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Antimicrobial Agents and Chemotherapy, January 2001, p. 30-37, Vol. 45, No. 1
Glaxo Wellcome Inc., Research Triangle Park,
North Carolina,1 and Laboratoire Glaxo
Wellcome, 781 Marly-le-Roi, France2
Received 16 February 2000/Returned for modification 4 July
2000/Accepted 28 September 2000
In a dose-ranging study of amprenavir (formerly 141W94), an
inhibitor of the protease enzyme of human immunodeficiency virus (HIV)
type 1, single-dose and steady-state pharmacokinetic parameters were
estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily
(b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected
adults, 59 of whom had pharmacokinetic data. Log-log regression
analysis (the power model) revealed that the steady-state area under
the curve (AUCss) and the maximum, minimum, and average concentrations at steady state (Cmax,ss,
Cmin,ss, and Cavg,ss, respectively) increased in a dose-proportional manner over the 300- to
1,200-mg dose range. Steady-state clearance was dose independent. AUCss/AUC0 As a drug class, the human
immunodeficiency virus type 1 (HIV-1) protease inhibitors are potent
and selective inhibitors of the HIV-1 protease enzyme (19)
and are capable of potent in vivo antiretroviral activity when combined
with HIV-1 reverse transcriptase inhibitors (5).
Nevertheless, there are differences in the pharmacokinetic profiles and
differences in the type, severity, and frequency of adverse events
associated with the currently available protease inhibitors. New
protease inhibitors are needed to increase the therapeutic options
available to HIV-infected individuals, as treatment failure is not
uncommon and intolerability or side effects can restrict use of the
currently available protease inhibitors.
Amprenavir (formerly 141W94), an N,N-disubstituted hydroxyethylamino
sulfonamide protease inhibitor (molecular mass, 506 Da), is a potent
inhibitor of recombinant HIV-1 protease (Ki = 0.6 nM) (8) and possesses potent in vitro antiviral
activity as demonstrated in a number of cell culture systems using
laboratory HIV strains and clinical isolates (1;
G. R. Painter, M. H. St. Clair, P. DeMiranda, D. Reynolds, S. Ching, R. Dornsife, D. J. Livingston, S. Pazhanisamy, and R. Tung,
Abstr. 2nd Int. Conf. Hum. Retroviruses Relat. Infect., abstr. LB5,
1995). Amprenavir is highly (~90%) bound to proteins in normal human
plasma or serum, with the greatest degree of fractional binding to
Single-dose pharmacokinetic studies of amprenavir in HIV-infected
adults and children have been conducted and have shown that amprenavir
can be given safely at doses of up to 1,200 mg and 20 mg/kg,
respectively (15; B. M. Sadler, G. E. Chittick, R. Yogev, A. Kovacs, Y. Lou, C. Pilati-Stevens, W. T. Symonds, and S. V. Hetherington, submitted for publication). We
report here the multiple-dose pharmacokinetics and pharmacodynamics of
five escalating, parallel, oral doses of amprenavir administered alone or in combination with the HIV reverse transcriptase inhibitor abacavir
in HIV-infected adult subjects (Glaxo Wellcome Protocol PROA1002). The
relationship between steady-state pharmacokinetic parameters and
antiviral activity was examined, as it has been suggested that a direct
correlation exists between protease inhibitor drug exposure and the
magnitude of reduction of HIV RNA (3, 11, 17;
G. L. Drusano, B. M. Sadler, J. Millard, W. T. Symonds, M. Tisdale, C. Rawls, A. Bye, and the 141W94 International Product Development Team, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-16, 1997). The relationship between steady-state pharmacokinetic parameters and safety was also examined. Together, these two pharmacodynamic analyses helped in the characterization of
doses of amprenavir that warranted further exploration in subsequent phase II and phase III studies.
(Preliminary pharmacokinetic data from this study were originally
reported at the 9th International Conference on Antiviral Research,
Fukushima, Japan, 19 to 24 May 1996 [16]. Preliminary pharmacodynamic data from this study were reported at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 28 September to 1 October 1997 [Drusano et
al., 37th ICAAC]. Preliminary clinical safety and efficacy data from
this study were reported at the 36th Interscience Conference on
Antimicrobial Agents and Chemotherapy, New Orleans, La., 15 to 18 September 1996 [R. T. Schooley and the International 141W94 Study
Team, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr.
