Population pharmacokinetic modelling of the changes in atazanavir plasma clearance caused by ritonavir plasma concentrations in HIV-1 infected patients.

Abstract

The aim of the present study was to develop a simultaneous population pharmacokinetic model for atazanavir (ATV) incorporating the effect of ritonavir (RTV) on clearance to predict ATV concentrations under different dosing regimens in HIV-1-infected patients. A Cross-sectional study was carried out in 83 HIV-1-infected adults taking ATV 400mg or ATV 300mg/RTV 100mg once daily. Demographic and clinical characteristics were registered and blood samples collected to measure drug concentrations. A population pharmacokinetic model was constructed using nonlinear mixed-effects modelling and used to simulate six dosing scenarios. The selected one-compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to the RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63mg l-1 predicted an 18% decrease in ATV clearance. The percentages of patients with an end-of-dose-interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15mg l-1 and 0.85mg l-1 favoured the selection of the simulated ATV/RTV once-daily regimens (ATV 400mg, ATV 300mg/RTV 100mg, ATV 300mg/RTV 50mg, ATV 200/RTV 100mg) over the unboosted twice-daily regimens (ATV 300mg, ATV 200mg). A one-compartment simultaneous model can describe the pharmacokinetics of RTV and ATV, including the effect of RTV plasma concentrations on ATV clearance. This model is promising for predicting individuals' ATV concentrations in clinical scenarios, and supports further clinical trials of once-daily doses of ATV 300mg/RTV 50mg or ATV 200mg/RTV 100mg to confirm efficacy and safety.