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Antimicrobial Agents and Chemotherapy, February 1998, p. 223-227, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Effect of Fluconazole on Indinavir Pharmacokinetics
in Human Immunodeficiency Virus-Infected Patients
S.
De Wit,1
M.
Debier,1
M.
De
Smet,2
J.
McCrea,3
J.
Stone,3
A.
Carides,3
C.
Matthews,3
P.
Deutsch,4 and
N.
Clumeck1,*
Division of Infectious Diseases, C.H.U.
Saint-Pierre,1 and
Merck Research
Laboratories,2 Brussels, Belgium,
Merck Research Laboratories, West Point,
Pennsylvania3; and
Merck Research
Laboratories, Rahway, New Jersey4
Received 25 March 1997/Returned for modification 10 October
1997/Accepted 15 November 1997
 |
ABSTRACT |
To evaluate a potential pharmacokinetic interaction of
coadministration of fluconazole, and indinavir, a human
immunodeficiency virus (HIV) protease inhibitor, 13 patients were
enrolled in a multiple-dose, three-period, placebo-controlled,
crossover study. Patients were randomly assigned to receive indinavir
at 1,000 mg every 8 h for 7
days (with fluconazole placebo), fluconazole at 400 mg once daily for 8 days (with indinavir placebo), and indinavir with fluconazole in combination. The
pharmacokinetics of both drugs were measured on day 8 of each treatment
period. The peak concentration in plasma (Cmax)
and the time to reach Cmax were obtained by
inspection, and the area under curve (AUC) was calculated for indinavir
and fluconazole for each treatment period in which the respective drugs
were administered. There was a marginally (P = 0.08)
statistically significant decrease in the AUC from 0 to 8 h
(AUC0-8) for indinavir when it was administered with
fluconazole. However, the magnitudes of the decreases in
Cmax and the concentration at 8 h
postdosing (C8) were not as great as the
decrease in AUC0-8. Although the 90% confidence interval
for the geometric mean ratio was within the hypothesized limits, the
clinical significance is not clear. Indinavir coadministration with
fluconazole had no statistically (P > 0.5) or
clinically significant effect on the Cmax and
C8 of indinavir. Fluconazole coadministration
with indinavir had no statistically or clinically significant effect on
the pharmacokinetics of fluconazole. One patient was discontinued
because of mild to moderate abdominal pain and diarrhea while on
indinavir and fluconazole in combination. No serious adverse experience
according to the results of laboratory tests was noted. Total bilirubin
levels in serum were mildly increased in most patients treated with
indinavir. This was not clinically significant and was not affected by
the coadministration of fluconazole. Although the values of the
pharmacokinetic parameters for indinavir decrease in the presence of
fluconazole, indinavir and fluconazole can be administered
concomitantly to HIV-infected patients without adjustment of the dose
of either drug, and both drugs are generally well tolerated.
| |
INTRODUCTION |
Human immunodeficiency virus (HIV)
protease inhibitors are a new class of antiretroviral drugs with a high
in vitro antiviral potency and a favorable toxicity profile. Recent
clinical trials have demonstrated very promising results in terms of
viral load, CD4-cell count, morbidity, and mortality, particularly in
patients with advanced HIV infection.
Although these agents demonstrate antiretroviral effects exceeding
those of the nucleoside analogs, as measured by CD4-cell count and
plasma viremia levels, their long-term clinical benefit and their
usefulness in patients with higher CD4-cell counts remain to be
determined. Nevertheless, HIV protease inhibitors are increasingly used
in the treatment of HIV-infected patients, particularly in those with
advanced HIV disease and low CD4-cell counts. These patients are
generally exposed to multiple drug interventions including other
antiretroviral agents, drugs used as primary prophylaxis for and
treatment of opportunistic infections, cancer chemotherapy, and
symptomatic therapies.
Indinavir is an orally bioavailable protease inhibitor that has shown a
significant antiviral in vivo effect alone at the indicated dosage of
800 mg every 8 h (q8h) and in combination with zidovudine and
lamivudine, with a 1- to 2-log reduction in the number of HIV type 1 (HIV-1) RNA copies in plasma and increases in the CD4-cell number of up
to 80 to 140 after 48 weeks of treatment (5).
