The study, led by a team at the Mahidol Oxford Research Unit (MORU) in Bangkok, said DP did not cause dangerously long QT-intervals, a measure of the heart’s electrical cycle, in 16 healthy patients. These findings suggest that the drug combination may be used safely to treat the most dangerous form of malaria, which may result in death when left untreated.
Applying a pharmacokinetic and pharmacodynamic (PK/PD) modelling approach, the researchers isolated the effect of piperaquine in DP and observed that piperaquine caused a small prolongation of the QT-interval – but not a dangerous one. A large prolongation of the QT-interval can cause dangerous arrhythmias (i.e. irregular heart rhythms) that can lead to sudden death.
Although some previously published reports have raised concerns about potentially harmful cardiotoxic effects associated with piperaquine, DP remains a World Health Organisation (WHO)-recommended artemisinin-based combination therapy (ACT) and frontline antimalarial treatment.
“The findings showed that piperaquine does not cause QT prolongation of clinical concern, such as the kind resulting in sudden death,” said Palang Chotsiri, a PhD candidate at Mahidol University, Thailand, and the lead author of the study. “We have confirmed what many already suspected about an important antimalarial treatment in common use”.
In addition, the study also evaluated the safety of DP when adding a single low dose of primaquine with the intention of reducing malaria transmission among infected patients who are receiving treatment.
While DP attacks malaria parasites in the bloodstream, primaquine can reduce transmission of malaria by affecting the gametocytes, the sexual-stage of malaria that is needed for production of new infective malaria parasites in the mosquito.
The researchers found that primaquine did not affect the pharmacokinetic properties of dihydroartemisinin or piperaquine, i.e. dihydroartemisinin and piperaquine had the same properties in the body irrespective of the co-administration of primaquine. These findings demonstrated that the combination of DP and primaquine is safe, which could have a significant impact in low-endemic countries with fewer cumulative infections.
“In some settings the transmission of falciparum malaria might be drastically reduced by adding a single low dose of primaquine”, said Prof Joel Tarning, the senior author of the study and WWARN's Head of Pharmacometrics. “Showing that this combination is safe is definitely an important step in the battle to eliminate malaria”.
Understanding the science and health implications of using primaquine with artemisinin combination therapies (ACTs) is a key focus of WWARN's Low-dose Primaquine Efficacy and Safety Study Groups, which seek to inform clinical and policy decisions on use of low dose primaquine as a transmission-blocking agent.
Chotsiri, P., Wattanakul, T., Hoglund, R. M., Hanboonkunupakarn, B., Pukrittayakamee, S., Blessborn, D., Jittamala, P., White, N. J., Day, N. P. J., and Tarning, J. (2017), ‘Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers,’ British Journal of Clinical Pharmacology, doi: 10.1111/bcp.13372