Multi-Drug Combination-Therapies to Prevent the Development of Drug Resistance:
Phase II Controlled Clinical Trial Assessing Candidate Regimens of Multiple-Antimalarial Combinations for the Treatment of Uncomplicated Malaria in Africa
Antimalarial drug resistance is one of the most important challenges in the control and elimination of malaria. Artemisinin combination therapy (ACT) as bi-therapy is the standard of care in all malaria endemic countries. However, the efficacy of ACTs as bi-therapy declined in the past decade in the Greater Mekong Region of South East Asia (SEA). Subsequently, epidemiological genomic studies confirmed that in fact artemisinin resistance developed much earlier in numerous foci, resulting in resistant parasites. Importantly, drug resistance against the partner drugs evolved simultaneously leading to decreasing cure rates of first line antimalarial treatments in SEA. One pharmacokinetic consideration, which may explain the failure of all currently employed ACTs to avoid the development of drug resistance, is their pharmacokinetic mismatch. Whereas the artemisinin derivative has a remarkably short half-life of < 3 hours, the partner drugs are characterized by intermediate (lumefantrine) to exceptionally long half-lives (mefloquine, piperaquine with half-lives of more than 4 weeks). This pharmacokinetic mismatch allows for a very short period where the two drugs protect each other and a long period of time when the slowly eliminated partner drug is unprotected from the rapidly eliminated artemisinin derivative in prolonged sub-therapeutic drug levels, and therefore paves the way for the parasite to develop resistance to these drugs if reinfection occurs during the convalescence period. Multi-drug combination therapy is therefore particularly appealing to increase the barriers for resistance if partner drugs with matched half-lives are combined. Therefore, the MultiMal study aims at describing the pharmacokinetic properties of each partner drug and their principal active metabolites in the two antimalarial combination treatments artesunate-pyronaridine-atovaquone/proguanil (APAP) and artesunate-fosmidomycin-clindamycin.
COmbination Regimen for Mass Drug Administration
It is an increasingly common concept in antimicrobial chemotherapy to use a number of active agents as combination treatment to prevent the emergence and spread of drug resistance. Re-purposing of already existing drugs is an efficient way of developing such novel multidrug combinations. Occasionally, specific antimicrobial agents demonstrate simultaneous activity against multiple microorganisms. This introduces the promising possibility of creating drug regimens to be potentially used for more than only one treatment indication. Furthermore, the value of such multi-disease drug regimens rises when designed for important infectious diseases that affect a similar target population; an aspect making such regimens appealing to be operationally implemented not only, but particular in low resource settings. Two important infectious diseases with large endemic overlap are malaria and urogenital schistosomiasis, both affecting mainly children and adolescents in sub-Saharan Africa. Importantly mass drug administration programs are currently used in endemic regions to target schistosomiasis and malaria independently. A combined multi-drug combination targeting both poverty-related infectious diseases would therefore constitute an important operational progress.
To date the recommended treatment of uncomplicated malaria are artemisinin combination therapies (ACT) which contain two active antimalarial agents. Treatment of urogenital schistosomiasis is based on praziquantel, which is the only available drug for this indication. The two antimalarial drugs artesunate (an artemisinin derivative) and pyronaridine have been demonstrated to exert activity against Schistosoma haematobium. Furthermore, praziquantel has been shown in preliminary studies to exert an anti-plasmodial activity; however, this effect has not yet been further investigated. Given the available preliminary evidence the CORMA project aims at assessing the safety, tolerability and efficacy of drug regimens containing praziquantel and pyronaridine-artesunate in the treatment of asymptomatically infected Gabonese study participants with Plasmodium falciparum and Schistosoma haematobium.