the individual patient.
Advantageously, while the benzodiazepine family of
medications are absorbed fully by the digestive tract,
being very lipophilic in neutralized form, they are not
significantly metabolized by the liver. Consequently,
simple relationships exist between oral intake and urine
output, as corrected for patient weight and urine specif is
gravity. Moreover, if the compounds are psychotropically
and physiologically inactive at low doses, their ingestion
will not adversely affect the patient. Therefore it is
preferable that pharmacologically inert quantities of a
benzodiazepine be used as a marker.
A benzodiazepine quantitative compliance marker may be
added to a medical formulation by being mixed homogeneously
throughout the formulation or as a film or coating on a
tablet or capsule containing the formulation.
Additionally, the marker may be mixed in a solution or
introduced as particulates in a suspension. If more than
one medication has been prescribed, a separate quantitative
compliance marker may be used in association with each
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medication. Preferably the markers have biological half-
lives of between 24 and 48 hours so that they will appear
in a urine sample long after ingestion.
A general example using this type of quantitative
compliance marker, is the following:
A clinical examination shows that a patient needs to
ingest three pills of medication a day. If 0.5 mgs of a
long-acting inactive metabolite of alprazolam or diazepam
(having plasma half-lives greater than 24 hours) is added
to each pill as a compliance marker, each compliant patient
will have a specified and constant amount of the compliance
marker in each urine sample. The average amount measured,
as normalized for urine specific gravity, and a constant
patient body weight, will be directly related to the number
of pills ingested, for instance 12o concentration units
assuming each pill contains 40 concentration units.
Persons taking only 2 pills will have 80 concentration
units, and persons taking only 1 pill will have 40
concentration units. Having this data, a pharmaceutical
company can then create dose-response curves for the drug
since they will have patients taking different amounts of
drugs due to variations in compliance.
A second general example is the following:
A quantitative compliance marker is used in a
methadone concentrate at a constant ratio, i.e., one
compliance marker per ten methadone. Therefore the amount
of methadone ingested will be proportional to the amount of
compliance marker taken. Consequently, taking less or more
methadone than prescribed will show up as less or more
marker in the urine, thus helping to eliminate diversion of
a drug to a second individual or supplementing of a
patient's drug intake from another source. In this way a
number of distinct markers may be used to monitor the
compliance of a variety of medications.
'i.
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Other inert substances may also serve as markers in
the following method of monitoring consumption compliance
with therapeutic agents. For example, the barbiturate
phenobarbital may be used as a compliance marker in
conjunction with other prescribed medications, providing
the dosage of the compliance marker is low, and there is no
drug cross-reactivity with the prescribed medication or
other medication that the patient is currently taking.
S~~ecifics of Method
A patient is initially.prescribed a medication and
dose based on several factors. These ordinarily include
the severity and duration of illness, amounts and types of
medications previously used, current or previous
physiological and/or physical dependence upon other
prescription or illicit drugs, previous medical history,
patient sex, pregnancy status, patient weight and ingestion
of other therapeutic medications. Often medication dose is
adjusted upwardly until a patient no longer complains of
residual signs and symptoms of his or her psychiatric
and/or medical illness, is no longer experiencing
withdrawal signs and symptoms if on a medication-
replacement taper to abstinence program, or loses his or
her desire to use illicit medications if a substance abuse
problem exists. Medication dose is increased per published
and accepted standard medical protocols for each family of
psychiatric and medical drug, usually "x" mg every few
days. A compliance marker is associated with the
prescribed medication at a preestablished ratio so that as
the patient takes his/her prescription, he/she also takes
a correlative amount of the compliance marker.
Testing for Adulte;~ation
In certain circumstances it may be appropriate to
first test for adulteration of urine samples. Such a
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circumstance may be appropriate in drug
rehabilitation/addiction treatment settings. If this is
necessary, a supervised, spot sample of urine should be
first collected from a patient. The urine sample is
collected by simply providing the patient with a standard
urine collection bottle into which he or she can urinate.
Alternatively, a sample can be collected by catheterization
or withdrawn from a urine collection bag. Only several
milliliters of urine are required for analysis. With this
l0 sampling method, it is not necessary to record the volume
collected or completely void the bladder. Loss of a
portion of the sample is also not detrimental as long as a
sufficient sample remains for analysis.
