Time Course of the Changes in Novel Trioxane Antimalarial 99/411 Pharmacokinetics upon Antiepileptic Drugs co-administration in SD Rats

Abstract

Objective: The study aimed to evaluate the influences of co-administration of antiepileptic drugs (AEDs) on an anti-malarial candidate 99/411 pharmacokinetic (PK) profile. Method: For this, single oral dose PK drug interaction studies were conducted between 99/411 and FDA approved AEDs viz. Phenytoin (PHT), Carbamazepine (CBZ) and Gabapentin (GB) in both male and female SD rats, to assess the co-administered and inter-sexual influences on 99/411 PK profile. Results: Studies revealed that there were no significant alterations in the PK profile of 99/411 upon PHT and CBZ co-administration in both male and female rats, while systemic exposure of 99/411 was significantly increased by about 80% in female rats upon GB co-administration. In terms of AUC, there was an increase from 2471 ± 586 to 4560 ± 1396 ng.h/mL. It was concluded that simultaneous administration of AEDs with 99/411 excludes the requirements for dose adjustment, additional therapeutic monitoring, contraindication to concomitant use and /or other measures to mitigate risk, except for GB co-administration in females. These findings are further helpful to predict such interactions in humans, when potentially applied through proper allometric scaling to extrapolate the data.