LB8, 1996], and the final clinical safety and efficacy data have been
submitted for publication [R. T. Schooley, N. Clumeck, R. Haubrich, M. Thompson, S. A. Danner, M. E. van der Ende, D. Sereni, F. Antunes, D. Blake, R. E. Myers, M. Tisdale, J. Millard, N. Mustafa, and P. Nacci, submitted for publication].)
Study population and design.
Sixty HIV-positive subjects
(male and female, 18 years of age or older) were planned to be enrolled
into six treatment cohorts. Study entry criteria were as described by
Schooley et al. (submitted). Briefly, 62 HIV-positive subjects were
sequentially enrolled into one of five amprenavir-only groups, with
enrollment in the only combination treatment group conducted
concurrently with that of the group receiving only amprenavir at 1,050 mg twice daily (b.i.d.). The six treatment cohorts were as follows:
amprenavir at 300 mg b.i.d., amprenavir at 300 mg three times daily
(t.i.d.), amprenavir at 900 mg b.i.d., amprenavir at 1,050 mg b.i.d.,
amprenavir at 1,200 mg b.i.d., and amprenavir at 900 mg b.i.d. in
combination with abacavir at 300 mg b.i.d. After completion of the
4-week treatment period, zidovudine (300 mg b.i.d.) and lamivudine (150 mg b.i.d.) were added to the regimens of subjects who remained in the
amprenavir-only treatment groups, or zidovudine (300 mg b.i.d.),
lamivudine (150 mg b.i.d.), and abacavir (300 mg b.i.d.) were added to
the regimen of subjects who remained in the amprenavir-abacavir group.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.30-37.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Pharmacokinetic and Pharmacodynamic Study of the
Human Immunodeficiency Virus Protease Inhibitor Amprenavir after
Multiple Oral Dosing
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
decreased linearly with dose
and correlated significantly with treatment-associated decreases in
1-acid glycoprotein. After 3 weeks, the dose of 1,200 mg
b.i.d. provided a median amprenavir Cmin,ss (0.280 µg/ml)
that was higher than the median in vitro 50% inhibitory concentration
for clinical HIV isolates (0.023 µg/ml), even after adjustment for
protein binding. The median amprenavir Cmin,ss
was also greater than the estimated in vivo trough concentration
calculated to yield 90% of the maximum antiviral effect (0.228 µg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship
between steady-state pharmacokinetic parameters and safety revealed
headache and oral numbness to be the only side effects significantly
associated with Cmax. The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d.
as the approved dose of amprenavir.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
1-acid glycoprotein (AAG) (89%) and albumin (42%)
(10). The mean 50% inhibitory concentration
(IC50) of amprenavir against 334 HIV clinical isolates is
14.6 ± 12.5 ng/ml (B. M. Sadler, P. J. Piliero, S. L. Preston, Y. Lou, M. Sale, and D. S. Stein, Abstr. 7th Conf.
Retroviruses Opportunistic Infect., abstr. 77, 2000). The metabolism of
amprenavir appears to be primarily dependent upon the CYP3A4 isozyme of
the hepatic cytochrome P450 system, based on in vitro and in vivo studies (4; J. Woolley, S. Studenberg, C. Boehlert,
G. Bowers, A. Sinhababu, and P. Adams, Abstr. 37th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. A-60, 1997).
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
150 and 
400/mm3, no prior HIV protease inhibitor
use, no active infections, and no evidence of malabsorption syndrome.
It should be noted that amprenavir was supplied as a hard gelatin
capsule in this study, a formulation that has since been shown to have
the same bioavailability as the more stable soft gelatin capsule, which
is the formulation now in clinical use. A relative bioavailability
study comparing the pharmacokinetics of the two amprenavir formulations
found no significant difference in area under the concentration-time curve (AUC) between the two formulations (15).
Blood collection.
