Summary
Aims
The aims of the presented study were to evaluate the pharmacokinetic properties of dihydroartemisinin and piperaquine, potential drug-drug interactions with concomitant primaquine treatment, and piperaquine effects on the electrocardiogram in healthy volunteers.
Methods
Population pharmacokinetic properties of dihydroartemisinin and piperaquine were assessed in 16 in healthy Thai adults using an open-label randomized crossover study. Drug concentration-time data and electrocardiographic measurements were evaluated with nonlinear mixed-effects modelling.
Results
The developed models described dihydroartemisinin and piperaquine population pharmacokinetics accurately. Concomitant treatment with primaquine did not affect the pharmacokinetic properties of dihydroartemisinin or piperaquine. A linear pharmacokinetic-pharmacodynamic model described satisfactorily the relationship between the individually corrected QT-intervals and piperaquine concentrations; the population mean QT-interval increased by 4.17 ms per 100 ng/mL increase in piperaquine plasma concentration. Simulations from the final model showed that monthly and bi-monthly mass drug administration in healthy subjects would result in median maximum QT-interval prolongations of 18.9 and 16.8 ms, respectively, and would be very unlikely to result in prolongation of more than 50 ms. A single low dose of primaquine can be added safely to the existing dihydroartemisinin-piperaquine treatment in areas of multi-resistant falciparum malaria.
Conclusions
Pharmacokinetic-pharmacodynamic modelling and simulation in healthy adult volunteers suggested that therapeutic doses of DHA-piperaquine in prevention or treatment are very unlikely to be associated with dangerous QT-prolongation.
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