Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents

Abstract

Aims: To investigate atazanavir (ATV) population pharmacokinetics in children and adolescents, establish factors that influence ATV pharmacokinetics and investigate the ATV exposure after recommended doses. Methods: Atazanavir concentrations were measured in 51 children/adolescents during a mean therapeutic monitoring follow up of 6.6 months. A total of 151 ATV plasma concentrations were obtained, and a population pharmacokinetic model was developed with NONMEM. Patients received ATV alone or boosted with ritonavir. Results: Atazanavir pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The effect of bodyweight was added on both apparent elimination clearance (CL/F) and volume of distribution using allometric scaling. Atazanavir CL/F was reduced by ritonavir by 45%. Tenofovir disoproxil fumarate (TDF) co-medication (300mg) increased significantly by 25% the atazanavir/ritonavir (ATV/r) CL/F. Mean ATV/r CL/F values with or without TDF were 8.9 and 7.1Lh -1 (70kg) -1, respectively. With the recommended 250/100mg and 300/100mg ATV/r doses, the exposure was higher than the mean adult steady-state exposure in the bodyweight range of 32-50kg. Conclusions: To target the mean adult exposure, children should receive the following once-daily ATV/r dose: 200/100mg from 25 to 39kg, 250/100mg from 39 to 50kg and 300/100mg above 50kg. When 300mg TDF is co-administered, children should receive (ATV/r) at 250/100mg between 35 and 39kg, then 300/100mg over 39kg. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.