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Antimicrobial Agents and Chemotherapy, February 1998, p. 409-413, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Zalcitabine Population Pharmacokinetics:
Application of Radioimmunoassay
John M.
Adams,1,2,3
Mark J.
Shelton,1,2,3
Ross G.
Hewitt,3,4,5
Mary
DeRemer,1
Robin
DiFrancesco,1
Thaddeus H.
Grasela,2 and
Gene D.
Morse1,2,3,4,5,*
Laboratory for Antiviral Research1
and Departments of
Pharmacy Practice2
and
Medicine,4 State University of New
York at Buffalo, and
Antiviral Clinical Pharmacology Unit,
Immunodeficiency Clinic, Erie County Medical
Center,3 Buffalo, New York, and
AIDS
Clinical Trials Unit, University of Rochester School of Medicine,
Rochester, New York5
Received 30 September 1996/Returned for modification 25 February
1997/Accepted 15 October 1997
 |
ABSTRACT |
Zalcitabine population pharmacokinetics were evaluated in 44 human
immunodeficiency virus-infected patients (39 males and 5 females) in
our immunodeficiency clinic. Eighty-one blood samples were collected
during routine clinic visits for the measurement of plasma zalcitabine
concentrations by radioimmunoassay (1.84 ± 1.24 samples/patient;
range, 1 to 6 samples/patient). These data, along with dosing
information, age (38.6 ± 7.13 years), sex, weight (79.1 ± 15.0 kg), and estimated creatinine clearance (89.1 ± 21.5 ml/min), were entered into NONMEM to obtain population estimates for
zalcitabine pharmacokinetic parameters (4). The standard
curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The
observed concentrations of zalcitabine in plasma ranged from 2.01 to
8.57 ng/ml following the administration of doses of either 0.375 or
0.75 mg. A one-compartment model best fit the data. The addition of
patient covariates did not improve the basic fit of the model to the
data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume
of distribution was estimated to be 87.6 liters (1.18 liters/kg;
CV = 54.0%). We were also able to obtain individual estimates of
oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg)
and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in
NONMEM. Our value for oral clearance agrees well with other estimates
of oral clearance from traditional pharmacokinetic studies of
zalcitabine and suggests that population methods may be a reasonable
alternative to these traditional approaches for obtaining information
on the disposition of zalcitabine.
| |
INTRODUCTION |
Zalcitabine has been extensively
evaluated as monotherapy and in combination regimens for patients with
human immunodeficiency virus (HIV) infection (11, 15, 30).
Early trials of zalcitabine monotherapy noted an unacceptable incidence
of peripheral neuropathy (5, 10, 22-24, 25, 31, 32, 38). As
a result, subsequent trials were designed to evaluate lower doses
(12, 13, 22, 25, 31). Zalcitabine is usually prescribed at
dosages of 0.375 or 0.75 mg every 8 h. However, certain aspects of
zalcitabine therapy such as optimal dosage reductions or dosing
interval adjustments in patients with decreased renal function or
receiving dialysis remain to be clarified.
One obstacle to the further refinement of zalcitabine dosing has been
the lack of an assay which is sensitive enough to reliably quantitate
concentrations in plasma after the administration of currently
prescribed doses. Phase I pharmacokinetic studies used a
high-performance liquid chromatography assay; however, this method is
not sensitive enough for the study of current doses (17-21). Other techniques such as combined gas or liquid
chromatographic-mass spectrometric assays have been reported
(28); however, their application to clinical studies of
current zalcitabine doses has not been evaluated. The reagents for a
zalcitabine radioimmunoassay have been available for quite awhile, and
a prior report described the enhanced sensitivity of this assay method
(7). However, the description of this method also indicated
the need for an initial solid-phase sample preparation step, which
requires 0.5 ml per sample. We have also validated this
radioimmunoassay method, but without an additional sample preparation
step and with a requirement for 200 µl per sample. This report
summarizes the assay validation and describes its use in a population
pharmacokinetic analysis of zalcitabine.
| |
MATERIALS AND METHODS |
Chemicals and reagents.
Zalcitabine and the primary and
secondary antibodies were purchased from Sigma Chemical Company Inc.
