Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study.
OBJECTIVE
The aim of this 2NN pharmacokinetic substudy was to investigate the population pharmacokinetics of nevirapine and efavirenz.


METHODS
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.


RESULTS
Clearance of nevirapine in the induction phase (<14 days) and at steady state (>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.


CONCLUSIONS
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.
Kappelhoff
Bregt S
BS
Slotervaart Hospital, Department of Pharmacy Et Pharmacology, Amsterdam, The Netherlands. apbkp@slz.nl
van Leth
Frank
F
MacGregor
Thomas R
TR
Lange
Joep
J
Beijnen
Jos H
JH
Huitema
Alwin D R
AD
D000328:Adult; D000480:Alkynes; D000704:Analysis of Variance; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D019829:Nevirapine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010078:Oxazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018119:Stavudine / Q000008:administration & dosage
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine; C098320:efavirenz