Piperaquine Monotherapy of Drug-Susceptible Plasmodium falciparum Infection Results in Rapid Clearance of Parasitemia but Is Followed by the Appearance of Gametocytemia

Cielo J. Pasay, Rebecca Rockett, Silvana Sekuloski, Paul Griffin, Louise Marquart, Christopher Peatey, Claire Y. T. Wang, Peter O'Rourke, Suzanne Elliott, Mark Baker, Jörg J. Möhrle, James S. McCarthy

 Piperaquine, co-formulated with dihydroartemisin is a component of a widely used Artemisinin Combination Therapy. There is a paucity of data on its antimalarial activity as a single agent, data that would inform selection of new co-formulations.  We undertook a study in healthy subjects using the induced blood stage malaria (IBSM) model to test the antimalarial activity of single doses of piperaquine (960, 640 and 480 mg) in three cohorts. In a pilot study in the third cohort, gametocyte clearance following administration of primaquine was investigated (15 mg, 45 mg, or no primaquine).  Parasite clearance, as determined by the Parasite Reduction Ratio over 48 hours post piperaquine administration, was more rapid in the 960 mg cohort compared to the 640 mg cohort (2,951; [95% CI 1,520 - 5,728] vs 586; [95% CI 351-978]; p<0-001). All subjects developed gametocytemia (n=24). Clearance ofpfs25transcripts was significantly faster in those receiving primaquine than in those not receiving primaquine (p<0-001).  Piperaquine possesses rapid parasite-clearing activity, but monotherapy is followed by the appearance of gametocytemia, which could facilitate the spread of malaria. This new information should be taken into account when developing future antimalarial co-formulations.