Alessandro Schipani1 (1), Laura Dickinson2 (1), Marta Boffito3 (2), Rupert Austin4 (3), Andrew Owen5 (1), David Back6 (1), Saye Khoo7 (1), Gerry Davies8 (1)
(1)Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK. (2) St. Stephen’s Centre, Chelsea and Westminster Hospital, London. (3) BAST Inc Limited, Nottingham, UK.
Objectives: Atazanavir (ATV) is a protease inhibitor (PI) used as part of combination HIV therapy. ATV is metabolised by CYP3A4/3A5. A target minimum effective concentration (MEC) of 0.15 mg/L at trough has been recommended for optimal viral suppression. ATV is co-administered with ritonavir (RTV) and licensed at a dose of ATV/RTV 300/100 mg once daily. The concentration of RTV maximal inhibition of CYP3A4 may occur with a lower RTV dose than 100 mg. There are clear advantages to lower doses of RTV (better tolerated, cheaper to manufacture, easier to co-formulate), but current there are also obstacles. The objective of this study was to develop a simultaneous population PK model to describe ATV/RTV PK (300/100 mg) and to assess the effect of RTV dose reduction on ATV PK. Simulations of ATV concentration-time profiles were performed at doses of ATV/RTV 300/50 mg, 200/50 mg and 200/100 mg once daily.
Methods: A total of 288 ATV and 312 RTV plasma concentrations from 30 patients were included to build a population pharmacokinetic model using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.2 software.
Results: A maximum-effect model in which RTV inhibited the elimination of ATV was used to describe the relationship between RTV concentrations and ATV clearance (CL/F). A RTV concentration of 0.22 mg/liter was associated with 50% maximum inhibition of ATV CL/F. The population prediction of ATV CL/F in the absence of RTV was 16.6 liters/h (relative standard error, 7.0%), and the apparent volume of distribution and absorption rate constant were 106 liters (relative standard error, 8%) and 0.87 h-1 (fixed), respectively. Simulated average ATV trough concentrations at ATV/RTV 300/50 mg, 200/50 mg and 200/100 mg once daily were 45%, 63% and 33% lower, respectively, than that of the standard dose.
Conclusions: A population model to simultaneously describe the pharmacokinetics of ATV and RTV was developed and validated in HIV-infected individuals. The simulated median ATV trough concentrations following dose reductions were reduced compared to the licensed dose but were still above the ATV MEC (2.9, 1.9 and 3.6 fold for ATV/RTV 300/50 mg, 200/50 mg and 200/100 mg, respectively). Simulated data for the 300/50 mg regimen are consistent with the clinical data. This modelling approach aids our understanding of the interaction between ATV and RTV and informs the design of dose reduction strategies, particularly in relation to RTV.
Reference: PAGE 21 (2012) Abstr 2452 [www.page-meeting.org/?abstract=2452]
Poster: Infection