Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals

Abstract

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor that is frequently used as part of the currently recommended combination therapy in the treatment of HIV-1 infection. NVP has been proven to be safe and effective, but when administered in suboptimal regimens, highly drug-resistant virus emerges rapidly limiting future options for treatment. Patient characteristics (e.g. demographics, co-morbidity) may have a large impact on the pharmacokinetics of nevirapine. Therefore, we explored the population pharmacokinetics of NVP in an unselected cohort of HIV-1-infected individuals. Included patients were ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, The Netherlands. Data were retrospectively collected from January 1997 to April 2000. The pharmacokinetics of NVP were described with a one-compartment model with first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (clearance (CL/F), volume of distribution (V/F), absorption rate constant (Ka)) were estimated. Interindividual (IIV) and interoccasion variability (IOV) were estimated with a proportional error model. Furthermore, the influence of patient characteristics on the pharmacokinetics of NVP were determined. From a small fraction of patients, baseline liver function test results were not available. In order to avoid bias, a covariate was included in the model indicating missing data. From 173 outpatients a total number of 757 NVP plasma concentrations at a single random timepoint and full pharmacokinetic curves of 13 patients were available resulting in a database of 1329 NVP plasma concentrations. CL/F of NVP was 3.49 l h−1 with an IIV and IOV of 28 and 21%, respectively. V/F was 93.1 l (IOV=46%) and the Ka was 1.65 h−1 (IIV=60%). CL/F of NVP was correlated with weight (WT), chronic hepatitis C infection (HepC), ASAT>1.5×upper limit of normal (ULN) at baseline, and the black race (RACE). These correlations are described by the following equation: CL/F=(3.49+0.0205×[WT-70])×0.483HepC× 0.66ASAT×(1−MISS)×0.671MISS×0.731RACE, in which HepC is 1 for individuals with hepatitis C infection and 0 for all others, ASAT is 1 for patients with baseline ASAT>1.5×ULN and 0 for all others, MISS is 1 for patients with no baseline ASAT value and 0 for all others, and RACE is 1 for black patients and 0 for all others. Thus, HepC, ASAT>1.5×ULN, and the black race reduce CL/F of NVP by 52%, 34%, and 27%, respectively, whereas an increase in WT of 10 kg increases the CL/F by 0.21 l h−1. The pharmacokinetics of NVP were adequately described with the developed population pharmacokinetic model. Weight, chronic hepatitis C infection, baseline ASAT>1.5×ULN, and the black race were found to be significant covariates for CL/F of NVP. The described model including these significant covariates could be an aid in optimizing NVP-containing therapy.