PHARMACOKINETICS AND DISPOSITION Eric Dailly Æ Eric Billaud Æ Ve´ ronique Reliquet Se´ bastien Breurec Æ Philippe Perre´ Æ Sophie Le´ autez Pascale Jolliet Æ Michel Bourin Æ Franc¸ ois Raffi No relationship between high nevirapine plasma concentration and hepatotoxicity in HIV-1-infected patients naive of antiretroviral treatment or switched from protease inhibitors Received: 2 February 2004 / Accepted: 30 March 2004 / Published online: 20 May 2004 Ó Springer-Verlag 2004 Abstract Objective: A prospective population pharma- cokinetic study of nevirapine (NVP) was performed to test the relationship between hepatotoxicity and NVP trough plasma concentration and to identify which covariates could influence NVP pharmacokinetics. Methods: All patients [77 HIV-1 (human immunodefi- ciency virus type 1)-infected patients (128 samples)] were either on first-line antiretroviral therapy or swit- ched from successful therapy containing protease inhibitor. Population pharmacokinetic parameters were estimated by a non-linear mixed-effect modelling method. Hepatotoxicity was evaluated by ASAT (aspartate aminotransferase) plasma level. Results: No correlation was found between high NVP trough plasma concentration and high ASAT level or the increase of ASAT level on NVP therapy. Age and Caucasian race were found to be significant covariates of NVP clearance (Cl/F). Population pharmacokinetic parameters (rate absorption constant=1.04 h )1 ; Cl/ F=3.31 h )1 ; apparent volume of distribution=92 l) are consistent with previous studies. Conclusion: High NVP trough plasma concentrations are not correlated with hepatotoxicity in our popula- tion. NVP clearance is decreased in the elderly patients, suggesting a potential increase of NVP plasma level and the interest of therapeutic drug monitoring for this population. Keywords Nevirapine Æ Hepatotoxicity Æ Therapeutic drug monitoring Introduction Various studies suggest that a relationship exists between therapeutic or toxic effects of protease inhibitors or non- nucleoside reverse-transcriptase inhibitors (NNRTI) used in the treatment of HIV-1 (human immunodeficiency virus type 1)-infected patients and plasma concentrations of these drugs [1]. Efavirenz and nevirapine (NVP) are the main NNRTI that are used in therapy. The relationship between plasma concentration and toxic or virological response was demonstrated for efavirenz [2]. For NVP, this relationship was established for efficacy [3]. Several studies evaluated the correlation between NVP plasma level and liver toxicity, showing inconsistent results. Gonzalez De Requena et al. found that the median NVP plasma concentration in subjects who developed any grade of hepatotoxicity was significantly higher than in patients without transaminase elevation [4]. In contrast, De Maat et al. concluded after a retrospective population analysis that the plasma concentration of NVP does not appear to be a predictive factor of hepatotoxicity [5]. To resolve this discrepancy, a prospective population phar- macokinetics study was performed. The goals of this study were: (i) to investigate the correlation between hepato- toxicity estimated by ASAT (aspartate aminotransferase) plasma level, which is a marker of hepatic cytolysis on NVP therapy and NVP trough plasma concentration and (ii) to identify which covariates could affect NVP pharmacokinetics and explain inter-individual variability of NVP plasma level. E. Dailly Æ P. Jolliet Æ M. Bourin Department of Pharmacology, Hoˆtel Dieu, Nantes, France E. Billaud Æ V. Reliquet Æ S. Breurec Æ F. Raffi Nantes reference center for HIV disease, Hoˆtel Dieu, Nantes, France P. Perre´ Æ S. Le´autez Department of Medicine, La Roche sur Yon Hospital, La Roche sur Yon, France E. Dailly (&) Laboratoire de Pharmacologie clinique, Hoˆtel Dieu, 9 Quai Moncousu, 44093 Nantes Cedex, France E-mail: eric.dailly@chu-nantes.fr Tel.: +33-2-40084095 Fax: +33-2-40083996 Eur J Clin Pharmacol (2004) 60: 343–348 DOI 10.1007/s00228-004-0769-5