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

Abstract

AimsTo study the population pharmacokinetics of nevirapine and to identify relationships between patient characteristics and pharmacokinetics in an unselected population of patients attending our outpatient clinic. Methods Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital who were being treated with a nevirapine-containing regimen were included. During each visit, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters. Variables that were collected at baseline were serology for hepatitis B (HBV) and C (HCV) viruses, liver enzymes, and total bilirubin (TBR). In addition, information about concomitant use of St John's wort and patient demographics were included. The pharmacokinetics of nevirapine were described by first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (apparent clearance (CL/ F ), volume of distribution ( V / F ), absorption rate constant ( k a )) were estimated, as were interindividual, interoccasion, and residual variability in the pharmacokinetics. The influence of patient characteristics on the pharmacokinetics of nevirapine was determined.Results From 173 outpatients a total number of 757 nevirapine plasma concentrations at a single random time point and full pharmacokinetic curves for 13 patients were available resulting in a database of 1329 nevirapine plasma concentrations. Mean CL/ F , V / F , and k a were 3.27 l h -1 , 106 l, and 01.66 h -1 , respectively. CL/ F of nevirapine was correlated with weight, chronic HCV infection, and baseline aspartate aminotransferase (ASAT). Chronic HCV and baseline ASAT > 1.5 ¥ upper limit of normal (ULN) decreased CL/ F by 27.4% and 13.2%, respectively, whereas an increase in body weight of 10 kg increased CL/ F by 0.14 l h -1 . A trend towards a lower CL/ F in patients of the Negroid race was observed. No significant covariates were found for V / F . Conclusions The pharmacokinetics of nevirapine were adequately described by our population pharmacokinetic model. Weight, chronic HCV infection, and baseline ASAT were found to be significant covariates for CL/ F of nevirapine. The model incorporating these significant covariates may be an important aid in further optimizing nevirapine-containing therapy.

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

“…The estimates from the final population pharmacokinetic model of CL/F, V/F and k a are consistent with previous reports of nevirapine population pharmacokinetics in other populations [24][25][26]. In our study, rifampicin induced the metabolism of nevirapine, seen as an increase in its CL/F by 37.4%, which is in agreement with previous reports of rifampicin altering the pharmacokinetics of nevirapine [4,9,10,12,13].…”

“…Consequently, weight and albumin level seem to reflect metabolic disturbances, and a positive correlation between albumin and weight has been found in HIVinfected patients [41]. An increase in clearance with weight has been reported [25,42], but the inclusion of weight in the model did not explain variability in CL/F, neither as the only covariate for CL/F or in combination with other covariates. Weight was therefore not included in the final model as a predictor of variability in CL/F.…”

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

“…Interestingly, the effect of nevirapine induction on CYP2B6 activity leads to an increased concentration of 3-hydroxynevirapine and a lower concentration of the 2-hydroxynevirapine metabolite formed through the CYP3A pathway. The pharmacokinetic characteristics of parent nevirapine in the present study agree with those of previous studies conducted in patients or volunteers after a single dose or at steady state, a finding which clearly demonstrates the autoinducing properties of nevirapine (10,(19)(20)(21)(22)(23)(24)(25)(26)(27). Indeed, the two populations studied herein differ by their ethnicity, demographics, and HIV infection status; the CYP2B6 *1*6 genetic polymorphism frequency is very close, but the significant difference remains when clearances are weight normalized (0.83 ml/ min/kg versus 0.29 ml/min/kg).…”

Evaluation of Saliva as an Alternative Matrix for Monitoring Plasma Zidovudine, Lamivudine and Nevirapine Concentrations in Rwanda

“…In plasma, the inter patient variability of antiretroviral drugs has been reported by us [11,12] and by others [22,23] and has been attributed to genetic influences, diet and/or presence of other drugs and diseases [24][25][26]. In saliva, the parameters responsible for drug concentration variations may be salivary flow rate, salivary pH, and drug pharmacokinetics.…”