Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum.

With the spread of artemisinin resistance throughout South East Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterized. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47±2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modeling. Ten participants were inoculated and administered 360 mg (n=4), 540 mg (n=4), or 720 mg (n=1) pyronaridine. One participant was withdrawn without receiving pyronaridine. Time to maximum pyronaridine concentration was 1-2 hours, the elimination half-life was 8-9 days, and parasite clearance half-life was approximately 5 hours. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (MIC: 5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC

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Déclaration de conflit d'intérêts

Declaration of competing interest BEB declares receipt of funding from Medicines for Malaria Venture (MMV) to perform the study. JJM, ACM, JF, SC and NG are employees of MMV. ACM declares holding shares in Novartis, Alcon and Idorsia. All other authors declare no conflicts of interest.