Date of Original Version
Applied Pharmaceutical Sciences
A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (ka ). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F),V/F, and ka were estimated, and model 2, in which V/F and ka were fixed to known values and only CL/F was estimated. Estimates 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, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-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 statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.
Jackson, K. A., Rosenbaum, S. E., Kerr, B. M., Pithavala, Y. K., Yuen, G., & Dudley, M. N. (2000). A Population Pharmacokinetic Analysis of Nelfinavir Mesylate in Human Immunodeficiency Virus-Infected Patients Enrolled in a Phase III Clinical Trial. Antimicrobial Agents and Chemotherapy, 44(7), 1832-1837. doi: 10.1128/AAC.44.7.1832-1837.2000
Available at: http://dx.doi.org/10.1128/AAC.44.7.1832-1837.2000