K. Brendel(1), M. Legrand(2), A.M. Taburet(3), G. Baron(1), C. Goujard(4), F. Mentré(1) and the Cophar-1 study group.
(1) INSERM E0357, Department of Epidemiology, Biostatistics and Clinical research, AP-HP, Bichat University Hospital
(2) Clinical Pharmacology Department, AP-HP, Pitié-Salpétrière University Hospital
(3)Clinical Pharmacy, AP-HP, Bicêtre University Hospital
(4)Internal Medicine, AP-HP, Bicêtre University Hospital
Objectives: The objectives of this study were to build a population pharmacokinetic model that describes plasma concentrations of indinavir in HIV-infected patients with sustained virological response under a stable antiretroviral combination, and to determine inter and intra-individual variability[1].
Methods: Data were obtained from 45 patients who received different doses of indinavir; among them, 14 received ritonavir booster[2]. Patients were required to have a baseline plasma HIV RNA < 200 copies/ml and to have unchanged antiretroviral treatment for 6 months. Indinavir concentrations were measured at the first visit (before and after drug intake, 5 samples) and at a second visit two to three month later (before and 1 or 3 h after drug intake). From the final model, simulations of the range of pseudo-observed individual steady-state trough concentrations were done for two usual dosage regimen: 800 mg tid for indinavir alone and 800 mg bid for indinavir with 100 mg bid of ritonavir (with 200 patients for each group of combination of covariates).
Results: The population analysis was performed with the First Order method by using WinNonMix. A one compartiment model with first order absorption and first order elimination best described the data. For patients treated with indinavir alone, absorption rate constant was 0.43 h-1, and oral clearance (Cl/F) was 33 L/h; they were 0.25 h-1and 19 L/h respectively for patients treated with indinavir plus ritonavir. Cl/F was found to increase by 1.45 fold in men and by 1.18 fold in patients with zidovudine. Oral volume of distribution (V/F) was 24 L. The inter-individual and intra-individual variability were 117 % and 205 % for V/F, 42 % and 58 % for Cl/F respectively. With simulations, the median, the 10 and 90 percentiles were the highest for women who did not take AZT and the lowest for men who took AZT, both with and without ritonavir.
Conclusions:
In this population analysis, we showed the effect of ritonavir on the absorption rate constant and on the clearance of indinavir. We also quantified a large inter and intra-individual variability. A population model including inter-occasion variability had never been implemented in WinNonMix before this study.
References:
[1] Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 1993;21(6):735-50.
[2] Hsu A, Granneman GR, Cao G, Carothers L, Japour A, Shourbagy T. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998;42(11) :2784-91.
Reference: PAGE 12 () Abstr 369 [www.page-meeting.org/?abstract=369]
Poster: poster