Mohamed Maiga (Bamako / ML), Prof. Sebastian Wicha (Hamburg / DE), Dr. Thomas Spangenberg (Eysins / CH), Prof. Laurent Dembélé (Bamako / ML), Dr Claudia Demarta Gatsi (Eysins / CH)
Abstract text
Introduction
Development and spreading of drug-resistant parasites substantially threaten malaria control and elimination. New antimalarial combination drugs are needed and required mandatory preclinical studies to determine the optimal combination partner, such as in vivo mice models and in vitro checkerboard assays. These models have been developed with long adapted P. falciparum laboratory strains leading to genetic modification and deletion of essential pathways of the parasites The translational value of these models to patient isolates is questionable and may explain the discrepancies observed between research and clinical trial data. This study is the first attempt to use freshly-derived P. falciparum isolates from patient to develop an in vitro checkerboard assay to assess drug-drug interaction (DDIs) using a promising new antimalarial combination of cabamiquine (M57171) and pyronaridine, soon entering Phase II.
Methods
Concentration and time-dependent in vitro cidial activity of cabamiquine and pyronaridine alone and in combination were determined against P. falciparum field isolates using standard 48 hours SYBR Green assay combined with Mitotracker readout. In vitro data were analyzed using non-linear mixed effects modelling describing the parasite growth and killing kinetics.
Results
For the first time in malaria, we used P. falciparum field isolates to assess DDIs using in vitro checkerboard assays. With cabamiquine and pyronaridine as experimental model, we successfully generate a range of EC50"s of the two drugs either alone or in combination. Moreover, we highlighted the importance of the combination in controlling possible adaptive resistance to one of the two drugs. The data were validated by using reference laboratory strains.
Conclusions
Being the first time that DDIs were studies using P. falciparum isolates directly from patient to inform the dose rate and dosing regiments of cabamiquine and pyrodnaridine in Phase II and III, offering a unique opportunity to validate the relevance of this new model. These data highlight the power of using non-adapted strains to better understand the future efficacy, resistance profile and safety of new antimalarial combination. If clinically confirmed these data are highlighting the central role that cutting edge African research needs to play in malaria control and eradication.