Clinical pharmacokinetics of nelfinavir combined with efavirenz and stavudine during rescue treatment of heavily pretreated HIV-infected patients.
Nelfinavir is a novel protease inhibitor that exhibits good inhibitory activity against human immunodeficiency virus type 1 (HIV-1) and is currently used in combination with reverse transcriptase inhibitors for the management of HIV infection. In this study we analysed the pharmacokinetic profile of nelfinavir after multiple oral doses in 18 HIV-infected patients during a combination regimen of nelfinavir plus efavirenz and stavudine. Patients who received the study drug for >/=4 weeks were considered for pharmacokinetic evaluation. Blood samples were obtained at the following times: 0 (before nelfinavir administration), 1, 2, 3, 4, 6 and 8 h after administration. Nelfinavir plasma concentrations were analysed by a specific and validated HPLC assay with ultraviolet detection. Nelfinavir concentration-time data were analysed by compartmental and non-compartmental techniques and the pharmacokinetic parameters of nelfinavir were determined according to a one-compartment model. We found a high variability between individuals in nelfinavir plasma concentrations. The mean average drug plasma concentration was 2.22 +/- 1.25 mg/L and the mean AUC during the dosing interval was 17.7 +/- 10.0 mg*h/L. The mean nelfinavir trough plasma concentration was 1.58 +/- 1.0 mg/L. A good relationship was found between AUC(0-8h) and the plasma concentrations measured at 6 h, and the trough plasma concentrations made total body exposure for nelfinavir less predictable. Alternatively, a 2 h abbreviated AUC provides a good estimate of the full AUC(0-8h). Comparing the pharmacokinetic parameters obtained in our patients with those reported for patients receiving nelfinavir monotherapy or nelfinavir combined with nucleoside analogues, one observes substantial overlap with nelfinavir concentrations achieved without efavirenz.
Regazzi
M B
MB
Department of Pharmacology and Department of Infectious Diseases, IRCCS Policlinico S. Matteo, P. le Golgi 2, 27100 Pavia, Italy. regazzim@smatteo.pv.it
Villani
P
P
Maserati
R
R
Seminari
E
E
Pan
A
A
LoCaputo
F
F
Gambarana
E
E
Fiocchi
C
C
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D048588:Benzoxazines; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D008297:Male; D019888:Nelfinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010078:Oxazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018119:Stavudine / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D018119:Stavudine; D019888:Nelfinavir; C098320:efavirenz