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 acti vity against human immunodeficiency virus type 1 (HIV-1) and is currently u sed 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 wh o received the study drug for greater than or equal to 4 weeks were conside red for phrarmacokinetic evaluation. Blood samples were obtained at the fol lowing times: 0 (before nelfinavir administration), 1, 2, 3, 4, 6 and 8 h a fter aidministration. Nelfinavir plasma concentrations were analysed by a s pecific and validated HPLC assay with ultraviolet detection. Nelfinavir con centration-time date were analysed by compartmental and non-compartmental t echniques and the pharmacokinetic parameters of nelfinavir were determined according to a one-compartment model. We found a high variability between i ndividuals in nelfinavir plasma concentrations. The mean average drug plasm a concentration was 2.22 +/- 1.25 mg/L and the mean AUC during the dosing i nterval was 17.7 +/- 10.0 mg.h/L. The mean nelfinavir trough plasma concent ration was 1.58 +/- 1.0 mg/L. A good relationship was found between AUC(0-8 h) and the plasma concentrations measured at 6 h, and the trough plasma con centrations made total body exposure for nelfinavir less predictable. Alter natively, 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.