Blood samples were collected to determine
amprenavir concentration, abacavir concentration, plasma HIV RNA
levels, and hematology and clinical chemistry. Blood samples for
single-dose and multiple-dose plasma drug concentrations were collected
during the scheduled visits on day 1 (amprenavir-only groups) and
during week 3 (all groups), respectively. At both times, samples were
taken prior to the subjects' first dose of the day (predose) and at
0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, and 8.0 h
postdose. Day 1 sampling also included collection at 10.0, 12.0, and
24.0 h postdose. Plasma samples from groups receiving study
medication on a b.i.d. schedule were also collected at 10 and 12 h
postdose during week 3. All subjects were instructed to fast overnight ( 8 h) before the scheduled morning dosing and collection of plasma sample. Water was permitted ad libitum. After the predose plasma
sample collection, subjects took their study medication with 200 ml of
water and fasted until 3 h postdose.
Safety evaluation. Safety and tolerability were evaluated and are described elsewhere (Schooley et al., submitted). Briefly, evaluations were conducted by physical examination, ophthalmologic examination, vital signs, electrocardiogram, hematology, clinical chemistry, AAG, urinalysis, and clinical adverse events.
Efficacy evaluation. Efficacy was evaluated as the time-weighted average decrease in log10 HIV RNA from baseline (AAUCMB) (6, 17, 18; Drusano et al., 37th ICAAC). Plasma samples for viral load determination were collected at predose and at day 4 and weeks 1, 2, 3, and 4. Viral load was measured using the quantitative HIV-1 RNA PCR assay (Roche Amplicor HIV-1 MONITOR); the limit of quantification was 400 copies/ml (12).
Pharmacokinetic evaluation.
Model-independent
pharmacokinetic parameters for amprenavir and abacavir after single or
multiple oral dosing were calculated using WinNonlin Pro version 1.5 (SCI, Cary, N.C.). Single-dose pharmacokinetic parameters included
maximum concentration (Cmax), time of the
maximum concentration (Tmax), apparent terminal
elimination rate constant (
z), and terminal
elimination half-life (t1/2). Individual
estimates of z for amprenavir were obtained
by log-linear regression of the terminal portions of the plasma
concentration-time curves; t1/2 was then
calculated as ln(2)/z. The
AUC0t, from time zero to the time of the last
quantifiable sample (tlast), was calculated for
each subject using the linear trapezoidal rule.
AUC0t was extrapolated from
tlast to infinity (AUC0) by adding Clast/z. The
apparent total clearance (CL/F) was calculated as
dose/AUC0. The apparent volume of distribution during
terminal elimination (Vz/F) was calculated as
(CL/F)/z.
). The Cmax,ss and
Tmax,ss were obtained by inspection of the
individual plasma concentration-time data.
Cmin,ss, the trough drug concentration at steady
state, was calculated as (C0 + C
)/2, where C0 is the
concentration in plasma before dosing and C
is the concentration in plasma for the last sample of the steady-state
dosing interval. The AUC0t from the time of
the predose sample to the last sample of the steady-state dosing
interval was calculated for each subject using the linear trapezoidal
rule. When the last quantifiable sample of the steady-state dosing
interval was not taken at t = ,
C was estimated as
C = Ct · e
z( t) and AUC0t was
extrapolated to (AUCss), the steady-state dosing
interval, by the formula AUCss = AUC0t + Ct/z · [1 
ez(
t)]. Actual sampling times were used to calculate
both single-dose and steady-state pharmacokinetic parameters.
Assay for amprenavir. Concentrations of amprenavir in plasma were quantified using validated and cross-validated reversed-phase high-performance liquid chromatographic methods. Solid-phase extraction or protein precipitation was coupled with fluorescence detection, as previously described (15), or mass spectrometry. The range of detection of amprenavir by fluorescence spectroscopy was 10 to 1,000 ng/ml, and that by mass spectrometry was 10 to 5,000 ng/ml. At least three serially diluted quality control samples were included at the beginning, middle, and end of each assay run. All samples from the runs in which the quality control data were not within control specifications were reassayed. For reporting purposes, concentrations were expressed in micrograms per milliliter. The between-assay bias was <15% for all assays.