(St. Louis, Mo.). [2',3'-3H]zalcitabine was purchased
from Moravek Biochemicals Inc. (LaBrea, Calif.). The following
reagent-grade chemicals were purchased from Fisher Scientific
(Rochester, N.Y.): concentrated hydrochloric acid, sodium azide, and
monobasic and dibasic sodium phosphate. Ecoscint scintillation fluid
was obtained from National Diagnostics (Manville, N.J.). Knox brand
gelatin (Knox Gelatine, Inc., Englewood Cliffs, N.J.) was used for the
assay buffer. Assay buffer contained 0.01% gelatin and 0.02% sodium
azide in 0.02 M sodium phosphate (pH 7.4). Dilution buffer was obtained
from zidovudine radioimmunoassay kits (INCStar, Stillwater, Minn.).
Working dilutions of antibody and tracer were prepared as follows:
antizalcitabine rabbit antiserum, 0.05 to 0.10 mg/ml in assay
buffer; 3H-zalcitabine, 0.002 nCi/ml in assay buffer.
Calibration standards were prepared as various dilutions of a 0.1-mg/ml
stock of zalcitabine in assay buffer, diluting with dilution buffer to
yield concentrations of 0.6, 1.0, 1.6, 2.2, 3.0, 4.0, 10, 16, 24, 33.3, and 50 ng/ml. The standards were stored at 
20°C in screw-top
cryotubes in aliquots with 1- and 4-ml volumes. Quality control samples
were diluted from a separately prepared 0.1-mg/ml stock in assay buffer
to attain 1.3, 2, 7, 12, and 30 ng/ml and were aliquoted and stored in
the same manner as the calibration standards.
Radioimmunoassay.
All reagents were equilibrated to room
temperature before use. One hundred microliters of each standard,
control, and plasma unknown was pipetted into borosilicate glass tubes
(12 by 75 mm) in duplicate. To ensure the best curve fit, the
calibration standards at the lowest three dilutions and the first two
quality controls were assayed in quadruplicate. No sample preparation
step was used. Two hundred microliters of dilution buffer was added to nonspecific binding tubes and 100 µl was added to reference tubes. One hundred microliters of diluted tracer was added to every tube. One
hundred microliters of the antizalcitabine was added to each tube
except the nonspecific binding and total counts tubes. All tubes were
vortexed briefly and were incubated at room temperature for 1 h.
Secondary antibody, goat antirabbit antiserum (250 µl), was added to
all tubes except the total counts tube. The tubes were vortexed
briefly, incubated at 4°C for 30 min, and then centrifuged at
2,200 × g for 45 to 60 min and the supernatant was
decanted. The pellet was dissolved in 200 µl of 0.1 N HCl and
transferred to a scintillation vial containing 5 ml of scintillation
fluid. The vials were vortexed vigorously and counts were measured for 20 min on a Wallac model 1409 liquid scintillation counter (Wallac, Gaithersburg, Md.).
Quantitation.
The disintegrations per minute for the
calibration standards were fitted to a smoothed, spline function by
using RIACalc software, version 2.65 (Wallac). Calibration standards
within the quantitation range (2 to 50 ng/ml) were deleted if they were
not within ±20% of the nominal value and the coefficient of variation
(CV) of the duplicates was not 
20%. The curve fit was considered
acceptable if five or more points remained. The concentrations in the
quality control and plasma unknown samples were then derived from this curve. Quality controls were considered acceptable if they had concentrations within ±20% of the nominal values and had a 20% CV
between duplicates.
Method validation.
The fitted calibration standard values
and quality control values were used to determine assay variation.
Statistics for the mean and standard deviation of fitted calibration
standard values and quality controls were calculated with Lotus 1-2-3, version 4.0, software. The percent CV was calculated as (standard
deviation/mean) × 100, and the percent true error was calculated as
[(mean true value)/true value] × 100. Blank plasma samples
from 14 individuals not receiving zalcitabine were analyzed to
determine if there were false-positive measurements. Four of the
samples were repeated with four or six replicates on 3 other days to
test variations in the background from assay to assay.