Several properties of the urine are measured to
evaluate whether the urine is adulterated, adulteration
being the altering by a patient of his or her urine in an
effort to prevent detection of illicit drug use or
diversion of a drug. Adulteration typically is
accomplished by adding foreign substances to the urine such
as salt, bleach, or vinegar. Many patients attempt to
dilute amount of drugs in the urine sample by drinking
large quantities of water or by adding water to the sample.
Adulteration may also occur by substituting another
person's urine for the patient's own urine, including
instillation of foreign urine into the patient's bladder.
In checking for adulteration, urine pH is measured, as
with the use of a pH Data Logger type meter available from
oakton, to see if it is within the normally expected pH
range of 4.5 to 8.5. Urine specific gravity is also
measured to see if it is within the normal range of 1.004
to 1.035 units. A Digital Urinometer by Biovation may be
used for this test. Creatinine, an end product of glycine
and arginine metabolism excreted through the kidneys, is
measured to evaluate renal function. The creatinine level
in human' urine usually ranges from 8 to 500 mg/dl, the
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range being affected by variables such as age, sex, diet,
lifestyle and geographic location. Creatinine levels
generally are homeostatically maintained by the body at a
constant value for each individual patient over his or her
lifetime. Creatinine levels may be determined on many
different analyzers, including a TDx REA Creatinine System
available from Abbott Laboratories. All of these tests are
helpful in establishing normally expected ranges for each
patient and the overall population of patients.
to Once pH, specif is gravity, and creatinine level values
for the spot urine sample are obtained for a particular
patient, comparisons can be made between the sample in
question and values previously measured (if already
available) both for the patient and for normals to
ascertain whether the urine sample is adulterated. If no
adulteration is found, a data base is created or extended
for the patient so that a basis of comparison exists for
future spot urine samples. Of the three measures, urinary
creatinine level is generally the most useful indicator as
to whether the spot sample is that of the patient or of
someone else. If it is not necessary to test for
adulteration of urine samples, then random urine samples
are simply obtained from the patient to be analyzed in the
following manner.
Measurement of Specific Gravit~r or Osmolalitv
Once a representative urine sample has been obtained,
specific gravity (SG) is measured for the urine at room
temperature, (22-23 degree C) which typically ranges from
1.004 to 1..035 for normal urine. A Digital Urinometer by
Biovation may be used for this test. Occasionally, urine
samples may exhibit artificially elevated specific gravity
values. This situation occurs whenever the urine contains
a significant amount of protein, such as in the nephrotic
syndrome] and/or glucose, as in diabetes mellitus.
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Occasionally, this can also occur when urinary cleared,
radiopaque dyes are used for diagnostic purposes.
Osmolality measurement may therefore be preferred in
lieu of specific gravity measurement in order to avoid
these inflated values, since osmolality values are less
dramatically affected by the presence of glucose and
protein in the urine, and since there is a recognized
relationship in scientific literature that exists between
urine osmolality and urine specific gravity. Furthermore,
osmolality values are not sensitive to temperature
variations as are specific gravity values.
Measuring Raw Urine Compliance Marker Concentration
The unadulterated sample is next analyzed for raw
urine compliance marker concentration, preferably using
fluorescence polarization immunoassay (FPIA) technology.
In this regard an Abbott TDX or ADX Analyzer may be
profitably employed. Other standard analytical methods may
also be used such as chromatography or other types of
immunoassay. The value, u, obtained is the raw urine
compliance marker concentration expressed in ng/ml. If
appropriate, the value a includes the compliance marker
metabolite concentration in the urine as well. Metabolites
are those substances which result from the body's
metabolism of the compliance marker.
The raw urine compliance marker concentration, u, is
next converted to a normalized urine compliance marker
concentration, nu, as discussed below. A historical
database is then created for these values.
Calculating Normalized Urine Complia~ce_Marker
Concentration
Parameters of a patient's urine, such as pH and
specific gravity, vary from one day to the next dependent
upon the~:type and quantities of foods and beverages
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ingested. Additionally, individuals metabolize endogenous
substances, as well as medications, at different rates.
Due to variations in these daily urine parameters,
concentration levels for creatinine, other endogenous
compounds, and drug metabolites can vary over time. Since
many endogenous compounds and drugs are weak acids under
normal conditions of urine pH, significant tubular
resorption does not occur and renal clearance is primarily
the result of glomerular filtration. For these compounds,
the major variable responsible for observed variations in
urine metabolite and drug concentrations is tubular
resorption or excretion of free water. The kidneys
regulate urine production rates so to maintain normal blood
pressure and blood osmolality. This property of the
kidneys is indicated by the urine specific gravity, a
physical variable relating to urinary solids and urine
volume production rate. A mathematical relationship has
been discovered to exist between urine compliance marker
concentrations and urine specific gravity, which herein is
given by the specific gravity normalized compliance marker
concentration, nu.