Assay for abacavir. Concentrations of abacavir in plasma were determined using a validated, reversed-phase high-performance liquid chromatographic assay with UV detection as previously described (9). The between-assay bias was <6%, and the range of detection of abacavir was 25 to 5,000 ng/ml. For reporting purposes, concentrations were expressed in micrograms per milliliter.
Assay for AAG. Concentrations of AAG in serum were quantified using a validated fixed-time nephelometric method (Quest Diagnostics, Capistrano, Calif.). The limits of quantification were 20 to 660 ng/dl, with an interassay variability of <6%.
Statistical analyses. (i) Single- and multiple-dose pharmacokinetics. Descriptive statistics were performed to compare treatment cohorts. Dose proportionality and linearity for amprenavir pharmacokinetic parameters at day 1 and week 3 were evaluated using the power model (mixed linear models procedure; SAS PROC MIXED) described by the equation log(Y) = a + b · log(dose), where Y is the pharmacokinetic parameter of interest, a and b are the estimated coefficients, and dose is the dose received by each subject (total daily dose for steady state) (7). Dose dependence and independence were determined by the inclusion of 1 and 0 in the 90% confidence interval (CI), respectively, estimated for the slope of the parameter of interest.
To evaluate the effect of abacavir on amprenavir at steady state (data were analyzed after loge transformation), a one-way analysis of variance (SAS PROC MIXED, version 6.12) was used to compare the ratio of the geometric least-squares (GLS) means for amprenavir pharmacokinetic parameters obtained for the 900 mg b.i.d. amprenavir monotherapy and the b.i.d. amprenavir-plus-abacavir combination therapy groups. A similar analysis was used to evaluate the effect of amprenavir on abacavir steady-state pharmacokinetics, in which the amprenavir-plus-abacavir combination therapy group was compared with a historical control group (300 mg, b.i.d., abacavir monotherapy). Two one-sided tests (90% CI) were used to compare the pharmacokinetic parameters AUCss, Cmax,ss, Cmin,ss, Cavg,ss, and CL/Fss. An effect was considered significant if the 90% CI for the ratio of the GLS means fell between 0.70 and 1.43.(ii) Pharmacodynamics.
The relationship between the
steady-state pharmacokinetic parameters Cmax,ss,
Cmin,ss, and Cavg,ss and
antiviral activity (AAUCMB) was examined using simple and sigmoid
Emax models, with and without a baseline effect.
The models were described by the following equations: AAUCMB = Emax · Cpk,ss/(EC50 + Cpk,ss) (simple), AAUCMB = E0 + Emax · Cpk,ss/(EC50 + Cpk,ss) (simple with baseline effect),
AAUCMB = Emax · Cpk,ss
/(EC50 + Cpk,ss) (sigmoid), and AAUCMB = E0 + Emax · Cpk,ss/(EC50 + Cpk,ss) (sigmoid with baseline). In the
equations, Cpk,ss is the steady-state parameter
of interest, Emax is the predicted maximum
effect on AAUCMB, EC50 is the Cpk,ss
producing 50% of the maximal effect, E0 is the
baseline AAUCMB when Cpk,ss is 0, and 
is a
unitless shape parameter for sigmoid models. The equations were used to evaluate each of the parameters after appropriate substitution. Nonlinear curve fitting was performed with WinNonlin Pro version 1.5 (SCI) using an unweighted analysis. Estimates of
Emax, EC50, and were calculated
for the models and used to determine the concentration of amprenavir
that produced various percent changes in AAUCMB.
) and
baseline CD4+-cell count, baseline viral load
(VLbaseline), AAUCMB for CD4+-cell count
(AAUCMBCD4), AAUCMB for viral load (AAUCMBVL),
and the absolute or percent change in AAG (
AAG or %AAG,
respectively). A stepwise regression (SAS PROC Reg.) was applied
to the full model, ln(AUCratio) = AAG (or
%AAG) + CD4baseline + VLbaseline + AAUCMBCD4 + AAUCMBVL + race + sex + ln(dose), to
evaluate the association between the single-dose and steady-state
amprenavir AUCratio and the absolute or percent change from
baseline in AAG concentrations. A reduced model with absolute or
percent change in AAG and ln(dose) would be used to estimate the
association with AUCratio if other covariates were not significant.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subject demographics and accountability. This study was conducted between November 1995 and November 1997 at eight centers in Portugal, Belgium, France, Holland, and the United States. Subject demographics were similar across all treatment groups at baseline. Baseline characteristics were also comparable among all cohorts (median CD4+-cell count range, 254 to 305 cells/mm3; median plasma HIV RNA range, 4.71 to 5.08 log10 copies/ml).
