JAC Advance Access originally published online on June 30, 2008
Journal of Antimicrobial Chemotherapy 2008 62(4):784-792; doi:10.1093/jac/dkn268
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Original research |
Once- or twice-daily dosing of nevirapine in HIV-infected adults: a population pharmacokinetics approach
1 ‘Lluita contra la SIDA’ Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 2 Universidad Autónoma de Barcelona, Barcelona, Spain 3 Centre d'Investigació del Medicament, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 4 ‘IrsiCaixa’ Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 5 Department of Internal Medicine, Hospital de Vic, Vic, Spain 6 Department of Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Received 1 April 2008; returned 19 May 2008; revised 30 May 2008; accepted 3 June 2008
* Correspondence address. Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet, s/n, 08916 Badalona, Barcelona, Spain. Tel: +34-93-497-88-87; Fax: +34-93-465-76-02; E-mail: jmolto{at}flsida.org
Objectives: The aim of this study was to develop and validate a population pharmacokinetic model for nevirapine in a population of HIV-infected adults and to evaluate the influence of nevirapine dosing regimen and patient characteristics on nevirapine trough concentration.
Methods: HIV-infected adults receiving oral nevirapine for at least 4 weeks were included. A concentration–time profile was obtained for each patient, and nevirapine concentrations in plasma were determined by HPLC. Pharmacokinetic parameters, inter-individual variability and residual error were estimated using non-linear mixed effects modelling. The influence of patient characteristics on the pharmacokinetics of nevirapine was explored, and the predictive performance of the final model was evaluated in an external data set of observations.
Results: Totals of 40 and 18 Caucasian patients were included in two data sets for model building and model validation, respectively. A mono-compartmental model with first-order absorption and elimination best described the pharmacokinetics of nevirapine. Body weight influenced oral clearance (CL/F) and volume of distribution (V/F). The estimated population pharmacokinetic parameters (inter-individual variability) for an individual weighing 70 kg were CL/F 2.95 L/h (24%), V/F 95.2 L (30%) and ka 1.8 h–1 (96%). The final model predicted nevirapine concentrations in the external model-validation data set with no systematic bias and adequate precision. Bayesian estimates of nevirapine trough concentrations were lower when nevirapine was administered once instead of twice daily, and nearly half of the patients weighing 90 kg had drug concentrations <3.0 mg/L when nevirapine was dosed once daily.
Conclusions: A population model to describe the pharmacokinetics of nevirapine was developed and validated in HIV-infected patients. Body weight influenced CL/F and V/F. Based on Bayesian estimates of individual nevirapine concentrations, twice- instead of once-daily administration of nevirapine would be more optimal in patients weighing >70 kg.
Keywords: antiretroviral agents , non-linear mixed effects models , suboptimal concentrations , body weight