It is now realized that renal excretion rates (mg/dl)
for drugs and urine metabolites are relatively constant for
any patient during a typical day. This constancy has now
been experimentally verified by examining the renal
excretion rates of methadone, benzodiazepines, other drugs
and creatinine and other endogenous metabolites as a
function of urine volume production rate. For example,
sequential, complete and timed (1-8 hours holding periods)
aliquots of urine for 12 compliant control subjects were
collected over 24 to 72 hour periods. For each urine
aliquot, urine volume production rate (ml/min), specific
gravity and creatinine concentration (mg/dl) (as the tested
substance) were determined. Using this data, a
dimension~less, linear relationship was found to exist, that
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is the same for all patients, between a urine volume
production rate factor (UVPRF) and a reverse urine
creatinine excretion factor (RUCEF). For each individual,
control, urine collection period, the UVPRF is defined by
the ratio of urine volume production rate for each urine
aliquot collected, v, to the urine volume production rate
for the most concentrated sample in the collection period
with a specific gravity usually near 1.030 (ie that
specific gravity of a normal urine sample at room
l0 temperature, typical of a morning void ), v',
UVPRF = v/v'. (1)
Similarly, in this example, RUCEF factor is defined by the
ratio of the creatinine concentration of the most
concentrated urine aliquot with a specific gravity usually
near 1.030, u', to the creatinine concentration for each
urine aliquot collected, u,
RUCEF = u'/u. (2)
This linear relationship is shown in Figure 1. The best
fit linear regression line is given by the expression,
RUCEF = 0.942~UVPRF + 0.121 (3)
u'/u = 0.942~v/v' + 0.121 (4)
where statistical evaluation results in an adjusted squared
multiple R - 0.985, a standard error of the estimate -
0.242, and a F-ratio = 4965.
Therefore, contrary to the traditional teachings of
those skilled in the art, urine drug and metabolite
concentrations, u, are inversely related to the volume of
urine produced by the kidneys, v, clearly demonstrating
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that the product (u~v) is constant at any particular time
point and urine pH.
since (u~v) at any time is a constant, steady-state
value, it follows that from Equation (4) some empirical
mathematical relationship must exist between a and v such
that given an arbitrary urine volume production rate v' and
an equivalent u' at a reference point (a specific gravity
of 1.030):
~u'v~.~.~w.~ ° (u' 'v' ~m.o3o
or upon rearrangement for u' gives,
u' = u~(v/v') (6)
where the products given in Equation (6) are those measured
for a spot urine sample collected with an actual specific
gravity and a corrected specif is gravity typical of a
morning void of 1.030.
Using controlled urine collections, a urine volume
production rate v' of 0.44 ml/min for persons with
reasonably normal renal functions at a specific gravity of
1.030 was initially measured. A specific gravity factor is
then calculated by the equation (rsg - 1.000)/(msg -
1.000), where rsg is the reference specific gravity, which
in this case is equal to 1.030, and where msg is the
measured specific gravity. The specific gravity factor is
an adjustment of the measured specific gravity value to
account for the difference between the measured specific
gravity value and a reference specific gravity value.
It has been found that a linear relationship exists
between the urine volume production rate factor and the
specific gravity factor, (SGF) as shown in Figure 2 and
given as follows:
t.
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UVPRF = v/v' = 2.43~SGF - 1.43 (7)
where the adjusted squared multiple R - 0.856, standard
error of the estimate = 0.787, F-ratio = 482.
Substituting Equation (7) into Equation (6) the
specific gravity normalized creatinine concentration, nu,
(since we are testing for creatinine) is then calculated by
adjusting the actual urine creatinine concentration, u, for
compounding effects of urine specific gravity at 1.030:
nu = u' = u~(v/v') - u~UVPRF = u~[k,~SGF - k,,] (8)
wherein k, is a constant equal to 2.43 and k, is a constant
equal to 1.43.
Usina Osmolality Measurement In Lieu of Specific Gravity
Measurement in Calculations
It has been noted that specific mathematical
relationships exist between the rate of urine formation
(ml/min) and the concentration of creatinine in the urine.