Fluconazole is the most widely used azole antifungal compound in
HIV-infected patients. This implies that coadministration of indinavir
and fluconazole could be a frequent situation in the clinical setting.
The major role of the P-450 isozyme CYP3A4 in the metabolism of
indinavir suggests that coadministration with drugs such as fluconazole
which inhibit P-450 enzymes might alter the pharmacokinetics of
indinavir (1, 2, 7). The objectives of this study were
to determine the effect of coadministration of fluconazole and
indinavir on the pharmacokinetic profile of indinavir in plasma and to
evaluate the safety and tolerability of coadministration. The effect of
indinavir on the pharmacokinetic profile of fluconazole in plasma was
also assessed.
| |
MATERIALS AND METHODS |
Patients.
HIV-positive patients of both sexes (provided
that, for females, a serum pregnancy test was negative and barrier
contraception was used) between the ages of 18 and 60 years, with a
CD4-cell count of greater than 50 cells/mm3, and with no
active AIDS-defining opportunistic infection were evaluated for the
trial, provided that their weight was above 45.5 kg.
They were excluded in the case of a history of hepatic disease, a
positive test for hepatitis B virus surface antigen or hepatitis C
virus antibodies, or any elevation of serum aspartate aminotransferase, alanine aminotransferase, or bilirubin levels during the previous 3 months or a history of threefold or greater elevations in the levels of
these components in the past. Other biological exclusion criteria
included a serum creatinine level above 1.5 mg/dl, a granulocyte count
below 1,000/mm3, or a hemoglobin level below 9.5 g/dl. No
concomitant medication with the exception of acetaminophen
(paracetamol) and prophylaxis with co-trimoxazole, aerosolized
pentamidine, or topical antifungals agents was allowed. Daily intakes
of greater than six 12-oz. portions of caffeine-containing beverages,
more than two drinks of alcohol (wine, beer, or spirits), or more than
20 cigarettes were prohibited. This protocol was approved by the
Ethical Review Committee of Centre Hospitalier Universitaire
Saint-Pierre, and informed consent was obtained.
Study design and procedures.
The trial was designed as a
multiple-dose, randomized, three-period, crossover study. Patients were
randomly assigned to treatment sequences arranged according to a
two-balanced 3-by-3 Latin Square design consisting of active indinavir
with fluconazole placebo (treatment A), indinavir placebo with active
fluconazole (treatment B), and active indinavir with active fluconazole
(treatment C). Thus, data for six sequences of treatment were obtained:
ABC, BCA, CAB, ACB, BAC, and CBA. Indinavir was administered at a
dosage of 1,000 mg q8h for 7 days on an empty stomach (2 h
following or 1 h prior to a meal). At the time that the trial was
designed, this was the highest dose shown to be well tolerated. Fluconazole was administered at a dosage of 400 mg once daily (q.d.)
for 8 days. There was at least a 7-day washout period between each
final dose of one treatment and the first dose of the subsequent treatment. Blood and urine for laboratory tests for drug safety were
obtained prior to the administration of dose 1 and 4 h following the administration of the final dose of each treatment (day 8). Additionally, liver function tests (total and direct bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels) were determined on days 3 and 5 of each treatment.
Physical examinations were performed prior to the administration of the
first dose (day 1) and between 0 and 8 h following the
administration of the final dose for each treatment (day 8). Electrocardiograms were performed prior to the administration of the
first dose (day 1) of the first treatment, as well as 1 h
following the administration of the final dose of each treatment (day
8). Vital signs were measured at frequently scheduled times on the
first and last days of dosing. Patients were asked to maintain a diary
on a card to record the times of administration of all doses and to
note any adverse experiences during each treatment. A poststudy
evaluation for safety consisting of laboratory tests, physical
examination, and electrocardiogram was performed 24 h following
the final treatment.
Pharmacokinetics.
