Effect of Ritonavir Concentrations on Atazanavir Pharmacokinetics: Population Pharmacokinetic Analysis
J. Moltó1,2*, J. Estévez3,4*, C. Miranda1,2, S. Cedeño5, M. Barbanoj^, B. Clotet1,2,5, M. Valle3,4.
1 Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 2 Departamento de Medicina, Universidad Autónoma de Barcelona, Barcelona, Spain 3 Modelado y simulación farmacocinético/farmacodinámico, CIM-St Pau, Institut Recerca HSCSP, Barcelona, Spain 4 Departamento de Farmacología, Terapéutica y Toxicología, Universidad Autónoma de Barcelona, Barcelona, Spain 5 Fundació IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain * JM and JE have equally worked on this study ^ Deceased
Objectives: Atazanavir (ATV) is a protease inhibitor indicated for the treatment of HIV infection, with approved doses of unboosted 400mg (2 capsules, approved in the USA) or 300mg boosted with 100mg of ritonavir (2 capsules, approved in the EU and USA), both qd. The aim of this study was to develop a population pharmacokinetic (pk) model for atazanavir and ritonavir in a population of HIV-infected adults. The model sought was to detect possible pk differences in ATV when administered unboosted or boosted with ritonavir (RTV), and to incorporate patient characteristics influencing variability in ATV and/or RTV concentrations.
Methods: HIV-infected adults on stable therapy with oral atazanavir unboosted (400mg qd) or boosted (400mg/100mg rRTV, qd) in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and serial blood samples were collected immediately before and over 24h after a morning-dose or between 12 and 24h after a night-dose. ATV and RTV concentrations in plasma were determined by high performance liquid chromatography. A population pharmacokinetic model was developed for ATV and RTV. Pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of ATV and RTV was explored. The final model incorporated the effect of RTV exposure on ATV oral clearance (CL/F). Population analysis was performed using non-linear mixed effects modeling (NONMEM, version VI).
Results: A total of 29 Caucasian patients were included in the study. Atazanavir and ritonavir pharmacokinetics were described with one-compartment models with first order absorption and elimination. An absorption lag-time was needed to describe ATV absorption phase.
Atazanavir CL/F was inhibited by RTV concentrations following an exponential model. The model predicted a 30% decrease in ATV oral CL/F at a 0.63mg/mL of RTV in plasma. This concentration represents the average observed concentration of RTV in the dosing interval. The final model appropriately predicted plasma concentrations, with no systematic bias and adequate precision.
Conclusions: No differences in the pharmacokinetics of atazanavir were found apart from a decrease in plasma clearance when co-administered with ritonavir. Bayesian estimates of the individual parameters of ritonavir and atazanavir could be useful to predict boosted and unboosted atazanavir exposure in an individual manner.