Compartmental pharmacokinetic analysis of oral amprenavir with secondary peaks.

TitleCompartmental pharmacokinetic analysis of oral amprenavir with secondary peaks.
Publication TypeJournal Article
Year of Publication2007
AuthorsOkusanya O, Forrest A, DiFrancesco R, Bilic S, Rosenkranz S, Para MF, Adams E, Yarasheski KE, Reichman RC, Morse GD
Corporate AuthorsACTG 5043 Protocol Team
JournalAntimicrob Agents Chemother
Volume51
Issue5
Pagination1822-6
Date Published2007 May
ISSN0066-4804
KeywordsAdministration, Oral, Adult, Aged, Anti-HIV Agents, Carbamates, Female, Humans, Male, Middle Aged, Models, Biological, Sulfonamides
Abstract

Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

DOI10.1128/AAC.00570-06
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID17283195
PubMed Central IDPMC1855557
Grant ListM01 RR00034 / RR / NCRR NIH HHS / United States
M01 RR00036 / RR / NCRR NIH HHS / United States
M01 RR00037 / RR / NCRR NIH HHS / United States
M01 RR00044 / RR / NCRR NIH HHS / United States
M01 RR00051 / RR / NCRR NIH HHS / United States
M01 RR00052 / RR / NCRR NIH HHS / United States
M01 RR00070 / RR / NCRR NIH HHS / United States
M01 RR00750 / RR / NCRR NIH HHS / United States
R01 DK049393 / DK / NIDDK NIH HHS / United States
R01 DK049393-09A1 / DK / NIDDK NIH HHS / United States
R01 DK059531 / DK / NIDDK NIH HHS / United States
R01 DK059531-01 / DK / NIDDK NIH HHS / United States
R01 DK059531-02 / DK / NIDDK NIH HHS / United States
R01 DK059531-03 / DK / NIDDK NIH HHS / United States
R01 DK059531-04 / DK / NIDDK NIH HHS / United States
R01 DK059531-05 / DK / NIDDK NIH HHS / United States
U01 AI25859 / AI / NIAID NIH HHS / United States
U01 AI25903 / AI / NIAID NIH HHS / United States
U01 AI25924 / AI / NIAID NIH HHS / United States
U01 AI27658 / AI / NIAID NIH HHS / United States
U01 AI27664 / AI / NIAID NIH HHS / United States
U01 AI27666 / AI / NIAID NIH HHS / United States
U01 AI27668 / AI / NIAID NIH HHS / United States
U01 AI32770 / AI / NIAID NIH HHS / United States
U01 AI38855 / AI / NIAID NIH HHS / United States
U01 AI38858 / AI / NIAID NIH HHS / United States