The specificity of the assay was also evaluated by testing for
interference from other nucleoside analogs including zidovudine, didanosine, and stavudine. Interference from concomitant medications was also tested by assaying samples with clinically relevant
concentrations of doxepin, fluoxetine, ranitidine,
pyrimethamine, pyrazinamide, hydroxyzine, thiamine,
L-ascorbic acid, dextromethorphan, isonicotinic acid
hydrazide, cyclobenzaprene, dexbrompheniramine, megestrol, ibuprofen,
diphenhydramine, penicillin G, and sulfamethoxazole.
Data on the stability of plasma samples containing zalcitabine, which
were either refrigerated or frozen, were obtained by
assaying high- and
low-quality control samples. The frozen samples
were also tested
through six repeated freeze-thaw cycles.
Recovery of zalcitabine from plasma samples spiked with zalcitabine at
concentrations ranging from 1.0 to 10 ng/ml was evaluated.
The samples
with greater than 2.0 ng/ml were assayed with and
without dilution.
Population pharmacokinetics.
Patients were enrolled as part
of a clinic-wide population pharmacokinetics program. After enrollment
in the study, patients filled out a questionnaire during each visit to
the clinic. Information obtained from the questionnaire included the
date, time, and dose of zalcitabine taken most recently, as well as
whether any doses had been missed in the 24 h prior to the clinic
visit. In addition to dosing history, the questionnaire asked for
information regarding the time of the patient's last meal and recent
over-the-counter medication use. Also at each clinic visit, in addition
to the collection of blood for routine laboratory tests, a whole-blood sample (approximately 5 ml) was collected into an EDTA-containing tube
and the tube was labeled with the patient's identification number, the
date and time that the sample was obtained, and the dose of zalcitabine
taken by the patient. The blood samples were centrifuged at 2,000 rpm
(Marathon centrifuge) for 15 min. The plasma layer was then transferred
into a polypropylene test tube, and the tube was stored at 20°C
until its contents were assayed. Patient clinic charts were reviewed to
verify zalcitabine dosing histories and to obtain pertinent demographic
information.
Prior to assay, all samples were heat inactivated in a water bath for
30 min at 56°C. Plasma zalcitabine concentrations were
determined by
the radioimmunoassay method described above. The
concentrations of
zalcitabine in plasma and dosing history information
were input into a
Lotus database and were later converted into
a NONMEM-ready input file.
Various models for determining the
population pharmacokinetic
parameters of zalcitabine were evaluated
with the nonlinear regression
program NONMEM, version IV, level
1.0. Potential fixed effects on oral
clearance (total body weight,
age, gender, calculated creatinine
clearance, administration of
zalcitabine with food, and concomitant
administration of zalcitabine
and zidovudine) and volume of
distribution (total body weight)
were considered in the development of
the model. Model discrimination
criteria included the minimization of
the objective function value,
precision of parameter estimates, and the
magnitude of residual
variability. Finally, individual estimates of
zalcitabine oral
clearance and volume of distribution were obtained for
each patient
by using the POSTHOC option within NONMEM (
3,
29).
| |
RESULTS |
Radioimmunoassay.
Table 1 shows
the calibration standard and quality control values generated during
the measurement of zalcitabine concentrations in specimens. The
variation between duplicates at concentrations below 2 ng/ml often
exceeded 20%; therefore, measurements were done in quadruplicate.
Calibration standards of 0.5, 0.8, and 1.5 ng/ml were omitted if the
fitted value differed by more than 25% from the target value; other
calibration standards were omitted if the fitted value differed from
the target value by more than 15%. More calibration standards were
omitted at the lower end of the concentration range, where the
variability of fit was higher. The 1.0-ng/ml quality control standard
reflected this variation, displaying a CV of 27% and an accuracy of
12%. Calibration standards at 3.2 ng/ml and above had consistently
better fits with less variation. The 10-ng/ml quality control standard
was also much less variable, exhibiting 9.5% variation and +4%
accuracy.
The results for blank plasma specimens from 14 individuals ranged from
0 to 0.9 ng/ml; therefore, the limit of quantitation
was established as
2 ng/ml. Of the 20 compounds tested for cross-reactivity,
only
ranitidine and didanosine exhibited measurable cross-reactivity
at 0.10 mg/ml. Results for stability testing showed that the controls
containing both high and low concentrations of zalcitabine showed
no
statistical differences either for storage effect or for freeze-thaw
cycles.
