Introduction: Dihydroartemisinin-piperaquine (DHA-PQP) is a well-established first-line therapy for uncomplicated malaria. However, resistance to this combination has emerged throughout Southeast Asia, resulting in substantially reduced treatment efficacy1,2. To counter the development of resistance, novel triple combinations of antimalarials have been trialed, adding another long acting antimalarial to a current antimalarial combination. One such combination is adding mefloquine (MQ) to DHA-PQP. The present study aimed to evaluate the pharmacokinetics properties and potential drug-drug interactions between the drugs involved in this new triple combination therapy in healthy volunteers, as well as evaluating the cardiovascular effects of these drugs.
Methods: A healthy volunteer trial with 15 healthy Thai adults (29 – 56 years old) were conducted to investigate potential drug-drug interactions between DHA-PQP and MQ3. A dense sampling design was utilized and collected samples were quantified for DHA, PQP, and MQ concentrations. The drug concentration-time profiles, and collected electrocardiographic measurements were analyzed using nonlinear mixed-effects modelling (NONMEM) v7.4. Potential drug-drug interactions were evaluated as a categorical covariate.
Results: Pharmacokinetic models were successfully developed for all three drugs and it was found that co-administration of MQ resulted in an increased mean transit time and reduced relative bioavailability of DHA, leading to a reduction in maximum concentration and exposure. The analysis of QT-prolongation showed an expected slight increase in ΔQT with increasing PQP concentrations, but MQ administration did not affect this relationship.
Conclusion: The present study successfully described the population pharmacokinetic properties and cardiovascular effects of the triple combination DHA-PQP-MQ in healthy volunteers. A significant impact of concomitant MQ administration was found on the absorption of DHA. The clinical impact of this interaction needs to be evaluated further.
References:
- Leang R, Barrette A, Bouth DM, et al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrob Agents Chemother. 2013;57:818-826.
- van der Pluijm RW, Imwong M, Chau NH, et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis. 2019;19:952-961.
- Hanboonkunupakarn B, van der Pluijm RW, Hoglund R, et al. Sequential Open-Label Study of the Safety, Tolerability, and Pharmacokinetic Interactions between Dihydroartemisinin-Piperaquine and Mefloquine in Healthy Thai Adults. Antimicrob Agents Chemother. 2019;63.