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

Abstract

AIMSThe 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. METHODSA Cross-sectional study was carried out in 83 HIV-1-infected adults taking ATV 400 mg or ATV 300 mg/RTV 100 mg 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. RESULTSThe 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 0.63 mg l -1 predicted an 18% decrease in ATV clearance. The percentages of patients with an endof-dose-interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15 mg l -1 and 0.85 mg l -1 favoured the selection of the simulated ATV/RTV once-daily regimens (ATV 400 mg, ATV 300 mg/RTV 100 mg, ATV 300 mg/RTV 50 mg, ATV 200/RTV 100 mg) over the unboosted twice-daily regimens (ATV 300 mg, ATV 200 mg). British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The once-daily ATV 300 mg/RTV 100 mg regimen is widely used in highly active antiretroviral therapy.• In some patients, dose adjustments may be necessary to prevent concentrations outside the therapeutic range leading to undesired effects or therapeutic failure.• Population pharmacokinetic modelling enables us to detect and quantify the effect of different patient characteristics associated with variability. WHAT THIS STUDY ADDS• A simultaneous population pharmacokinetic model described the decrease in atazanavir clearance with an exponential function of ritonavir (RTV) concentrations in HIV-1-infected adults.• RTV plasma concentrations explained 17.5% of interindividual variability in ATV clearance.• The model supports further clinical trials of once daily doses of atazanavir (ATV) 300 mg/RTV 50 mg or ATV 200 mg/RTV 100 mg to confirm efficacy and safety.