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Population pharmacokinetic analysis of indinavir in HIV‐infected patient treated with a stable antiretroviral therapy
Author(s) -
Brendel Karl,
Legrand Mayeule,
Taburet AnneMarie,
Baron Gabriel,
Goujard Cécile,
Mentré France
Publication year - 2005
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2005.00315.x
Subject(s) - indinavir , antiretroviral therapy , pharmacokinetics , human immunodeficiency virus (hiv) , medicine , population , population pharmacokinetics , sida , virology , pharmacology , viral load , viral disease , environmental health
The objectives of this study were to build a population pharmacokinetic model that describe plasma concentrations of indinavir in human immunodeficiency virus (HIV)‐infected patients with sustained virological response under a stable antiretroviral combination, and to characterize the effect of covariates and comedications on indinavir pharmacokinetics. Data were obtained from 45 patients who received different dosages of indinavir: either indinavir alone t.i.d. (mostly 800 mg), either indinavir b.i.d. (mostly 800 mg) with a booster dose of 100 mg of ritonavir. 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 a first visit (one sample before drug administration and five after) and at a second visit 3 months later (before and 1 or 3 h after drug administration). A one‐compartment model with first‐order absorption and first‐order elimination best described indinavir pharmacokinetics. For patients treated with indinavir alone, absorption rate constant was estimated to be 0.43/h, and oral clearance Cl / F was 33 L/h. For patients treated with indinavir plus ritonavir these estimates were 0.25/h and 19 L/h, respectively. Cl / F was found to increase by 1.45‐fold in men and by 1.18‐fold in patients also receiving 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. This population analysis in patients with sustained virological response, quantified the effect of ritonavir on the absorption rate constant and on the clearance of indinavir, showed an increase of Cl / F in men and can be used to draw reference curve for therapeutic drug monitoring.