Pooled Multicenter Analysis of Cardiovascular Safety and Population Pharmacokinetic Properties of Piperaquine in African Patients with Uncomplicated Falciparum Malaria.
Thanaporn WattanakulBernhards OgutuAbdunoor M KabanywanyiKwaku-Poku AsanteAbraham OduroAlex AdjeiAli SieEsperanca SeveneEusebio MaceteGuillaume CompaoreInnocent ValeaIsaac OseiMarkus WinterbergMargaret GyapongMartin AdjuikSalim AbdullaSeth Owusu-AgyeiNicholas J WhiteNicholas P J DayHalidou TintoRita BaidenFred BinkaJoel TarningPublished in: Antimicrobial agents and chemotherapy (2020)
Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicenter trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90-ms mean QTc prolongation per 100-ng/ml increase in piperaquine concentration. The effect of piperaquine on absolute QTc interval estimated a mean maximum QTc interval of 456 ms (50% effective concentration of 209 ng/ml). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98 to 2.46% risk of having QTc prolongation of >60 ms in all treatment settings. Although piperaquine administration resulted in QTc prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern. (This study has been registered at ClinicalTrials.gov under identifier NCT02199951.).
Keyphrases
- plasmodium falciparum
- drug administration
- end stage renal disease
- mass spectrometry
- ejection fraction
- multiple sclerosis
- newly diagnosed
- peritoneal dialysis
- ms ms
- young adults
- heart failure
- clinical trial
- study protocol
- left ventricular
- cross sectional
- patient reported outcomes
- molecular dynamics
- double blind
- phase ii