Blood was drawn for determination of the
concentration of indinavir in plasma at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and
8 h following the administration of the final dose of each
treatment (day 8). Blood was drawn for determination of the
concentration of fluconazole in plasma prior to the administration of
the morning dose on days 3, 5, 6, 7, and 8 during each treatment as
well as following the administration of the final dose of each
treatment (day 8) at 1, 2, 4, 8, 12, 24, and 48 h postdosing. The
blood drawing schedule was identical during each treatment to preserve
the blinding of the sequence of treatments, but plasma was actually
analyzed for indinavir and/or fluconazole levels only for the
treatments when the active drug was administered. On day 8 urine was
collected from 0 to 8 h for assay of indinavir levels. A blood
sample as a blank for assays for fluconazole levels and a blood sample
and a urine sample as blanks for assays for indinavir levels were obtained prior to administration of the first dose of the first treatment only.
The concentrations of indinavir in plasma were determined by the
high-pressure liquid chromatography technique (
10). We
used
a modified version of the high-pressure liquid chromatography
assay
reference procedure in which the assay limit of quantitation
was 25 ng/ml (40.7 nM) instead of the originally described limit
of 5 ng/ml (8 nM). The range of the linear standard curve was
25 to 5,000 ng/ml. The
interday coefficient of variation was 6%
for 75 ng/ml and 3.1% for
3,500 ng/ml. The concentrations of fluconazole
in plasma were
determined by solvent extraction followed by separation
on a methyl
silicone capillary column with electron capture detection.
The limit of
quantitation was 5.72 µg/ml. The range of the linear
standard curve
was 5.1 to 50 µg/ml. The interday coefficient of
variation was 3.6%
for 6.03 µg/ml and 6.8% for 55.28 µg/ml.
The peak concentration in plasma (
Cmax) and the
time to reach
Cmax (
Tmax)
were obtained by inspection, and the areas under
the curve (AUCs) were
calculated for indinavir and fluconazole
for each treatment in which
the respective drugs were administered.
AUCs for both indinavir and
fluconazole were calculated over the
interval from 0 to 8 h
(AUC
0-8) by the modified trapezoidal
method by using
stable piecewise cubic polynomials (
11). For
indinavir, the
0- to 8-h interval represents the final dosing
interval. For
fluconazole the 0- to 8-h interval represents the
dosing interval of
indinavir on day 8 because indinavir was not
continued throughout the
fluconazole dosing interval. The trough
concentration was also assessed
for both indinavir and fluconazole
by using the concentration at 8 h postdosing (
C8) for indinavir
and the predose
concentration (
C0) for fluconazole
(
C0 was the
last measurement of the trough
concentration of fluconazole with
indinavir coadministration). The
actual times at which plasma
was sampled were used to calculate the
AUC. All concentrations
below the limit of quantification were treated
as zero for pharmacokinetic
calculations.
Data analysis.
The a priori primary hypotheses to be tested
were as follows. (i) The AUC0-8 and the
C8 of indinavir after 1 week of coadministration
with fluconazole would not be substantially altered compared to those
observed after 1 week of coadministration with placebo; i.e., the 90%
confidence interval about the geometric mean ratio (with fluconazole or
with placebo) for both parameters would lie between 0.50 and 2.0 (hypothesis 1). (ii) Indinavir and fluconazole administered together at
multiple doses for 1 week would be sufficiently safe and well tolerated
to permit coadministration in subsequent studies (hypothesis 2).
The effect of fluconazole on indinavir was assessed by evaluating the
relationship between the pharmacokinetics for indinavir
given alone
versus the pharmacokinetics for indinavir when indinavir
and
fluconazole were given in combination. The converse, the relationship
between fluconazole given alone and in combination with indinavir,
was
also evaluated in an exploratory analysis. The primary pharmacokinetic
parameters of interest for indinavir were AUC
0-8 and
C8.
The AUC and the trough concentrations of
indinavir and fluconazole
were natural log transformed prior to
analysis. An analysis of
variance appropriate for a three-period
two-balanced Latin Square
crossover design with the factors subject,
period, treatment,
and carryover was used. The method of Tomasko et al.
(
9) was
used to test for an interaction of treatment by
pairs of periods.
