1 Scientific RepoRts | 5:17264 | DOI: 10.1038/srep17264 www.nature.com/scientificreports Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99–411, with long acting prescription antimalarials, lumefantrine and piperaquine Isha taneja 1,2,* , Kanumuri siva Rama Raju 1,2,* , sheelendra pratap singh 3 & Muhammad Wahajuddin 1,2 the pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99–411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99–411 and of piperaquine and 99–411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99–411 increased when administered with either lumefantrine or piperaquine. However, co-administration of 99–411 signifcantly decreased the systemic exposure of piperaquine by half-fold while it had no efect on the kinetics of lumefantrine. 99–411, thus, seemed to be a good alternative to artemisinin derivatives for combination treatment with lumefantrine. To explore the reason for increased plasma levels of 99–411, an in situ permeability study was performed by co-perfusing lumefantrine and 99–411. In presence of lumefantrine, the absorption of 99–411 was signifcantly increased by 1.37 times than when given alone. Lumefantrine did not afect the metabolism of 99–411 when tested in vitro in human liver microsomes. Additionally, ATPase assay suggest that 99–411 was a substrate of human P-gp, thus, indicating the probability of interaction at the absorption level in humans as well. Malaria is an infective disease with ongoing transmission in 97 countries and territories. In 2013, there were 198 million reported cases of malaria leading to an estimated 584,000 deaths worldwide. Malaria caused 453,000 deaths among children under the age of fve, 437,000 of them occurring in Africa. In 2014, approximately 1.2 billion people were estimated to be at high risk of malaria. WHO currently recommends the use of combination drug therapy (especially, artemisinin based combination therapy (ACT)) for treating all cases of uncomplicated malaria infection. Te available ACT treatment options are: artemether/lumefantrine (AL); dihydoartemisinin/piperaquine (DP); artesunate/amodiaquine (ASAQ); artesunate plus sulfadoxine/pyrimethamine (in areas where SP is still efcacious); artesunate/mefoquine (in areas with moderate transmission). In accordance with WHO guidelines, 79 out of 87 P. falciparum 1 Academy of Scientifc and Innovative Research, New Delhi, India. 2 Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow-226031, India. 3 Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Lucknow-226001, India. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to M.W. (email: wahajuddin@cdri.res.in or wahajuddin@gmail. com) Received: 05 May 2015 accepted: 19 October 2015 Published: 25 November 2015 opeN