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

José Moltó, Javier A. Estévez, Cristina Miranda, Samandhy Cedeño, Bonaventura Clotet, Marta Valle

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Abstract

© 2016 The British Pharmacological Society Aims: 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. Methods: A 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. Results: 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 0.63 mg l–1predicted 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 0.15 mg l–1and 0.85 mg l–1favoured 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). Conclusions: 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 300 mg/RTV 50 mg or ATV 200 mg/RTV 100 mg to confirm efficacy and safety.
Original languageEnglish
Pages (from-to)1528-1538
JournalBritish Journal of Clinical Pharmacology
Volume82
Issue number6
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • atazanavir
  • dose reduction
  • HIV-1-infected patients
  • interaction
  • population pharmacokinetics
  • ritonavir

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