Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy

Background: Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors. Objectives: The primary objective of this analysis was to evaluate the pharmacokinetics of 2.0 mg/kg enfuvirtide in human immunodeficiency virus 1 (HIV-1)-infected children and adolescents when administered in combination with at least 3 other antiretrovirals. Methods: Twenty-five HIV-1-infected pediatric patients (5-16 years of age) enrolled in an ongoing phase I/II study were included in this analysis. Patients received enfiuvirtide 2.0 mg/kg se twice daily (bid) for at least 7 days. Blood samples were collected on day 7, and plasma concentrations of enfuvirtide and its metabolite were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetics measures [ C-max, t(max), C-trough, and area under the concentration time curve time 0 to 12 hours (AUC(12 hours))] were calculated from plasma concentration-time data by standard noncompartmental methods. Results: There was no significant difference between children and adolescents for enfuvirtide C-max (6.43 versus 5.88 mug/mL), C-trough (2.87 versus 2.98 mug/mL) and AUC(12hours) (56.1 versus 52.7 hours mug/mL). Similarly no significant differences were found when the pharmacokinetic measures were compared based on sexual maturity stages. A post hoc regression analysis based on AUC(12hours) showed that body weight-adjusted dosing of enfuvirtide provides drug exposure that is independent of age group, body weight and body surface area. Conclusions: Body weight-adjusted dosing of enfuvirtide, at a dose of 2.0 mg/kg sc bid, in HIV-1-infected pediatric patients at least 5 years of age, provides drug exposure comparable with that previously observed in HIV-1-infected adults after 90 mg sc bid dosing. Drug exposure in children and adolescents is independent of age group, body weight, body surface area and sexual maturity stage.