Of the 62 enrolled subjects, 56 completed the 4 weeks of amprenavir treatment to which they were assigned. Five subjects prematurely discontinued treatment; one of these subjects was never treated, and four withdrew due to the following adverse events (Schooley et al., submitted): skin rash (amprenavir at 300 mg t.i.d., one subject), abdominal discomfort and pain with diarrhea (amprenavir at 1,200 mg b.i.d., one subject), skin rash and paresthesia (amprenavir at 1,200 mg b.i.d., one subject), and dysarthia and erythematous skin condition (amprenavir-abacavir, one subject). Fifty-nine subjects had day 1 and/or week 3 plasma amprenavir profiles, 53 subjects had single-dose (day 1) concentration-time profile data, and 55 subjects had multiple-dose (week 3) concentration-time profile data. Irregularities in plasma sampling (i.e., deviations in sampling time) and dosing at individual clinical sites prompted a duplicate analysis of both the single- and multiple-dose plasma profiles used to estimate pharmacokinetic parameters. Two populations were therefore analyzed; one consisted of all subjects and one consisted of "well-characterized" subjects. Subjects were excluded from the well-characterized population on day 1 because of dosing deviations. Either they received the wrong dose to start or they took a second (or third) dose during the 24-h single-dose pharmacokinetic profile. Subjects were excluded from the well-characterized population on week 3 because their dosing history or pharmacokinetic profile clearly indicated that they were not at steady state. Either the recorded time of the prior dose did not fall within 2 h of the dosing interval specified by the protocol or there were gross (i.e., 5- to 10-fold) differences between C0 and C (these should
be equal under true steady-state conditions). Analysis of
pharmacokinetic profiles from either all subjects or well-characterized
subjects yielded similar interpretations of the study results.
In this paper, 36 well-characterized day 1 plasma drug concentration
profiles were included in the analysis of single-dose pharmacokinetic
parameters, and 42 well-characterized week 3 plasma drug concentration
profiles were included in the analysis of the multiple-dose
pharmacokinetic parameters.
Single-dose pharmacokinetics.
Figure
1 shows the median plasma amprenavir
concentration over time after single oral doses of amprenavir
(amprenavir-only cohorts). In individual profiles for each of the
amprenavir-only cohorts (data not shown), the curve was typically
biphasic, with a small second peak occurring between 6 and 12 h
after administration. Variations in the timing of the peak between
individuals damped the effect on the median plasma drug concentration
curves in Fig. 1. It is unclear whether the second peak frequently
observed in the amprenavir single-dose profiles is from a second site
of absorption or from recirculation. Cmax was
rapidly reached at ~1.5 h after dosing; the terminal-phase
t1/2 was ~6 h.
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increased in
a slightly greater-than-dose-proportional manner (slope = 1.239;
90% CI = 1.022 to 1.455). CL/F decreased with increasing dose (slope = 0.239; 90% CI = 0.455 to
0.022). Both t1/2 and
Vz/F were dose-independent.
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Multiple-dose pharmacokinetics. The median plasma amprenavir concentrations over time, after 3 weeks of dosing for each of the five monotherapy regimens, are shown in Fig. 1. For all regimens, Cmax was reached within 1 to 2 h after dosing and amprenavir concentrations declined in a biphasic manner.