All statistical tests were performed at the significance level of 0.05.
P values which fall in the region of 0.05 to 0.1 are
referred to as marginally statistically significant.
The 90% confidence interval for the mean natural log ratio of the
pharmacokinetic parameters for combination treatment versus
monotreatment was also calculated by using the mean square error
from
the analysis of variance. No clinically significant interaction
for the
primary hypothesis stated above would be concluded if
the observed 90%
confidence interval around the ratio of the geometric
mean
AUC
0-8 and the concentration in plasma for the combination
treatment versus monotreatment for indinavir fell within the
equivalence
interval (0.50 to 2.0).
Safety data were analyzed by tabulation of adverse events and
inspection of the safety data for each treatment group.
Given a three-period, crossover study with 12 patients and a type I
error of 0.05, there was a 99% probability that the observed
90%
confidence interval for the ratio of geometric mean AUCs of
indinavir
(combination/indinavir alone) would fall within the
equivalence
interval (0.50 to 2.0) if the true ratio was 1.0.
There was 99% probability that the observed 90% confidence interval
for the ratio of the geometric mean
C8 of
indinavir (combination/indinavir
alone) would fall within the
equivalence interval (0.50 to 2.0).
| |
RESULTS |
Patients.
Thirteen HIV-seropositive patients participated in
the study. The demographic characteristics of the group are as
follows. Of the 13 patients 11 were males, 2 were females,
11 were Caucasian, and 2 were black. The mean ± standard deviation (SD) age was 39 ± 10.4 years. The mean ± SD weight was 74.1 ± 10.7 kg. Two patients were discontinued from
the study due to clinical adverse experiences. One patient was
discontinued from the study while receiving both active drugs and was
not replaced. One patient was discontinued from the study on day 2 and
was replaced. Data for all 11 patients who completed the study are
included in the pharmacokinetic analysis. Data for all 13 patients are
included in the safety analysis.
Pharmacokinetics. (i) Effect of fluconazole on indinavir.
The
geometric means, geometric mean ratios, and 90% confidence intervals
for AUC0-8, Cmax, and
C8 for indinavir administered alone and in
combination with fluconazole are summarized in Table 1. Figures 1, 2, and 3 illustrate the
individual AUC0-8, Cmax, and
C8 ratios and geometric mean ratios with 90%
confidence intervals for indinavir, respectively. Hypothesis 1 states
that the AUC0-8 and C8 of indinavir
after 1 week of coadministration with fluconazole would not be
substantially altered compared to those observed after 1 week of
coadministration with placebo (geometric mean ratio of values for
combination therapy to those for monotherapy, no less than 0.50 and no
more than 2.0). The geometric mean AUC0-8 values for
indinavir administered alone and indinavir administered in combination
with fluconazole were 39,142.3 and 29,831.4 nM · h, respectively
(Table 1; Fig. 1). The geometric mean
ratio of the values with combination therapy to the values with
monotherapy was 0.76. This ratio was marginally statistically
significant different from 1.0 (P = 0.08). The
geometric mean AUC0-8s for indinavir did not differ by
more than 41% between combination therapy and monotherapy. This is
shown by the 90% confidence interval for the geometric mean ratio of
0.59 to 0.98. This was within the hypothesized interval of 0.50 to 2.0. The geometric mean Cmaxs of indinavir
alone and in combination with fluconazole were 17,216.3 and
15,018.5 nM, respectively. The geometric mean ratio of the Cmax with combination therapy to the
Cmax with monotherapy was 0.87. The 90%
confidence interval for the geometric mean ratio is 0.72 to 1.05 (Table
1; Fig. 2). This was within the interval of 0.50 to 2.0. The geometric mean C8s of
indinavir administered alone and indinavir administered in combination
with fluconazole were 235.2 and 210.6 nM, respectively (Table 1; Fig.
