Metabolism of Piperaquine to Its Antiplasmodial Metabolites and Their Pharmacokinetic Profiles in Healthy Volunteers

As a partner antimalarial for artemisinin drug-based combination therapy (ACT), piperaquine (PQ) can be metabolized into two major metabolites, including piperaquine N -oxide (M1) and piperaquine N , N -dioxide (M2). To better understand the antimalarial potency of PQ, the antimalarial activity of the PQ metabolites (M1 and M2) was studied in vitro (in Plasmodium falciparum strains Pf 3D7 and Pf Dd2) and in vivo (in the murine species Plasmodium yoelii ) in this study. The recrudescence and survival time of infected mice were also recorded after drug treatment. The pharmacokinetic profiles of PQ and its two metabolites (M1 and M2) were investigated in healthy subjects after oral doses of two widely used ACT regimens, i.e., dihydroartemisinin plus piperaquine phosphate (Duo-Cotecxin) and artemisinin plus piperaquine (Artequick). Remarkable antiplasmodial activity was found for PQ (50% growth-inhibitory concentration [IC_{50}], 4.5 nM against Pf 3D7 and 6.9 nM against Pf Dd2; 90% effective dose [ED_{90}], 1.3 mg/kg of body weight), M1 (IC_{50}, 25.5 nM against Pf 3D7 and 38.7 nM against Pf Dd2; ED_{90}, 1.3 mg/kg), and M2 (IC_{50}, 31.2 nM against Pf 3D7 and 33.8 nM against Pf Dd2; ED_{90}, 2.9 mg/kg). Compared with PQ, M1 showed comparable efficacy in terms of recrudescence and survival time and M2 had relatively weaker antimalarial potency. PQ and its two metabolites displayed a long elimination half-life (∼11 days for PQ, ∼9 days for M1, and ∼4 days for M2), and they accumulated after repeated administrations. The contribution of the two PQ metabolites to the efficacy of piperaquine as a partner drug of ACT for the treatment of malaria should be considered for PQ dose optimization.