The estimated values of the steady-state pharmacokinetic parameters for amprenavir after multiple oral dosing, both alone and in combination with abacavir, are presented in Table 1. Data from 38 well-characterized multiple-dose plasma drug concentration profiles (amprenavir-only cohorts) showed that the amprenavir AUCss (slope = 1.03; 90% CI = 0.77 to 1.28), Cmax,ss (slope = 0.81; 90% CI = 0.56 to 1.07), Cmin,ss (slope = 1.02; 90% CI = 0.67 to 1.38), and Cavg,ss (slope = 0.91; 90% CI = 0.65 to 1.17) increased in a dose-proportional manner. The CL/Fss (slope =0.15; 90%
CI = 0.42 to 0.12) was dose independent. The comparatively larger CL/Fss noted in the group receiving 1,200 mg of amprenavir was due mainly to the exceptionally small
AUCss of one subject; exclusion of this subject from the
analysis reduced the CL/Fss to a value of 1,011 ml/min, which is similar to the value obtained with the 1,050-mg dose
(1,031 mL/min). The mean Tmax was reached within
2.25 h after dosing (range, 0.50 to 3.98 h). The ratio of
AUCss/AUC0 (slope = 0.30; 90%
CI = 0.49 to 0.11) decreased linearly with dose but was not
dose proportional.
Amprenavir-abacavir coadministration. The multiple-dose pharmacokinetic parameters for amprenavir at 900 mg b.i.d. in the presence of abacavir at 300 mg b.i.d. were not different from those observed in the cohort receiving only amprenavir at 900 mg b.i.d. (Table 1). The Cmax,ss was reached at ~2 h after dosing, and plasma amprenavir concentrations declined in a biphasic manner. Abacavir did not alter the characteristic shape of the plasma amprenavir concentration-time curve. Moreover, neither Cmax nor t1/2 for amprenavir appeared to be altered by coadministration with abacavir.
Analysis of five subject profiles showed that in the presence of amprenavir, abacavir multiple-dose pharmacokinetic parameters were not different from those previously reported for monotherapy with abacavir at 300 mg b.i.d. (J. A. McDowell, W. T. Symonds, and S. W. LaFon, Abstr. XI Int. Conf. AIDS, abstr. MoB1140, 1996), with one exception: there were minor differences in Cmax,ss, where the GLS mean ratio between combination and monotherapy regimens was 0.79 (90% CI = 0.63 to 0.99). The median concentrations of abacavir with and without amprenavir are very similar (data not shown).Pharmacodynamics analysis of safety.
Five adverse events
occurring over the 4-week period, i.e., headache (n = 11), nausea or vomiting (n = 12), diarrhea
(n = 12), oral numbness (n = 5), and
rash (n = 4), were selected for analysis of the
relationship between steady-state pharmacokinetic parameters and safety
based on their incidence and potential for pharmacokinetic dependence.
Categorical analysis (Table 2) indicated significant associations between increasing
Cmax,ss and headache (P = 0.01)
and oral numbness (P = 0.02).
Cavg,ss was also associated with oral numbness
(P = 0.02). A trend toward a higher occurrence of
nausea and/or vomiting with higher Cavg,ss was
noted (P = 0.05). Logistic regression analysis found no
significant associations between the incidence of subjects with adverse
events and each pharmacokinetic parameter as a continuous variable,
except for borderline associations with Cmax,ss
(odds ratio = 1.31; 95% CI = 0.99 to 1.82) and
Cavg,ss (odds ratio = 1.06; 95% CI = 0.99 to 1.13) for oral numbness.
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Pharmacodynamics analysis of efficacy.
Four
Emax models were used to examine the
relationship between Cmax,ss,
Cmin,ss, Cavg,ss, and
antiviral activity over 4 weeks in subjects with well-characterized
steady-state pharmacokinetic data. All four models provided a
statistically significant fit to the data (P < 0.0001); however, the sigmoid Emax model
was favored over the other models because it had the lowest Akaike information criterion with a better model fit. Both
Cmin,ss and Cavg,ss were
somewhat better predictors of the decrease in AAUCMB than was
Cmax,ss, based upon the resulting
r2. The relationship between
Cmin,ss and the AAUCMB, with the modeled curve,
is shown in Fig. 2.
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Pharmacodynamics analysis of AAG.
