Model-Based Approach for Optimization of Atazanavir Dose Recommendations for HIV-Infected Pediatric Patients

Abstract

ABSTRACT Atazanavir (Reyataz; ATV) is a well-tolerated protease inhibitor (PI) that is indicated as a once-daily treatment for HIV infections. These features of ATV, combined with its virologic potency, make it particularly desirable for the treatment of HIV-infected pediatric patients. The objective of this study was to use a model-based approach to recommend body weight-based ATV capsule doses for pediatric patients. ATV concentration-time data from three adult studies and one pediatric study were described by a C 0 -delinked one-compartment model to guard against introducing bias in pharmacokinetic (PK) parameter estimates due to the potential nonadherence in outpatient studies. The apparent clearance (CL /F ) and apparent volume of distribution ( V/F ) were determined to increase with body weight, and CL /F was 40.9% lower in patients receiving ATV comedication with ritonavir (RTV). The relative bioavailability ( F rel ) of ATV was 132% higher with RTV comedication and was 35.5% lower for the ATV powder formulation than the capsule formulation. Model-based simulations were used to recommend weight-based ATV capsule doses of 150 to 300 mg boosted with 100 mg RTV for pediatric patients weighing ≥15 kg, such that the exposures in these patients are similar to those obtained in HIV-infected adults treated with the recommended ATV/RTV dose of 300/100 mg.