Population pharmacokinetics of nelfinavir (NFV) and its metabolite M8 when administered with ritonavir (RTV)

Abstract

RTV, a potent CYP3A4 inhibitor, is used at low doses to enhance plasma concentrations of other protease inhibitors being primarily metabolised by CYP3A4. NFV, as part of an antiretroviral combination regimen, is approved for the treatment of HIV-1 infected adults and children. NFV was given alone or in combination with RTV to HIV-1 infected patients. Patients received 1250 mg of NFV with or without 200 mg of RTV bid for 48 weeks. In total, 83 patients with sparse PK samples contributed to 611 concentrations each of NFV and its major metabolite M8 having in vitro antiviral activity comparable to NFV. The analysis method was based on non-linear mixed effect modelling. Individual estimates for AUCt, C12h & Cmax were assessed for NFV and M8. The model that fitted NFV and M8 data was a one-compartment model with first order elimination and absorption with lag time for NFV and M8. Oral clearance and distribution volume for NFV were 31.5 L/h and 345 L, and were not influenced by RTV. At week 48, NFV AUCt, C12h & Cmax were 42 h.mg/L, 2.3 & 4.6 mg/L with NFV, and 39 h.mg/L, 2.2 & 4.1 mg/L with NFV & RTV. The clearance of M8 was decreased by 42% when NFV was given with RTV. At week 48, M8 AUCt, C12h & Cmax were 13 h.mg/L, 0.7 & 1.4 mg/L with NFV, and 24 h.mg/L, 1.5 & 2.6 mg/L with NFV & RTV. Clinical Pharmacology & Therapeutics (2004) 75, P84–P84; doi: 10.1016/j.clpt.2003.11.322