3). The geometric mean ratio of the
C8 with therapy combination to that with
monotherapy was 0.90. The geometric mean C8 of
indinavir did not differ by more than 28% between combination therapy
and monotherapy. This is shown by the 90% confidence interval for the
geometric mean ratio of 0.72 to 1.12. This was within the hypothesized
interval of 0.50 to 2.0. The individual C8s of
indinavir when it was coadministered with fluconazole ranged from 92.1 to 332.8 nM. The range is within the 95% confidence interval of 25 to
100 nM. Thus, there was a marginally statistically significant decrease
in the AUC0-8 for indinavir when it was administered with
fluconazole. Although the 90% confidence interval for the geometric
mean ratio was within the hypothesized limits, the clinical significance is not clear. There was no statistical or clinical significant effect of coadministration of indinavir with fluconazole on
Cmax or C8. In summary,
there is no evidence of a clinically significant pharmacokinetic effect
of the coadministration of indinavir and fluconazole on indinavir.
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FIG. 1.
Individual AUC0-8 ratios and geometric mean
ratio with 90% confidence interval for indinavir (ratio = indinavir and fluconazole in combination/indinavir alone).
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FIG. 2.
Individual Cmax ratios and
geometric mean ratio with 90% confidence interval for indinavir
(ratio = indinavir and fluconazole in combination/indinavir
alone).
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FIG. 3.
Individual C8 ratios and
geometric mean ratio with 90% confidence interval for indinavir
(ratio = indinavir and fluconazole in combination/indinavir
alone).
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(ii) Effect of indinavir on fluconazole.
The pharmacokinetic
parameters analyzed for fluconazole, which was administered at a dosage
of 400 mg q.d. included AUC0-8 and
C0 (or the trough concentration 24 h after
dosing on day 7). There were two limitations to the study design.
First, in order to evaluate the effect of indinavir on fluconazole over
the 24-h dosing interval, all three indinavir doses on day 8 must have been administered; this was not required according to the protocol. Therefore, the AUC0-8 and C0 rather
than AUC0-24 and C24 were
calculated on day 8 for fluconazole. Second, fluconazole was
administered for 8 days. However, trough concentrations indicated that
the fluconazole concentrations did not reach steady state on day 8. The
geometric mean AUC0-8 and C0 for
fluconazole administered alone and in combination with indinavir are
summarized in Table 2. The
Cmax and Tmax for
fluconazole were calculated but were not analyzed statistically. The
Tmax values for fluconazole administered alone
ranged from 0 to 24 h, and the Tmax values for fluconazole coadministered with indinavir ranged from 1 to 12 h. The arithmetic mean Cmax values for
fluconazole administered alone and coadministered with indinavir were
20.79 and 20.17 µg/ml, respectively. The half-life of fluconazole is
long, and thus concentrations in plasma are relatively constant
throughout the fluconazole dosing interval on day 8. For a drug with
this type of concentration profile in plasma (with no clear peak) after
the administration of multiple doses, the parameters
Tmax and Cmax are of
limited value. The geometric mean AUC0-8 values for
fluconazole administered alone and in combination with indinavir were
145.3 and 146.0 µg · h/ml, respectively. The geometric mean
ratio of the AUC0-8 with combination therapy to that with
monotherapy was 1.00 (Table 2; Fig. 4).
The geometric mean AUC0-8 for fluconazole did not differ
by more than 5% between combination therapy and monotherapy. This is
shown by the 90% confidence interval for the geometric mean ratio of
0.96 to 1.05. This was within the interval of 0.50 to 2.0. The
geometric mean C0s of fluconazole administered
alone and in combination with indinavir were 13.5 and 13.5 µg/ml,
respectively (Table 2; Fig. 5). The
geometric mean ratio of the C0 with combination
therapy to the C0 with monotherapy was 1.00. The
geometric mean C0 of fluconazole did not differ by more than 20% between combination therapy and monotherapy. This is
shown by the 90% confidence interval for the geometric mean ratio of
0.84 to 1.20. This was within the interval of 0.50 to 2.0. Collectively, the pharmacokinetic data indicate that the coadministration of fluconazole with indinavir had no statistically or
clinically significant effect on the pharmacokinetics of fluconazole.
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FIG. 4.
Individual AUC0-8 ratios and geometric mean
ratio with 90% confidence interval for fluconazole (ratio = indinavir and fluconazole in combination/fluconazole alone).
