RT Journal Article
T1 Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling
A1 Ferrer Bazaga, Santiago
AB BackgroundArtemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemicalmode of action in the global portfolio of marketed antimalarials is extremely limited.Addressing the urgent need for the development of new antimalarials, a chemical class ofpotent antimalarial compounds with a novel mode of action was recently identified. Herein,the preclinical characterization of one of these compounds, ACT-451840, conducted inpartnership with academic and industrial groups is presentedMethod and FindingsThe properties of ACT-451840 are described, including its spectrum of activities againstmultiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murinemalaria models that permit infection with the human and the rodent parasites P. falciparumand Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentrationof 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparumNF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kgagainst P. falciparum (95% confidence interval: 3.3±4.9 mg/kg) and 13 mg/kg against P.berghei (95% confidence interval: 11±16 mg/kg). ACT-451840 potently prevented malegamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquitowith a 50% inhibitory concentration of 30 nM (range: 23±39). The compound's preclinicalsafety profile is presented and is in line with the published results of the first-in-man study inhealthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic(PK/PD) modeling was applied using efficacy in the murine models (definedeither as antimalarial activity or as survival) in relation to area under the concentration versustime curve (AUC), maximum observed plasma concentration (Cmax), and time above athreshold concentration. The determination of the dose±efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the humanefficacious exposure.ConclusionThe dual activity of ACT-451840 against asexual and sexual stages of P. falciparum andthe activity on P. vivax have the potential to meet the specific profile of a target compoundthat could replace the fast-acting artemisinin component and harbor additional gametocytocidalactivity and, thereby, transmission-blocking properties. The fast parasite reductionratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in aclinical proof-of-concept (POC) study.
PB Public Library of Science
SN 1549-1277
YR 2016
FD 2016-10-01
LK https://hdl.handle.net/10016/38814
UL https://hdl.handle.net/10016/38814
LA eng
NO This work was funded by ActelionPharmaceuticals Ltd and Medicines for MalariaVenture.
DS e-Archivo
RD 30 jun. 2024