Drug Interaction\nStudies of Cabamiquine:Ganaplacide\nCombination against Hepatic <i>Plasmodium berghei</i>

New antimalarial combination therapies with novel modes\nof action\nare required to counter the emergence and spread of <i>Plasmodium</i> drug resistance against existing therapeutics. Here, we present\na study to evaluate the preventive activity of a combination of clinical\nantimalarial drug candidates, cabamiquine and ganaplacide, that have\nmultistage activity against the liver and blood stages of <i>Plasmodium</i> infection. Cabamiquine (DDD107498, M5717) inhibits\nparasite protein synthesis, and ganaplacide (KAF156) inhibits protein\ntrafficking, blocks the establishment of new permeation pathways,\nand causes endoplasmic reticulum expansion. The pharmacodynamic parameters\nof a combination of the two compounds were assessed employing a pharmacometrics\napproach in conjunction with <i>in vitro-in silico</i> checkerboard\nanalysis. The <i>in vitro</i> study was performed on a previously\nestablished 3D infection platform based on human hepatic cell lines\nthat sustain infection by rodent <i>P. berghei</i> parasites.\nThe <i>in vivo</i> efficacy of this drug combination was\nassessed against the liver stage of the <i>P. berghei</i>. Our results show that the combination of both drugs at the tested\nconcentrations does not interfere with the drugs respective mode of\naction or affect hepatocyte cell viability. The drug combination was\nfully effective in preventing the appearance of blood stage parasites\nwhen a systemic plasma C<sub>av0‑24</sub>/EC<sub>50</sub> ratio\n>2 for ganaplacide and >5 for cabamiquine was achieved. These\nfindings\ndemonstrate that chemoprevention using a combination of cabamiquine\nand ganaplacide has the potential to target the asymptomatic liver\nstage of <i>Plasmodium</i> infection and prevent the development\nof parasitemia.