title: A population pharmacokinetic analysis of nelfinavir mesylate in human immunodeficiency virus-infected patients enrolled in a phase III clinical trial.
abstract: 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 (k(a)). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F), V/F, and k(a) were estimated, and model 2, in which V/F and k(a) 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.
authors.affiliation: Department of Applied Pharmaceutical Science, University of Rhode Island, Kingston, Rhode Island, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Jackson
authors.forename: S E
authors.initials: SE
authors.lastname: Rosenbaum
authors.forename: B M
authors.initials: BM
authors.lastname: Kerr
authors.forename: Y K
authors.initials: YK
authors.lastname: Pithavala
authors.forename: G
authors.initials: G
authors.lastname: Yuen
authors.forename: M N
authors.initials: MN
authors.lastname: Dudley
mesh_terms: D000328:Adult; D003710:Demography; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D017320:HIV Protease Inhibitors; D019888:Nelfinavir