Over the 3-week period
between obtaining day 1 and week 3 pharmacokinetic profiles, the AAG
concentration declined a median of 19.8%. The absolute and percent
changes in AAG level were strongly correlated with
AUCss/AUC0
(r2 = 0.639 and 0.664, respectively;
P < 0.0001 for both). Of all variables tested, only
the percent change in AAG was significantly associated with the
AUCss/AUC0 (P = 0.014,
full model). In the reduced model, with the percent change in AAG and
the ln(dose) as independent predictors, only the percent change in AAG
remained significantly associated with the
AUCss/AUC0 (P = 0.002).
Models using the absolute change in AAG gave findings similar to those
using the percent change.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In this 4-week multiple-dose, dose-escalating study, amprenavir administration, either alone or in combination with abacavir, resulted in a significant exposure-related change in viral load. Safety and tolerability findings were consistent with those of previous single-dose studies (15; Sadler et al., submitted) and with subsequent phase II and III clinical studies (L. Pednealt, A. Fetter, C. Hanson, J. Wilson, P. Nacci, and J. Millard, Abstr. 6th Conf. Retroviruses Opportunistic Infect., abstr. 386, 1999). The most frequently reported drug-related adverse events in this study were of mild intensity. Headache and oral numbness were significantly associated with Cmax. Oral numbness was also significantly associated with Cavg,ss, and a trend toward significance was observed for nausea and/or vomiting with Cavg,ss.
All single-dose and multiple-dose pharmacokinetic analyses were performed using data both from all subjects and from well-characterized subjects. No meaningful difference in the interpretation of the study resulted from the use of pharmacokinetic profiles from all subjects versus well-characterized subjects.
Analyses of the estimates of single-dose amprenavir pharmacokinetic
parameters for amprenavir doses of 300, 900, 1,050, and 1,200 mg showed
Cmax to increase dose proportionally, while
AUC0 increased with increasing amprenavir doses in a
slightly greater-than-dose-proportional manner. The
greater-than-dose-proportional increase in AUC was accompanied by a
corresponding decrease in CL/F with increasing dose. These
findings are consistent with those previously reported for HIV-infected
adults and children (15; Sadler et al., submitted). In the present study, Vz/F was dose independent
and slightly greater than previously reported; previous studies have
found this parameter to be inversely related to amprenavir dose
(15; Sadler et al., submitted). In the present
study, t1/2 was also dose independent.
Amprenavir pharmacokinetics at steady state showed AUCss,
Cmax,ss, Cmin,ss, and
Cavg,ss to be dose proportional (increasing with
increasing doses of amprenavir from 300 to 1,200 mg b.i.d.) and
CL/Fss to be dose independent. These findings
are in contrast to those from a single-dose study in which
within-subject dose proportionality was assessed (15).
Comparison of the single-dose and the steady-state pharmacokinetic
parameters suggests that amprenavir pharmacokinetics are time
dependent, especially with respect to Cmax and
AUC at the higher doses. The AUCss/AUC0 ratios decreased linearly with increasing dose (Table 1), and average
reductions of 29 and 48% from single dose to steady-state dose were
observed for doses of 1,050 mg b.i.d. and 1,200 mg b.i.d., respectively. The median decline in the
AUCss/AUC0 ratio between single- and
multiple-dose sampling across dose groups was 19.3%, which coincided
with a median decline in AAG concentration of 19.8%.
The relationship between AAG and amprenavir concentration was evaluated, since it is known that AAG levels are increased in HIV infection (13) and control of HIV replication with antiretroviral therapy could decrease these levels. The relationship was also investigated to possibly explain the decrease in amprenavir AUC observed after 3 weeks of therapy. A decrease in the AAG concentration would not be expected to produce a decrease in the free amprenavir concentration, and therefore, antiviral activity would not be affected (14). The percent change in AAG, which was almost identical to the percent change in AUC, remained significant in multivariate regression models that included the dose of amprenavir as a variable. Therefore, it seems likely that the decrease in total amprenavir concentration reflects a decrease in the concentration of the principle protein binding molecule.
