Blais, Johanne, Lakshminarayana, Suresh, Gal, Isabella Ramella, Demarta-Gatsi, Claudia, Fontinha, Diana, Arez, Francisca, Wicha, Sebastian G, Rottmann, Matthias, Nunes-Cabaco, Helena, Jain, Jay Prakash, Brito, Catarina, Prudencio, Miguel, Alves, Paula M and Spangenberg, Thomas (2024) Drug interaction studies of cabamiquine:ganaplacide combination against hepatic Plasmodium berghei. ACS infectious diseases.

Abstract

New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of Plasmodium 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 multi-stage activity against the liver and blood stages of Plasmodium 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 in vitro-in silico checkerboard analysis. The in vitro study was performed on a previously established 3D infection platform based on hepatic cell lines that sustain infection with rodent P. berghei parasites. The in vivo efficacy of this drug combination was assessed against the liver stage of P. berghei strain mCherry (Anka-Luci-GFP) ICB. Our results show that the combination of both drugs does not affect hepatocyte cell viability at the tested concentrations, and our analysis indicates that these drugs do not interfere with their respective mode of action. The drug-combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma Cav0-24/EC50 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 Plasmodium infection and prevent the development of parasitemia.

Item Type:	Article
Keywords:	Antimalarial; Cabamiquine; Combination therapy; Ganaplacide; in vivo, in vitro, Malaria; M5717; Preclinical, Plasmodium, KAF156; liver stage infection.
Date Deposited:	26 Dec 2024 00:45
Last Modified:	26 Dec 2024 00:45
URI:	https://oak.novartis.com/id/eprint/54492