A relationship also exists between these variables and
urine specific gravity. Generally, the relationships
between SGF and v/v' apply to persons with normal renal
function. However several situations exist in which the
SGF, especially when measured by refractometry or
hydrometer, is not directly related to v/v', thus creating
inaccuracies in the relationships heretofore described.
Such a situation occurs whenever the urine contains a
significant amount of protein and/or glucose. Occasionally
this can also occur whenever urinary cleared, radiopaque
dyes are used for diagnostic purposes. Each of these
compounds can affect the refractive index or drag
coefficients for a spinning hydrometer. In situations such
as these,, the presence of the abnormal components results
in the specific gravity value being artificially elevated.
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For example, protein in the urine, which is mainly albumin,
causes the specific gravity to increase by about 0.003
units for every 1000 mg of protein/100 ml urine. The
presence of glucose results in an increase of about 0.004
units for every 1000 mg of glucose/100 ml urine. If the
presence of these influencing compounds is not considered,
the specific gravity utilized in the correlation is
inaccurate. This inaccuracy is readily apparent because
the v/v' from the calculated SGF will fall outside of the
expected range, alerting the clinician to a possible
unusual situation. It will appear that the urine specific
gravity is too high for the amount of urine produced. In
this scenario, additional urine tests can be done to
quantify the amounts of protein, glucose and radiopaque
dyes. Once these figures are obtained, corrections can be
applied to the calculations. For example, another urine
sample can be collected after the radiopaque dye is out of
the urine and numerical corrections to the refractometer or
hydrometer specific gravity values can be made for protein
and/or glucose. The corrected specific gravity is
determined by subtraction so as to remove the effect of the
abnormal urine components. Once these corrections are
made, the normally expected relationships between SGF and
v/v' may be noted. .
However, in lieu of using SGF as a measure of urine
concentrating ability, specific gravity being the mass of
a unit volume of solution/mass of a unit volume of pure
solvent, urine osmolality factor (hereinafter UOF) can also
be used. Osmolality is the number of osmotic particles per
unit volume of pure solvent. A common relationship exists
in scientific literature relating urine osmolality to urine
specific gravity. For instance, urine osmolality, measured
in mOSM, is equal to 37500(SG-1.000). Furthermore, urine
osmolality is not temperature sensitive as is urine
specific sgravity. The urine osmolality factor is defined
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as the ratio of the urine osmolality at a specif is gravity
of a reference point, such as 1.030, to the urine
osmolality equivalent at the actual urine specific gravity.
Using this equation, the following figures may be generated
for protein/glucose free urines.
EXAMPLES
Measured Calculated Measured Calculated
Specific Specific Osmolality Urine
Gravity Gravity Osmolality
Factor Factor
sample 1 SG 1.003 SGF 10 Osm 112.5 UOF 10
sample 2 SG 1.015 SGF 2 Osm 562 UOF 2
sample 3 SG 1.030 SGF 1 Osm 1125 UOF 1
It is therefore evident from this data that SGF and
UOF values are equivalent and either one may be used in the
application of this invention.
Refinement of the Normalized Urine Compliance Marker
Equations
Independent data was gathered from 96 patients being
followed in a renal disease clinic. Data available from
these patients included 24 hour urine volumes, urine
specific gravity, urine creatinine concentration, serum
creatinine concentration, creatinine clearances measured
from 24 hour collections, presence of protein and glucose
in urine, urine osmolality, patient sex, age, lean body
weight, total body weight, height and diagnosis.
The independent data was first plotted by urine
production rate (ml/min) versus various mathematical
formulations of urine specific gravity as illustrated in
Figs. 3 and 4. Although several methods exist for plotting
specific gravity or its equivalent, osmolality, on the x-
axis, ie, SG ratio=1.030/SG, SGF or even SG, the SGF and
UOF relationship are preferable.
t.
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As a further example for demonstrating in greater
detail the inverse relationship between urine creatinine
and urine volume production rate, urine creatinine
concentration was plotted against urine production rate
revealing a hyperbola in Fig. 5.
Figure 6 plots the ratio v/v' using v' equal to 0.58
ml/min against SGF. Plotting this data gives a slope of one
and a zero intercept. Data gathered from normal subjects
supports this same conclusion.