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FIG. 5.
Individual C0 ratios and
geometric mean ratio with 90% confidence interval for fluconazole
(ratio = indinavir and fluconazole in combination/fluconazole
alone).
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Safety.
Data for all 13 patients were included in the safety
evaluation. Thirteen patients had clinical adverse experiences. The
most common clinical adverse experiences were diarrhea, nausea,
abdominal pain, acid regurgitation, headache, taste disturbances, hot
flushes, and eye accommodation disorder during treatment with either
indinavir alone, indinavir and fluconazole, or fluconazole alone. Eight patients had adverse experiences which were judged to be related to one
of the study drugs. Among patients receiving the combination of
indinavir and fluconazole, one patient had taste disturbance and one
patient had taste loss, and another patient receiving indinavir alone
reported taste loss. These were judged to be possibly related to study
drugs. Four patients experienced nausea which was judged to be possibly
drug related. One patient receiving indinavir alone and one patient
receiving fluconazole alone had nausea. One patient receiving indinavir
and fluconazole in combination had nausea. Two patients receiving
indinavir and fluconazole in combination and while not receiving a
study drug had nausea. All of these adverse experiences were mild or
moderate.
Two patients were discontinued from the study due to clinical adverse
experiences. One patient had a serious clinical adverse
experience
judged to be definitely not related to study drug.
He received
indinavir at 1,000 mg q8h plus fluconazole at 400
mg on day 1 while
complaining of cough and sputum production.
On day 2 he was
hospitalized for a lung disorder and was discontinued
from the study
while off of drug. The other patient experienced
nausea, taste
disturbance, hot flushes, abdominal pain, and diarrhea
while receiving
both indinavir at 1,000 mg q8h and fluconazole
at 400 mg q.d. He was
discontinued on day 5 of the second treatment
while receiving indinavir
alone. These clinical adverse experiences
were judged to be possibly
related to study drug.
All 13 patients were included in the safety evaluation performed with
data from laboratory tests. Three of 13 patients had
adverse
experiences according to the results of laboratory tests.
One patient
had pyuria on day 8 following the administration of
fluconazole at 400 mg q.d. and on day 26 while off of either study
drug. One patient had
pyuria predosing on day 1 and had activated
PT increased on day 25 following the administration of indinavir
at 1,000 mg q8h and
fluconazole at 400 q.d. The third patient
had hyperkalemia on day
8 following the administration of indinavir
at 1,000 mg q8h and
fluconazole at 400 mg q.d. No patient had
an adverse experience that
was judged on the basis of laboratory
test data to be related to study
drug. No adverse experience was
serious on the basis of laboratory test
data. No patient was discontinued
from the study due to an adverse
experience on the basis of laboratory
test data. Total bilirubin levels
in serum were increased in some
patients. The highest bilirubin level
was 1.9 mg/dl. No clinically
significant deviations in the evaluation
of the data from tests
for clinical safety such as physical
examination, vital signs,
or electrocardiogram were found.
| |
DISCUSSION |
Multiple drugs are commonly prescribed to HIV-infected patients,
and the potential for drug interactions leading to either adverse
events or reduced efficacy is great. It is thus particularly important
to carefully evaluate potential interactions between drugs whose
metabolic pathways are similar and which will commonly be administered
concomitantly. This is the case for HIV protease inhibitors and azole
derivatives, in particular, indinavir and fluconazole, whose
coadministration could lead to increased plasma indinavir levels
through inhibition of the CYP3A4 isozyme.
Several dosing regimens for indinavir have been investigated to date.
