2011 - Athens - Greece

PAGE 2011: Infection
Monia Guidi

Population Pharmacokinetics of Nevirapine in HIV-positive Patients

M. Guidi (1), M. Arab-Alameddine (1) (3), M. Rotger (2), M. Aouri (1), A. Telenti (2), L.A. Decosterd (1), T. Buclin (1), C. Csajka (1) (3)

(1) Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland; (2) Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland; (3) Department of Pharmaceutical Sciences, University of Geneva, Geneva Switzerland

Objectives: The aim of this observational study was to determine the population pharmacokinetic parameters of nevirapine, their variability, and to identify factors which might explain variations in drug levels in HIV+ patients. Simulations were performed to predict the concentrations at trough associated with the 400 mg once-daily (q.d) and the 200 mg twice-daily (b.i.d) dosage regimens and to compare their probability to stay over the suggested minimum target level of 3000 ng/mL.  

Methods: The analysis was performed on plasma samples of HIV infected patients of the Swiss HIV cohort study receiving nevirapine as part of their anti-retroviral therapy. A one compartment model with first order absorption and elimination was used to fit the data using NONMEM. Co-administered drugs and demographic, clinical variables and genetic polymorphisms of CYP2B6 and CYP3A4 were tested as covariates.    

Results: 734 plasma concentrations from 370 patients were included in the analysis. Average oral clearance was 3.1 L/hr (CV 31%), volume of distribution 97 L (CV 56%) and the absorption rate constant 0.98 h-1. Among all the evaluated covariates, body weight, concomitant administration of atazanavir/ritonavir (n = 62), elevated ASAT (n = 39), inducers of CYP3A4 (n = 10) and the CYP2B6*6 and CYP3A4*1B alleles significantly affected nevirapine clearance, however explaining only 4% of interpatient variability altogether. Simulated average concentrations at trough after 400 mg q.d or 200 mg b.i.d were 3964 ng/ml (95% prediction interval 1476-7746 ng/ml) and 4990 ng/ml (95% prediction interval 2162-9302 ng/ml), respectively. Taking into account variability, 64% and 82% of the simulated individual concentrations at trough would reach the therapeutic target of 3000 ng/ml in naïve patients, after 400 mg q.d and 200 mg b.i.d, respectively.     

Conclusion: The covariates identified as significant on NVP clearance had a limited impact on explaining interpatient variability. Concentration exposure appears less frequently maintained over the target trough level with the 400 mg q.d. regimen than with the currently recommended 200 mg b.i.d regimen, which could counterbalance the potential advantages of q.d. prescription regarding adherence.

Reference: PAGE 20 (2011) Abstr 2191 [www.page-meeting.org/?abstract=2191]
Poster: Infection