The antiplasmodial activity of the carboxylic acid metabolite of piperaquine and its pharmacokinetic profiles in healthy volunteers.

Abstract

The long-acting antimalarial drug piperaquine can be metabolized into the carboxylic acid metabolite (PQM). However, the clinical relevance of PQM remains unclear. The pharmacodynamics/pharmacokinetics of PQM were studied. The antimalarial activity of PQM was studied in vitro (Plasmodium strains Pf3D7 and PfDd2) and in vivo (murine Plasmodium yoelii). The toxicity of PQM was evaluated in mice, in terms of the general measures of animal well-being, serum biochemical examination and ECG monitoring. The pharmacokinetic profiles of piperaquine and its metabolite PQM were investigated in healthy subjects after recommended oral doses of piperaquine. PQM showed no relevant in vitro antimalarial activity (IC50 > 1.0 μM) with no significant toxicity. After recommended oral administration of piperaquine to healthy subjects, the maximum concentration of PQM was less than 30.0 nM, and it did not accumulate after repeated dosing. With a low antimalarial potency, PQM should not contribute to the efficacy of piperaquine with clinically acceptable doses.