Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV‐1‐infected patients

• Published in: British journal of clinical pharmacology 2005-02, Vol.59 (2), p.174-182
• Main Authors: Kappelhoff, Bregt S., Huitema, Alwin D. R., Crommentuyn, Kristel M. L., Mulder, Jan W., Meenhorst, Pieter L., Van Gorp, Eric C. M., Mairuhu, Albert T. A., Beijnen, Jos H.
• Format: Article
• Language: English
• Subjects: Adult; Anti-HIV Agents - pharmacokinetics; Biological and medical sciences; Female; HIV Infections - drug therapy; HIV Protease Inhibitors - pharmacokinetics; HIV-1; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Male; Medical sciences; Middle Aged; Models, Chemical; Pharmacokinetics; Pharmacology. Drug treatments; ritonavir; Ritonavir - pharmacokinetics; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2004.02241.x

Aims The aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics. Methods Ambulatory HIV‐1‐infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir‐containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero‐order and first‐order absorption, with and without absorption lag‐time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored. Results From 186 patients 505 ritonavir plasma concentrations at a single time‐point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one‐compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h−1 (95% prediction interval (95% PI) 9.38–11.7), 96.6 l (95% PI 67.2–121) and 0.871 h−1 (95% PI 0.429–1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7‐fold increase in the clearance of ritonavir (P value