Population Pharmacokinetics Of Nelfinavir In HIV-1-Infected Children
R.A.A. Mathôt1, R.P.G. van Heeswijk1, H.J. Scherpbier2, L.A. de Koning3, H.S.A. Heymans2, J.M.A. Lange3, J.H. Beijnen1, R.M.W. Hoetelmans1
1) Dept. Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, 2) Dept. Pediatrics, Emma Children Hospital, Academic Medical Center, Amsterdam, 3) National AIDS Therapy Evaluation Center, Dept. Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
Objective: The population pharmacokinetics (PK) of nelfinavir were assessed in human immunodeficiency virus type 1 (HIV-1)-infected children receiving nelfinavir 30 mg/kg tid or 45 mg/kg bid in combination with stavudine and lamivudine in an open label study (NAP-2).
Patients and methods: Sixteen patients (mean age 5.4 years; range 0.1-10.6) received nelfinavir 30 mg/kg tid (n=12) or 45 mg/kg (n=4) bid. After at least 7 days of dosing, the patients were admitted to the hospital for the assessment of a PK profile of nelfinavir during one dosing interval. In 7 patients PK sampling was performed on a second occasion after switching from the tid to the bid regimen (same daily dose). Covariates considered during nonlinear mixed-effect modelling (NONMEM) analysis included demographic and pathophysiological parameters and comedication.
Results: A total of 23 PK curves (222 samples) were included in the analysis. A one-compartment model with first-order absorption and lag time (Tlag) was fitted to the nelfinavir plasma concentrations. In patients receiving nelfinavir 45 mg/kg bid oral clearance (CL/F) was significantly increased with 86% in comparison with the 30 mg/kg tid regimen (p<0.005). Concomitant administration of co-trimoxazole reduced CL/F with 43% (p<0.005). For tid and bid dosing, the averaged individual CL/F was 1.02 and 1.49 L/h/kg, respectively; corresponding values for the 24 h AUC (area under the concentration versus time curve) were 105 and 69.5 h*mg/L. Interoccasion variability was large; values for CL/F, volume of distribution (V/F) and Tlag were 46, 107 and 59%, respectively.
Conclusion: Bid dosing of 45 mg/kg nelfinavir in HIV-1-infected children produces lower exposure to the protease inhibitor than 30 mg/kg tid. Due to its large variability in PK, therapeutic drug monitoring of nelfinavir may be necessary to ensure optimal treatment.