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Antimicrobial Agents and Chemotherapy, July 2000, p. 1832-1837, Vol. 44, No. 7
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

A Population Pharmacokinetic Analysis of Nelfinavir Mesylate in Human Immunodeficiency Virus-Infected Patients Enrolled in a Phase III Clinical Trial

Kimberley A. Jackson,1,dagger Sara E. Rosenbaum,1,* Bradley M. Kerr,2 Yazdi K. Pithavala,2 Geoffrey Yuen,2,Dagger and Michael N. Dudley1,§

Department of Applied Pharmaceutical Science, University of Rhode Island, Kingston, Rhode Island,1 and Agouron Pharmaceuticals, La Jolla, California2

Received 14 December 1999/Returned for modification 26 February 2000/Accepted 11 April 2000

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.

* Corresponding author. Mailing address: Department of Applied Pharmaceutical Science, University of Rhode Island, 41 Lower College Rd., Kingston, RI 02881. Phone: (401) 874-5021. Fax: (401) 874-2181. E-mail: sarar{at}uri.edu.

dagger Present address: Globomax, Hanover, Md.

Dagger Present address: Glaxo Wellcome Inc., Research Triangle Park, N.C.

§ Present address: Microcide Pharmaceuticals, Mountain View, Calif.

Antimicrobial Agents and Chemotherapy, July 2000, p. 1832-1837, Vol. 44, No. 7
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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