The recovery of zalcitabine from plasma samples spiked with the drug at
1.0 to 10 ng/ml is illustrated in Fig.
1.
The samples
with greater than 2.0 ng/ml were assayed with and without
dilution.
For concentrations above 2.0 ng/ml, the overall mean values
indicated
that the assay is accurate within ±20% of the target value.
Percent
error did not improve with dilution of the sample.
Patients.
A total of 44 patients (39 males and 5 females) were
enrolled, with 81 samples available for the analysis (1.84 ± 1.24 samples/patient; range, 1 to 6 samples/patient). The demographic
characteristics of these patients are summarized in Table
2.
Pharmacokinetics.
The observed concentrations of zalcitabine
in plasma ranged from 2.01 to 8.57 ng/ml following the administration
of a dose of either 0.375 or 0.75 mg (Fig.
2). A one-compartment model with first-order elimination best fit the data. The complete
pharmacostatistical model is presented in Table
3. None of the evaluated fixed effects on
oral clearance (total body weight, age, gender, calculated creatinine
clearance, administration of zalcitabine with food, and concomitant
administration of zalcitabine and zidovudine) or volume of distribution
(total body weight) improved the fit of the basic model to the data.
The population estimate for oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; 95% confidence interval, 0.18 to 0.21 liter/h/kg), which agrees well with a previous estimate reported from
traditional pharmacokinetic studies of zalcitabine (36). The
CV associated with this estimate of oral clearance was 23.8%. The
volume of distribution was estimated to be 87.6 liters (1.18 liters/kg;
95% confidence interval, 1.07 to 1.30 liters/kg), with a CV of 54.0%.
The absorption rate constant could not be modeled because of the
paucity of blood samples collected early in a dosing interval. Residual
variability was estimated to be 20.6% with a proportional error model.
Finally, we were able to obtain individual estimates of oral clearance
(range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liters/h/kg) and volume of distribution (range, 49.2 to 161 liter; 0.43 to 1.92 liters/kg) of
zalcitabine in these patients with the POSTHOC option in NONMEM.
| |
DISCUSSION |
The pharmacokinetics of zalcitabine have been studied to a limited
extent, primarily due to a lack of availability of an assay which is
sensitive enough to measure concentrations in the plasma of patients
receiving the currently recommended doses (37). The
dose-limiting toxicities of zalcitabine, primarily peripheral neuropathy, occur in an unpredictable manner and at different times
after the initiation of therapy (5, 6, 24, 30). While
zalcitabine is one of the more potent of the approved nucleoside analog
reverse transcriptase inhibitors, little is known about its
intracellular metabolism in patients. As with the measurement of
intracellular anabolites for zidovudine and didanosine, the analytical
ability to measure the phosphorylated anabolites of zalcitabine in
clinical samples has not proceeded rapidly and has been limited to in
vitro investigations (1, 2, 8, 9, 26, 33-36). Therefore,
the clinical pharmacokinetics of zalcitabine remain the most likely
tool for assessing the relationship between concentrations in plasma
and surrogate marker responses.
Burger et al. (7) described a false-positive recovery of
zalcitabine from blank plasma specimens, measuring up to 3.00 ng/ml,
and from urine samples, measuring up to 4.00 ng/ml. Our assay results
also found that false detection of zalcitabine was apparent; however,
the amounts that we found were less: up to 1.26 ng/ml for plasma. This
is likely attributable to the concentration of primary antibody we
used. Burger et al. (7) used a dilution threefold higher
than that suggested by the manufacturer. Our approach used a sixfold
higher dilution of the same product. On the basis of these observations
and the variation that we experienced during the measurement of lower
zalcitabine concentrations, the lowest concentration reported for our
population pharmacokinetics study was 2.0 ng/ml. Any plasma sample with
a zalcitabine concentration below this was considered to be
indistinguishable from blank plasma.
