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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Population pharmacokinetics has been studied in adult patients. Tenofovir disoproxil fumarate (TDF) co-medication could decrease atazanavir/ritonavir (ATV/r) exposure. WHAT THIS STUDY ADDS • This first ATV/r population analysis in children and adolescents provides useful insights into the fate of this drug and shows that the allometric scaling of clearance and volume parameters based on bodyweight reduced the associated between-subject variability. Moreover, the effects of combined ritonavir and tenofovir on ATV clearance are precisely quantified. 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 (300 mg) 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 7.1 L h−1 (70 kg)−1, respectively. With the recommended 250/100 mg and 300/100 mg ATV/r doses, the exposure was higher than the mean adult steady-state exposure in the bodyweight range of 32–50 kg. CONCLUSIONS To target the mean adult exposure, children should receive the following once-daily ATV/r dose: 200/100 mg from 25 to 39 kg, 250/100 mg from 39 to 50 kg and 300/100 mg above 50 kg. When 300 mg TDF is co-administered, children should receive (ATV/r) at 250/100 mg between 35 and 39 kg, then 300/100 mg over 39 kg.