Population pharmacokinetics of ritonavir-boosted atazanavir in HIV-infected patients and healthy volunteers

OBJECTIVES: The aim of this study was to develop and validate a population pharmacokinetic model to: (i) describe ritonavir-boosted atazanavir concentrations (300/100 mg once daily) and identify important covariates; and (ii) evaluate the predictive performance of the model for lower, unlicensed atazanavir doses (150 and 200 mg once daily) boosted with ritonavir (100 mg once daily). METHODS: Non-linear mixed effects modelling was applied to determine atazanavir pharmacokinetic parameters, inter-individual variability (IIV) and residual error. Covariates potentially related to atazanavir pharmacokinetics were explored. The final model was assessed by means of a visual predictive check for 300/100, 200/100 and 150/100 mg once daily. RESULTS: Forty-six individuals were included (30 HIV-infected). A one-compartment model with first-order absorption and lag-time best described the data. Final estimates of apparent oral clearance (CL/F), volume of distribution (V/F) and absorption rate constant [relative standard error (%) and IIV (%)] were 7.7 L/h (5, 29), 103 L (13, 48) and 3.4 h(−1) (34, 154); a lag-time of 0.96 h (1) was determined. Ritonavir area under the curve (AUC(0–24)) was the only significant covariate. Overall, 94%–97% of observed concentrations were within the 95% prediction intervals for all three regimens. CONCLUSIONS: A population pharmacokinetic model for ritonavir-boosted atazanavir has been developed and validated. Ritonavir AUC(0–24) was significantly associated with atazanavir CL/F. The model was used to investigate other, particularly lower, ritonavir-boosted atazanavir dosing strategies.