The availability of the zalcitabine radioimmunoassay also makes the
application of population pharmacokinetics a possibility. Zalcitabine
is usually dosed every 8 h, and the data presented in Fig. 2
indicate that at the recommended doses, plasma zalcitabine concentrations are measurable by the assay described here. These concentrations in plasma can, in turn, be used to generate population pharmacokinetic parameter estimates and estimates of individual zalcitabine clearance, which can be used to determine individual drug
exposures for use in pharmacodynamic studies. Our population estimate
of oral clearance was 14.8 liters/h (CV = 23.8%). This value
(0.19 liters/h/kg) agrees well with an estimate reported from
traditional pharmacokinetic studies and would suggest that random
collection of blood samples during routine clinic visits provides a
reasonable method for estimating zalcitabine clearance (14, 19,
27, 31). However, efforts to obtain a more even distribution of
samples collected at various times after the administration of a dose
would assist in more accurately describing population parameters.
Our estimate of volume of distribution (1.18 liters/kg) is larger and
more variable than what has been reported in previous pharmacokinetic
studies that used the traditional two-stage approach. This could be due
in part to the fact that we obtained relatively few blood samples early
in a dosing interval. Indeed, we were unable to obtain an estimate for
the absorption rate constant for the same reason. Future studies aimed
at estimating these population pharmacokinetic parameters should
attempt to obtain several blood samples from different patients during
this period, perhaps through the controlled administration of a dose of
zalcitabine in the clinic followed by blood sampling. Indeed,
controlled administration of zalcitabine doses in the clinic would
greatly reduce the error associated with patients not accurately
remembering when they took their previous dose. This would be
particularly important for drugs, like zalcitabine, with a short
half-life.
None of the fixed effects that we examined (age, sex, total body
weight, calculated creatinine clearance, coadministration of
zalcitabine with food, and concomitant zalcitabine and zidovudine therapy) improved the fit of the basic model to the data. This could be
at least partially explained by the fact that most of the factors were
not well distributed across the range of values. For example, many
patients had similar calculated creatinine clearances, despite a range
of 54 to 146 ml/min. Similarly, a significant majority of the patients
were white males whose risk factor for HIV infection was homosexual
activity. Future efforts should be directed toward enrolling patients
who can provide more heterogeneity for the analysis of these factors.
In addition, the collection of larger numbers of blood samples from
each patient would further assist in the estimation of individual
pharmacokinetic parameters.
Zalcitabine is primarily renally excreted, and therefore, dosage
requirements are most likely needed for HIV-infected patients with
reduced renal function. However, current dosing guidelines do not
include specific recommendations for adjusting the dose of zalcitabine
and suggest that estimates of creatinine clearance be used to guide
dosage changes. Furthermore, a recent report has examined the estimates
of creatinine clearance obtained with the common nomograms used
clinically and compared them to a measured creatinine clearance and
found that the calculated estimate overpredicts the measured value for
a majority of patients (16). As a result, zalcitabine dosing
in patients with renal impairment will be inaccurately predicted and
patients may receive excessive doses, possible leading to the
development of toxicity.
In summary, the use of chronic zalcitabine therapy is often complicated
by the development of peripheral neuropathy. The use of lower doses to
avoid neuropathy may in turn reduce the ratio of the concentration in
plasma to the 50% inhibitory concentration over each dosing interval.
Although unproven, this relationship may be important in clinical
outcomes. Since no results from intracellular studies with which
zalcitabine dosing can be adjusted are available, the current approach
to zalcitabine dosing does not allow for individualization. In
addition, patients with reduced renal function may accumulate
zalcitabine and may become predisposed to peripheral neuropathy. The
application of the zalcitabine radioimmunoassay and population
pharmacokinetic methods may allow clinical research to investigate
these issues and help to provide a more individualized approach to
zalcitabine dosing. Individualized approaches to zalcitabine dosing
need to be investigated for their potential clinical utility in
maximizing therapeutic outcomes.
| |
ACKNOWLEDGMENTS |
This study was supported in part by grant 01874-14-RGR from the
American Foundation for AIDS Research, National Institute of Health
grant AI-27658, and a grant from Roche Laboratories.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: 247 Cooke Hall,
Laboratory for Antiviral Research, Department of Pharmacy Practice, State University of New York at Buffalo, Amherst, NY 14260. Phone: (716) 645-3635. Fax: (716) 645-2001. E-mail:
emorse{at}acsu.buffalo.edu.
| |
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Antimicrobial Agents and Chemotherapy, February 1998, p. 409-413, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
