Physiologically Based Pharmacokinetic Modelling of the Co-administration of Ritonavir-Boosted Atazanavir and Rifampicin in Children Co-treated for HIV and Tuberculosis

Abstract Purpose A dosing strategy for ritonavir-boosted atazanavir (ATV/r) to overcome the drug-drug interaction (DDI) effect with standard doses of rifampicin (10mg/ kg) was investigated in children aged between 7 and 18 years who were divided into 3 weight bands: 25-30 kg, 30-49 kg, and 50-70 kg. Methods We developed a paediatric physiologically-based pharmacokinetic (PBPK) model from a validated adult PBPK model with the necessary DDI components. The paediatric PBPK model was validated using relevant clinical data of ATV/r alone and rifampicin alone in children. Results Dose escalation to twice-daily dosing of ATV/r was predicted to boost ATV Ctrough adequately. With ATV/r 300/100 mg twice daily dosing in the presence of standard doses of rifampicin, predicted ATV Ctrough was higher than 150 ng/ml in over 90% of the paediatric population. Conclusions This model results suggests ATV/r 300/100 mg twice daily could maintain sufficient concentrations for antiviral efficacy when co-administered with standard dose of rifampicin taken once daily in children between 7 and 18 years. However, clinical studies are still warranted to confirm safety and efficacy of the dose escalation in children.