At the time that this study was designed a progressive dose-response
from 200 mg every 6 h (q6h) (0.8 g/day) to 600 mg q6h (2.4 g/day)
had been demonstrated. In view of a potential risk of the development
of resistance with dosages of less than 2.4 g/day, a study aimed at
determining the maximum antiretroviral response possible with indinavir
monotherapy was initiated. Three dosage regimens were investigated: 800 mg q8h (2.4 g/day), 1,000 mg q8h (3.0 g/day), and 800 mg q6h (3.2 g/day). At the time that the indinavir-fluconazole study started, the
dosage of 1,000 mg q8h had been shown to be well tolerated and was
selected for use in the trial. Following completion of the comparative
trial with the three dosage regimens, the lower dosage (800 mg q8h) was
selected for clinical development. Indinavir dosages above 2.4 g/day
did not appear to exert a greater antiviral effect (8). The
dosage of fluconazole chosen for the study, 400 mg q.d., is the highest dosage indicated for the treatment of fungal infections.
There was a decrease in the AUC0-8,
C8, and Cmax for
indinavir when it was coadministered with fluconazole. However, the
magnitudes of the decreases in Cmax and
C8 are not as great as the decrease observed for
AUC0-8. Due to the nonlinear pharmacokinetics of
indinavir, the AUC0-8 of indinavir when it is
coadministered with fluconazole is anticipated to be reduced, but it is
greater than the AUC0-8 seen with indinavir given at 600 mg q8h. The mechanism for the decrease in the AUC0-8 could
be due to induction of P-450 metabolism by fluconazole. Fluconazole
appears to induce some mammalian P-450 enzymes, and thus, in theory,
fluconazole has the potential to increase as well as decrease the
clearance of P-450-metabolized drugs (3).
However, the effects of fluconazole on the pharmacokinetics of other
drugs (such as phenytoin, cyclosporine, and anticoagulants) appear to
be mediated predominantly by P-450 inhibition, not P-450 induction. In
this study, no increase in the AUC0-8 for indinavir
consistent with P-450 inhibition was observed. In contrast, coadministration of indinavir with ketoconazole does result in an
increase in plasma indinavir concentrations (6). This is consistent with the greater potency of ketoconazole versus that of
fluconazole as a P-450 inhibitor (7). Another possibility for the apparent effect of fluconazole on indinavir pharmacokinetics is
interference with absorption, but there is no known precedent for such
an effect of fluconazole. Given that the effect of fluconazole on
indinavir did not quite reach statistical significance, this result
could well have been a chance occurrence. In any event, the clinical
significance of this small decrease in the AUC0-8 for
indinavir is unclear. However, this does not warrant a dose adjustment.
The AUC0-8 and C0 values for
fluconazole when it was and those for fluconazole when it was
administered alone in combination with indinavir did not differ
significantly. This suggests that indinavir, a potential CYP3A4
inhibitor, did not affect the metabolism of fluconazole. This is
consistent with the minor role of hepatic metabolism in the clearance
of fluconazole. The Tmax and
Cmax values for fluconazole administered alone
and coadministered with indinavir are of limited value. The half-life of fluconazole is long, and thus, concentrations in plasma are relatively constant, with no clear Cmax or
Tmax on day 8 (4).
A review of reports of adverse experiences and tabulated summaries of
selected laboratory values indicate that indinavir and fluconazole
administered alone or together were generally well tolerated. Two
patients were discontinued from the study due to clinical adverse
experiences. One patient had a serious clinical adverse experience,
judged not to be drug related, following day 1 of treatment with
indinavir plus fluconazole. He was hospitalized for a lung disorder.
The other patient was discontinued from the study due to nausea, taste
disturbance, hot flashes, abdominal pain, and diarrhea while receiving
both indinavir and fluconazole. These clinical adverse experiences were
judged to be possibly drug related. No patient had an adverse
experience that was judged on the basis of data from laboratory tests
to be related to one of the study drugs. No adverse experience was
serious on the basis of data from laboratory tests. No patient was
discontinued from the study due to an adverse experience on the basis
of data from laboratory tests.
In summary, indinavir and fluconazole may be administered concomitantly
to HIV-seropositive patients without adjustments of the dose of either
drug. The two drugs given concurrently generally appear to be well
tolerated.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Infectious Diseases (PL5), C.H.U. Saint-Pierre, rue Haute 322, B-1000
Brussels, Belgium. Phone: 32.2/535.41.30. Fax: 32.2/539.36.14. E-mail:
NCLUMECK{at}ULB.AC.BE.
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Abstract
Introduction
