| |
DONUT: The Pharmacokinetics (PK) of Once Daily Nevirapine (NVP) and Efavirenz (EFV) When Used in Combination A. I. VELDKAMP*1, R. M. W. HOETELMANS1, J. H. BEIJNEN1, M. HARRIS2, J. S. G. MONTANER2, M. YOULE3, W. HUTMAN4, H. CARLIER5, B. GAZZARD6, and J. M. A. LANGE7.
1Slotervaart Hosp., Amsterdam; 2St. Paul's Hosp., Vancouver, Canada; 3Royal Free Hosp., London; 4SFBC, Miami, FL; 5Boehringer Ingelheim Intl.; 6Chelsea & Westminster Hosp., London, UK; and 7Natl. AIDS Therapy Evaluation Ctr., Amsterdam, The Netherlands Introduction: To date, no data are available on the PK of the combined use of NNRTIs. Since NVP and EFV can induce and/or inhibit CYP450 isoenzymes, a PK interaction cannot be ruled out. This study was conducted to investigate the PK of NVP and EFV when administered in combination.
Methods: HIV-1-infected individuals who already used EFV (600 mg qd) for at least two weeks were included. The PK of EFV were determined during 24 hours at baseline. Subsequently, NVP was added to the regimen: the first 2 weeks at 200 mg qd, followed by 400 mg qd. The PK of EFV and NVP were assessed on day 29. The following PK parameters were determined: area under the plasma concentration versus time curve (AUC0-24h), maximum (Cmax), and minimum (Cmin) plasma concentrations. The PK of NVP were compared with historical controls. Differences in EFV PK with and without NVP were analysed using the Wilcoxon matched pairs signed ranks test.
Results: 12 patients (of a total of 20 patients to be enrolled) were analysed thus far. Plasma HIV-1 RNA was below 400 copies/mL in 10/12 patients. No changes in HIV-1 RNA were observed during the study. Median EFV PK parameters on day 1 and day 29, respectively, were: (AUC0-24h), 54.06 and 35.58 h*mg/L (p=0.002); Cmax: 3.56 and 3.09 mg/L (p=0.10), and Cmin: 1.26 and 0.96 mg/L (p=0.002). Median NVP PK parameters on day 29 were: (AUC0-24h): 107.16 h*mg/L; Cmax: 5.76 mg/L; and Cmin: 3.48 mg/L.
Conclusions: NVP PK are not affected by the coadministration of EFV. The exposure to EFV, however, is significantly decreased by approximately 22% (measured as AUC), and 36% (measured as Cmin) when combined with NVP. It may be appropriate to increase the dose of EFV to 800 mg qd.
Key Words: efavirenz, nevirapine, pharmacokinetics
|
