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.)

中文翻译：

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定义西帕加明在实验性受血期恶性疟原虫感染的健康志愿者中的抗疟活性

螺环吲哚酮西敏是一种抑制疟原虫ATP4的新型抗疟疾化合物，目前正在临床开发中。这项研究旨在表征西帕加明在实验上感染了血液阶段恶性疟原虫的健康志愿者中的抗疟活性。八名受试者静脉内接种了寄生虫感染的红细胞，并在7天后接受了一次口服10 mg西米加明的口服剂量。收集血液样本以监测寄生虫病和血浆西葫芦素浓度的发生和清除。寄生虫的再生长用哌喹单一疗法治疗，以清除无性寄生虫，同时允许调查配子体对蚊子的传播能力。服用西葫芦素后所有参与者的寄生虫血症最初都迅速减少，寄生虫清除半衰期为3.99小时。如从所选择的剂量所预期的，在给药后3至8天，所有8名受试者中发生了寄生虫再生长，并使得可以确定药代动力学/药效学关系。基于来自单个亚治疗剂量组的有限数据，MIC为11。⁹寄生虫/毫升。哌喹治疗后，所有受试者均检测到低配子体密度，但未传播至蚊子。在三名受试者中观察到严重的不良肝功能变化，导致研究提前终止。尽管该化合物的肝脏安全性值得进一步评估，但该研究中表征的抗疟活性支持西帕加明作为恶性疟原虫疟疾的新疗法的进一步临床开发。（该研究已在ClinicalTrials.gov上注册，标识为NCT02543086。）