Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study

• Published in: Antiviral therapy 2005, Vol.10 (1), p.145-155
• Main Authors: KAPPELHOFF, Bregt S, VAN LETH, Frank, MACGREGOR, Thomas R, LANGE, Joep M. A, BEIJNEN, Jos H, HUITEMA, Alwin D. R
• Format: Article
• Language: English
• Subjects: Adult; Analysis of Variance; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - blood; Anti-HIV Agents - pharmacokinetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral Therapy, Highly Active; Antiviral agents; Benzoxazines; Biological and medical sciences; Female; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - metabolism; HIV-1; Humans; Lamivudine - administration & dosage; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Models, Biological; Nevirapine - administration & dosage; Nevirapine - blood; Nevirapine - pharmacokinetics; Oxazines - administration & dosage; Oxazines - blood; Oxazines - pharmacokinetics; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - blood; Reverse Transcriptase Inhibitors - pharmacokinetics; Stavudine - administration & dosage
• ISSN: 1359-6535; 2040-2058
• DOI: 10.1177/135965350501000114

The aim of this 2NN pharmacokinetic substudy was to investigate the population pharmacokinetics of nevirapine and efavirenz. Treatment-naive, HIV-1-infected patients received nevirapine (once or twice daily), efavirenz or a combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Using non-linear mixed effects modelling, pharmacokinetics of nevirapine and efavirenz and factors involved in the inter-individual variability were investigated. Clearance of nevirapine in the induction phase (28 days) were 2.02 I/h and 2.81 I/h, respectively. Volume of distribution and absorption rate constant were 77.0 l and 1.66 h(-1), respectively. Clearance of nevirapine was lower in females (13.8%) and in patients with hepatitis B (19.5%). Patients from South America and Western countries had higher clearance of nevirapine compared with Thai and South African patients. The clearances of efavirenz in the induction phase and at steady state were 7.95 l/h and 8.82 l/h, respectively. The volume of distribution and absorption rate constant were 4181 and 0.287 h(-1), respectively. Concomitant use of nevirapine increased clearance of efavirenz (43%). Patients from Thailand had lower clearance than the rest of the population. The population pharmacokinetics of nevirapine and efavirenz were assessed in the 2NN trial. For both drugs, an induction phase was distinguished from the steady-state phase. Gender, hepatitis B and geographical region were involved in the variability of the pharmacokinetics of nevirapine. Region and concomitantly used nevirapine were determinants of the pharmacokinetics of efavirenz.