These functions differ from functions described
earlier in that v' is now equal to 0.58 and v is now equal
to SGF ~v' as compared to previous formulations where v was
equal to (2.43 ~ SGF-1.43) ~ v', where v' equals 0.44. The
refined normalized equation may be expressed generally as
follows (normalized to a specific gravity of 1.030):
nu = u' - u~(v/v') - u~UVPRF = u~SGF (9)
The equation for nu (9) may be further normalized to
adjust for a standard patient body weight such as of 70 kg
or 154 lbs. This normalized value for nu may be reflected
in the following equation:
nu = u' = u~(v/v') - u~SGF~(WGT/K) (10)
where WGT is equal to patient body weight, and K is a
constant equal in this case to 154 lbs. It should be noted
that this equation may be normalized to any reference value
for specific gravity or weight.
Comparison of nu Value With Established Values
The normalized urine compliance marker concentration
is then compared to established values for the patient. By
obtaining multiple urine samples from a patient, once or
twice a week, it is possible to establish an expected
normalized' compliance marker baseline against which a
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current or future value can be statistically compared. The
expected normalized compliance marker baseline is the mean
normalized compliance marker value from historical patient
data. This method of monitoring compliance is dependent
upon the assumption that the patient is initially compliant
in order to get the expected value. In the alternative,
expected ranges for normalized compliance marker
concentrations from independent patient databases may be
used for comparison. If any difference between calculated
nu and expected nu is not explained by statistically
acceptable deviation, then the patient is not in
compliance. The actual medication dosage ingested may then
be calculated as:
i(prescribed medication dose)~(calculated nut
expected nu
Specific Examples and Supporting Data Using Method
Several methadone patients were independently
prescribed diazepam for anxiety disorders. These patients
were utilized to determine if it would be possible to
compound a particular "marker" chemical in a set ratio to
methadone such that one could tell how many doses of
methadone each patient took. If the "marker" concentration
in the urine satisfied specified statistical requirements
as to the concentration level measured, then one would be
sure that the patient did not ingest extra doses or divert
methadone by not taking the full dose. These experiments
were designed as follows:
Experiment #1 Query
Does normalized urine concentration of compliance
marker correlate with doses of the underlying drug
methadone given to patient?
t
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Staaes of Experiment #1
1. A fixed diazepam/methadone hydrochloride mixture
ratio was chosen (1 mg diazepam per 15 mg methadone HCL).
Methadone-marker solutions were prepared by adding
sufficient diazepam liquid (l0 mg/ml concentrate) to
methadone concentrate (50 mg/ml) so as to manufacture unit
samples containing either (4mg diazepam/70 mg methadone) or
(8 mg diazepam/120 mg methadone) such that the final volume
(including water, color and flavor) of each dose was 15 ml.
2. To insure compliance with protocol for this
experiment, three rehabilitated and compliant patients
(each having been in methadone treatment for several years)
were chosen for this experiment. Two patients ingested
methadone 30 mg p.o. every 12 hours (half a bottle each
time) and one patient ingested methadone 60 mg p.o. every
12 hours (half a bottle each time). On a random basis,
each patient was asked to provide an observed urine sample
for analysis prior to being given his or her daily dose.
Each patient came to the office at least twice a week to
pick up medication, ingest half their dose and be
interviewed. Each experiment was conducted for a two month
period. During this period, the only sources of methadone
and diazepam available were given in the test site.
3. Diazepam was measured by FPIA normalized to a
urine specific gravity of 1.030 and a total body weight of
154 lbs:
3o nu concentration = (u)(s~F)(wgt/15~)
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4. Results.
PRESCRIBED COMPhIANCE MEAN NtJ FOR
MEDICATION MARKER COMPhIANCE MARKER
P-1 methadone 30mg diazepam 2mg 500 (SD 90, CV 18%)
p.o. ql2h p.o. ql2h
P-2 methadone 60mg diazepam 4mg 1068 (SD 233, CV 22%)
p.o. ql2h p.o. ql2h
P-3 methadone 30mg diazepam 2mg 499 (SD 73, CV 15%)
p.o. ql2h p.o. ql2h
Expected ratio of marker P-1/marker P-3 should be
1.00; actual ratio observed was 1.00. Expected ratio of
P-2/marker P-1 or P-3 should be 2.00; actual ratio was
2.13.
Experiment #2 Query
What happens if a patient were to ingest extra
methadone from another source also containing compliance
marker?
