Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic Plasmodium berghei

• Published in: ACS infectious diseases 2024-12
• Main Authors: Gal, Isabella Ramella, Demarta-Gatsi, Claudia, Fontinha, Diana, Arez, Francisca, Wicha, Sebastian G, Rottmann, Matthias, Nunes-Cabaço, Helena, Blais, Johanne, Jain, Jay Prakash, Lakshminarayana, Suresh B, Brito, Catarina, Prudêncio, Miguel, Alves, Paula M, Spangenberg, Thomas
• Format: Article
• Language: English
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.4c00563

New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of drug resistance against existing therapeutics. Here, we present a study to evaluate the preventive activity of a combination of clinical antimalarial drug candidates, cabamiquine and ganaplacide, that have multistage activity against the liver and blood stages of infection. Cabamiquine (DDD107498, M5717) inhibits parasite protein synthesis, and ganaplacide (KAF156) inhibits protein trafficking, blocks the establishment of new permeation pathways, and causes endoplasmic reticulum expansion. The pharmacodynamic parameters of a combination of the two compounds were assessed employing a pharmacometrics approach in conjunction with checkerboard analysis. The study was performed on a previously established 3D infection platform based on human hepatic cell lines that sustain infection by rodent parasites. The efficacy of this drug combination was assessed against the liver stage of the . Our results show that the combination of both drugs at the tested concentrations does not interfere with the drugs respective mode of action or affect hepatocyte cell viability. The drug combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma C /EC ratio >2 for ganaplacide and >5 for cabamiquine was achieved. These findings demonstrate that chemoprevention using a combination of cabamiquine and ganaplacide has the potential to target the asymptomatic liver stage of infection and prevent the development of parasitemia.