Enantioselective pharmacokinetics of primaquine in healthy human volunteers

Authors: TEKWANI, BABU - University Of Mississippi; AVULA, BHARATHI - University Of Mississippi; SAHU, RAJNISH - University Of Mississippi; CHAURASIYA, NARAYAN - University Of Mississippi; KHAN, SHABANA - University Of Mississippi; JAIN, SURENDRA - University Of Mississippi; FASINU, PIUS - University Of Mississippi; HERATH, H.M.T. - University Of Mississippi; STANFORD, DONALD - University Of Mississippi; NANAYAKKARA, N.P. - University Of Mississippi; MCCHESNEY, JAMES - University Of Mississippi; YATES, TRAVIS - University Of Mississippi; ELSOHLY, MAHMOUD - University Of Mississippi; KHAN, IKHLAS - University Of Mississippi; WALKER, LARRY - University Of Mississippi

Submitted to: Drug Metabolism and Disposition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/30/2015
Publication Date: 4/30/2015
Citation: Tekwani, B.L., Avula, B., Sahu, R., Chaurasiya, N.D., Khan, S.I., Jain, S., Fasinu, P.S., Herath, H.B., Stanford, D., Nanayakkara, N.D., Mcchesney, J.D., Yates, T.W., Elsohly, M.A., Khan, I.A., Walker, L.A. 2015. Enantioselective pharmacokinetics of primaquine in healthy human volunteers. Drug Metabolism and Disposition. 43(4):571-7.

Interpretive Summary: Malaria is global health challenge and still responsible for >400,000 deaths during 2015, according to a recent report by the WHO. Primaquine (PQ), a racemic drug, is the only treatment available for radical cure of relapsing vivax malaria and blocking transmission of falciparum malaria. Recently studies have shown differential pharmacologic and toxicologic profiles of individual PQ enantiomers in rodents, dog and primate animal models. A study was conducted in six healthy adult human volunteers to determine plasma pharmacokinetic profile of enantiomers of PQ and carboxyprimaquine (cPQ), the major plasma metabolite. The individuals were orally administered with PQ diphosphate, equivalent to 45 mg base, 30 min after a normal breakfast. Blood samples were collected at different time intervals and plasma samples were analyzed for enantiomers of PQ & cPQ. The results suggest more rapid metabolism of (-)-PQ to (-) cPQ compared to (+)-PQ. Alternatively, (+)-PQ or (+)-cPQ could be rapidly converted to another metabolite(s) or distributed to tissues. This is the first clinical report on enantioselective pharmacokinetic profiles of PQ and cPQ and supports further clinical evaluation of individual PQ enantiomers. This study confirms enantioselective pharmacokinetic and metabolic profiles of PQ and suggests the need for further clinical evaluation of the efficacy and safety of PQ enantiomers in humans

Technical Abstract: Primaquine (PQ), a racemic drug, is the only treatment available for radical cure of relapsing Plasmodium vivax malaria and blocking transmission of P. falciparum malaria. Recent studies have shown differential pharmacologic and toxicologic profiles of individual PQ enantiomers in rodent, dog, and primate animal models. This study was conducted in six healthy adult human volunteers to determine the plasma pharmacokinetic profile of enantiomers of PQ and arboxyprimaquine (cPQ), the major plasma metabolite. The individuals were orally administered PQ diphosphate, equivalent to 45-mg base, 30 minutes after a normal breakfast. Blood samples were collected at different time intervals, and plasma samples were analyzed for enantiomers of PQ and cPQ. Plasma PQ concentrations were low and variable for both parent enantiomers and peaked around 2-4 hours. Peak (2)-(R)-PQ concentrations ranged from 121 ng/ml to 221 ng/ml, and peak (+)-(S)-PQ concentrations ranged from 168 ng/ml to 299 ng/ml. The cPQ concentrations were much higher and were surprisingly consistent from subject to subject. Essentially all the cPQ detected in plasma was (2)-cPQ. The peak concentrations of (2)-cPQ were observed at 8 hours (range: 1104-1756 ng/ml); however, very high concentrations were sustained through 24 hours. (+)-cPQ was two orders of magnitude lower than (2)-cPQ, and in a few subjects it was detected but only under the limit of quantification. In vitro studies with primary human hepatocytes also suggested more rapid metabolism of (2)-PQ compared with (+)-PQ. The results suggest more rapid metabolism of (2)-PQ to (2) cPQ compared with (+)-PQ. Alternatively, (+)-PQ or (+)-cPQ could be rapidly converted to another metabolite(s) or distributed to tissues. This is the first clinical report on enantioselective pharmacokinetic profiles of PQ and cPQ and supports further clinical evaluation of individual PQ enantiomers.