Staqes of Experiment #2
1. For this experiment, patient P-3 was utilized.
In order to simulate a patient ingesting twice as much
methadone (underlying drug) each day (also with compliance
marker), patient P-3 was given his standard methadone dose
for several weeks prior to and following a one week change
in the amount of compliance marker (2 mg diazepam per 15 mg
methadone HCL) included in his normal 60 mg daily methadone
dose so as to simulate "double dosing." Included in the
following chart are sequential nu diazepam urine values for
the pre-change period, simulation of "double dosing" and
post-change period.
5.
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Date: marker status: nu diazepam:
02-19-96 post-change 534 ng/ml
02-09-96 post-change 482
02-02-96 post-change 404
01-31-96 post-change 591
O1-26-96 double marker 1163
marker returned to
1 mg/15 mg methadone
01-22-96 double marker 597
01-19-96 pre-change 450
marker increased to
2 mg/15 mg methadone
01-16-96 pre-change 519
01-03-96 pre-change 395
12-29-95 pre-change 516
12-26-95 pre-change 344
12-22-95 pre-change 591
If the patient was "double dosing" one would expect to
see (after about a week, since the average half-life of the
diazepam metabolites is about 48 hours) at the end of a
week, a compliance marker concentration about twice the
baseline concentration. Expected concentration would be
about 1000 ng/ml, while concentration observed was 1163
ng/ml. Therefore, if this patient had been non-compliant
and getting methadone from another clinic, doctors would
have been able to intervene.
Experiment ~~3 Ouerv
What happens if a patient were to divert a portion of
their daily doses?
Staaes of Experiment #3
1. f For this experiment, patient P-2 was utilized.
In order to simulate a patient diverting half of her daily
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methadone (has take-homes with one clinic visit a week), a
protocol similar to experiment #2 was done except
compliance marker was decreased to 0.5 mg diazepam per 15
mg methadone HCL.
Date: marker status: nu diazepam:
02-09-96 post-change 1019 ng/ml
02-06-96 post-change 1044
02-02-96 post-change 1073
I
01-30-96 post-change 1098
O1-26-96 half marker 445
increase marker to
1 mg/15 mg methadone
01-23-96 half marker 673
O1-19-96 half marker 997
decrease marker to
0.5 mg/15 mg methadone
O1-16-96 pre-change 1044
O1-12-96 pre-change 978
O1-09-95 pre-change 1029
Ol-05-96 pre-change 896
01-02-96 pre-change 1210
If a patient were diverting half of their take-home
doses, one would expect to see a decrease in the compliance
marker concentration of half after a week or so. This is
indeed what happened.
Experiment 4 Ouery
How to establish expected values for normalized urine
compliance marker concentrations ?
Based on data gathered from over 50 patients observed over
a four-yeah period, expected ranges for several normalized
urine compliance marker concentrations have been
established. For example, when diazepam is utilized as a
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compliance marker, the expected normalized value for urine
diazepam-like immunoreactivity is 125 ng/ml/mg diazepam
marker ingested. Statistical ranges for acceptable lows
and highs have been established as being between 75 to 175
ng/ml/mg diazepam marker ingested. The linear correlation
between normalized urine compliance marker concentration
and daily compliance marker dose is illustrated in Fig. 7.
Using preestablished data for normalized urine compliance
marker concentration will eliminate the need to establish
historical data bases for each individual patient.
It thus is seen that methods and compositions are now
provided for monitoring patients who have been placed on
medication maintenance programs or have been participants
in experimental drug programs. The method utilizes a
compliance marker concentration from evaluation of patient
urine samples by FPIA to determine normalized urine
compliance marker concentrations. Normalized urine
compliance marker concentration can then be compared to an
expected normalized urine compliance marker concentration.
The actual drug dose ingested may then be calculated to
determine compliance with the prescribed medication dose.
The methods and compositions are clinically practical
without high laboratory testing cost, the invasiveness of
withdrawing blood, and the added exposure to medical
professionals of patient blood having high probability of
hepatitis and HIV infection. Furthermore, the methods and
compositions do not require multiple equations to calculate
normalized concentration values, or the consideration of
numerous pharmacokinetics variables for each medication
being monitored.
While this invention has been described in detail with
particular references to preferred embodiments thereof, it
should be understood that many modifications, additions and
deletions may be made thereto, in addition to those
expressly recited without departure from the spirit and
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scope of the invention as set forth in the following
claims.