The lack of dose proportionality in AUC0 found with
the single-dose pharmacokinetics (observed in the present study and in
previous single-dose studies) may be due to saturation of first-pass
metabolism and/or P-glycoprotein-mediated transport. In vitro and in
vivo studies have shown that the metabolism of amprenavir is mediated
primarily by the 3A4 isozyme of the hepatic and intestinal cytochrome
P450 system, and its expression can vary considerably between
individuals. Amprenavir inhibits CYP3A4 to a degree comparable to that
exhibited by indinavir and nelfinavir (Woolley et al., 37th ICAAC), and
since 3A4 expression can vary considerably between individuals, it is
not surprising to find slight, but not significant, differences in
results from study to study. In fact, both the means and medians of
pharmacokinetic parameters from a previous study (15) were
all within the 95% CI of their respective parameters from the present
study. In contrast to the single-dose pharmacokinetics of amprenavir,
the steady-state pharmacokinetics of AUC (AUCss) are dose
proportional, suggesting that either first-pass metabolism or
P-glycoprotein-mediated transport may be functioning at a higher
capacity after multiple dosing.
Although few subject profiles were available to examine the effect of abacavir on amprenavir multiple-dose pharmacokinetics, no effect of the presence of abacavir on amprenavir was observed, and conversely, abacavir pharmacokinetics did not appear to be significantly affected by amprenavir. The lack of an appreciable pharmacokinetic interaction between these drugs was expected, since each is metabolized by different enzymes: abacavir is metabolized primarily by alcohol dehydrogenase and UDP-glucuronyl transferase (J. R. Ravitch, B. J. Bryant M. J. Reese, C. C. Boehlert, J. S. Walsh, J. P. McDowell, and B. M. Sadler, Abstr. 6th Conf. Retroviruses Opportunistic Infect., abstr. 634, 1998). While this does not preclude that induction of UDP-glucuronyl transferase or CYP3A4 has occurred, we did not find evidence of this possible effect. Consequently, these two agents can be administered in combination without adjusting the dosage for either drug.
Analysis of the relationship between steady-state concentrations of amprenavir and decreases in plasma HIV RNA revealed that both Cmin,ss and Cavg,ss were better predictors of the decrease in AAUCMB than was Cmax,ss. Cmin or AUC has been shown to be significantly associated with the antiviral efficacy or development of resistance with ritonavir, saquinavir, and indinavir (3, 11, 17). Modeling of viral load change versus AUCss and Cmin of a subset of the present study's data indicated that Cmin was a better predictor of antiviral efficacy than was AUCss (Drusano et al., 37th ICAAC). The Cmin,ss associated with the amprenavir dose of 1,200 mg b.i.d. would be greater than the IC50 of amprenavir as determined from 334 clinical isolates from subjects without prior protease exposure (IC50 = 14.6 ± 12.5 ng/ml) (Sadler et al., 7th Conf. Retroviruses Opportunistic Infect.) after adjustment for the 90% protein binding of amprenavir and would be similar to the in vivo trough concentration, estimated in the pharmacodynamic model, providing 90% of the maximum antiviral effect over the 4-week study period (EC90 = 0.228 µg/ml). On the basis of findings from the pharmacodynamic model described in this paper, the doses of 900, 1,050, and 1,200 mg b.i.d. were carried forward to phase II studies. The results of the pharmacodynamic model and phase II studies support 1,200 mg b.i.d. as the approved dose of amprenavir.
In summary, the steady-state pharmacokinetics of amprenavir dosed at 1,200 mg b.i.d. indicate that amprenavir can achieve adequate concentrations in plasma in a relatively short time (~2 h) and can maintain adequate trough concentrations. Pharmacodynamic modeling of steady-state parameters supports the selection of the dose of 1,200 mg b.i.d. as being effective in reducing plasma HIV RNA levels.
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ACKNOWLEDGMENTS |
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We thank Cindy M. Rawls for performing the bioanalytical studies, Belinda Ha for assistance in manuscript preparation, the clinical investigators, and all of the subjects who participated in the studies.
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Clinical Pharmacology, Glaxo Wellcome Inc., Research Triangle Park, NC 27709. Phone: (919) 483-1449. Fax: (919) 483-6380. E-mail: BMS44974{at}GLAXOWELLCOME.COM.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, January 2001, p. 30-37, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.30-37.2001
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