Abstract
Fast-acting antimalarial drugs are needed to address the emergence of artemisinin resistance in the protozoan parasite Plasmodium falciparum, the major cause of severe malaria worldwide. The pyrrolidinamide antimalarial drug MMV367 (GSK3772701) potentially interferes with parasite metabolism mediated by P. falciparum acyl-CoA synthetases 10 and 11. In this volunteer infection study, the antimalarial activity of MMV367 was tested against blood-stage P. falciparum in 12 healthy malaria-naïve adults. The study participants were inoculated with P. falciparum 3D7–infected erythrocytes on day 0 and received a single oral dose of MMV367 at 3 mg (n = 3), 5 mg (n = 2), 10 mg (n = 1), 20 mg (n = 3), 90 mg (n = 2), or 1500 mg (n = 1) on day 8. All participants received artemether-lumefantrine on or before day 24. Maximum MMV367 plasma concentrations occurred 2 to 4 hours postdose, and the elimination half-life was 12.9 to 18 hours. For doses of ≥20 mg, the parasite clearance half-life was 2.2 to 4.3 hours with viable parasites declining more rapidly (elimination half-life of 1.1 to 2.7 hours). A clearance pharmacokinetic/pharmacodynamic model described the relationship between MMV367 concentrations and parasite killing and subsequent clearance of nonviable parasites. Model-derived efficacy parameters included a minimum inhibitory concentration of 6.3 ng/ml (95% CI, 5.2 to 7.8) and a minimum parasiticidal concentration with 90% of maximum effect of 54 ng/ml (95% CI, 43 to 68). No reduction in in vitro susceptibility to MMV367 or genetic determinants of resistance were observed in drug-exposed parasite lines. Most adverse events were attributed to malaria challenge, and none were serious. Higher MMV367 doses were not associated with an increased incidence or severity of adverse events. These findings support further clinical development of MMV367.
