Palang Chotsiri (1,2), Thanaporn Wattanakul (1,2), Borimas Hanboonkunupakarn (2), Podjanee Jittamala (2), Salwaluk Panapipat (1), Richard Hoglund (1,3), Daniel Blessborn (1,3), Sasithon Pukrittayakamee (2), Nicholas J. White (1,3), Nicholas P.J. Day (1,3), and Joel Tarning (1,3)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand, (2) Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (3) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom
Objectives: This study aimed to characterise the pharmacokinetic properties of the antimalarial drug piperaquine and its propensity for QTc prolongation, and its potential drug-drug interaction with the transmission blocking agent primaquine.
Methods: Sixteen healthy volunteers were recruited to this study and randomly administered primaquine alone, dihydroartemisinin-piperaquine alone, and dihydroartemisinin-piperaquine with primaquine at three occasions. Nonlinear mixed-effects modelling was performed to characterise the pharmacokinetic properties of piperaquine. The effect of primaquine co-administration was evaluated separately as a categorical covariate on all individual pharmacokinetic parameters and by using a full covariate approach. All remaining covariates were evaluated by a stepwise addition/elimination approach. Double-delta Fredericia-corrected QT measurements (ΔΔQTcF) were modelled as a linear direct-response pharmacodynamic model.
Results: Piperaquine plasma concentrations were best described by two transit-absorption compartments followed by three-disposition compartments. No clinical covariates had a significant impact on the pharmacokinetic parameters, and co-administration of primaquine did not affect the pharmacokinetic properties of piperaquine. ΔΔQTcF increased linearly with increasing piperaquine concentrations. Simulations using the final pharmacokinetic-pharmacodynamic model suggested that 95% of individuals with peak piperaquine concentrations below 850 ng/mL will have a ΔΔQTcF below 60 mSec.
Conclusions: Data presented here demonstrated that co-administration of primaquine did not alter the pharmacokinetic properties of piperaquine. Simulated maximum piperaquine concentrations after a standard 3-day antimalarial therapy of dihydroartemisinin-piperaquine were below that considered to produce a clinically significant QTcF prolongation.
Reference: PAGE 24 () Abstr 3522 [www.page-meeting.org/?abstract=3522]
Poster: Drug/Disease modeling - Infection