Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparum

Abstract

The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia and plasma cipargamin concentrations. Parasite regrowth was treated with piperaquine monotherapy to clear asexual parasites, while allowing gametocyte transmissibility to mosquitoes to be investigated. An initial rapid decrease in parasitemia occurred in all participants following cipargamin dosing, with a parasite clearance half-life of 3.99 h. As anticipated from the dose selected, parasite regrowth occurred in all 8 subjects 3 to 8 days after dosing and allowed the pharmacokinetic/pharmacodynamic relationship to be determined. Based on the limited data from the single subtherapeutic dose cohort, a MIC of 11.6 ng/ml and minimum parasiticidal concentration that achieves 90% of maximum effect of 23.5 ng/ml were estimated, and a single 95-mg dose (95% confidence interval [CI], 50 to 270) was predicted to clear 109 parasites/ml. Low gametocyte densities were detected in all subjects following piperaquine treatment, which did not transmit to mosquitoes. Serious adverse liver function changes were observed in three subjects, which led to premature study termination. The antimalarial activity characterized in this study supports the further clinical development of cipargamin as a new treatment for P. falciparum malaria, although the hepatic safety profile of the compound warrants further evaluation. (This study has been registered at ClinicalTrials.gov under identifier NCT02543086.).

Keywords: Plasmodium falciparum; antimalarial agents; malaria.

Copyright © 2021 McCarthy et al.

Figures

FIG 1

Individual subject cipargamin plasma concentration-time profiles. For the purpose of graphing on a logarithmic scale, time points at which cipargamin could not be detected were assigned a value of 1 ng/ml.

FIG 2

Individual subject parasitemia-time profiles over the entire study (A) and up to 2 days post-cipargamin treatment (B). Subjects were inoculated with ∼1,800 viable parasites, and a single 10-mg dose of cipargamin was administered 7 days later (indicated by the vertical dashed line). A single 960-mg dose of piperaquine (PQP) was administered in response to first parasite regrowth (indicated by the shaded area). Standard therapy with artemether-lumefantrine (A/L) was initiated in response to second parasite regrowth or 20 days after cipargamin dosing if second parasite regrowth did not occur. A single dose of 45 mg primaquine (PQ) was administered prior to the end of study to clear gametocytemia. For the purpose of graphing on a logarithmic scale, time points at which parasitemia could not be detected by qPCR were assigned a value of 1 parasite/ml.

FIG 3

Individual subject gametocytemia-time profiles. Gametocyte density was quantified using qRT-PCR assays specific for female gametocytes (pfs25). The vertical dashed lines indicate timing of rescue treatment with artemether-lumefantrine (A/L) and primaquine (PQ). For the purpose of graphing on a logarithmic scale, time points at which gametocytemia could not be detected were assigned a value of 1 gametocyte/ml.