Population pharmacokinetics of nevirapine in an unselected cohort of HIV‐1‐infected individuals
Authors: De Maat M. M. R. , Huitema A. D. R. , Mulder J. W. , Meenhorst P. L. , Van Gorp E. C. M. , Beijnen J. H. 
Published: March 2003

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.