Population pharmacokinetic analysis of indinavir in HIV-infected patient treated with a stable antiretroviral therapy.
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 co-medications 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.
Brendel
Karl
K
INSERM E0357, Department of Epidemiology, Biostatistics and Clinical Research, AP-HP, Bichat University Hospital, Paris, France. karl.brendel@bch.ap-hop-paris.fr
Legrand
Mayeule
M
Taburet
Anne-Marie
AM
Baron
Gabriel
G
Goujard
Cécile
C
Mentré
France
F
D000328:Adult; D000368:Aged; D000465:Algorithms; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D001499:Bayes Theorem; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011153:Population; D012737:Sex Factors
D017320:HIV Protease Inhibitors; D019469:Indinavir