A population pharmacokinetic analysis of nelfinavir mesylate in human immunodeficiency virus-infected patients enrolled in a phase III clinical trial

A population pharmacokinetic analysis was conducted on nelfinavir in patien ts infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations f rom 174 patients who received nelfinavir at a dose of 500 or 750 mg three t imes a day. The analysis was performed using nonlinear mixed-effect modelin g as implemented in NONMEM (version 4.0; double precision). Ii one-compartm ent model with first-order absorption best described the data. The timing a nd small number of early postdose blood levels did not allow accurate estim ation of volume of distribution (V/F) and the absorption rate constant (k(a )). As a result, two models were used to analyze the data: model 1, in whic h oral clearance (CL/F), V/F, and k(a) were estimated, and model 2, in whic h V/F and k(a) were fixed to known values and only CL/F was estimated. Esti mates of CL/F ranged from 41.9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, bas eline viral lend, metabolite-to-parent drug plasma concentration ratio, his tory of liver disease, nor elevated results of liver function tests appeare d to be significant covariates for clearance. The only significant covariat e-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL /F. Patients who received concomitant therapy with fluconazole had a statis tically significant reduction in nelfinavir CL/F of 26 to 30%. Since seriou s dose-limiting toxicity and concentration-related toxicities are not appar ent for nelfinavir, this effect of fluconazole is unlikely to be of clinica l significance.