KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects

Abstract

KAE609 [(19R,39S)-5,79-dichloro-69-fluoro-39-methyl-29,39,49,99-tetrahydrospiro[indoline-3,19-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. This study investigated the absorption, distribution, metabolism, and excretion of KAE609 after oral administration of [ 14 C]KAE609 in healthy subjects. After oral administration to human subjects, KAE609 was the major radioactive component (approximately 76% of the total radioactivity in plasma); M23 was the major circulating oxidative metabolite (approximately 12% of the total radioactivity in plasma). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for approximately 3%-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized, such that KAE609 accounted for approximately 32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported semen discoloration after dosing in prior studies; therefore, semen samples were collected once from each subject to further evaluate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the rationale that this yellow-colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biologic matrices albeit at low levels. All 19 recombinant human cytochrome P450 enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was used to generate a sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in humans are summarized herein and M23 is the major metabolite in plasma and excreta.

Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria

“…As parasite densities decline, the more slowly cleared sexual-stage parasites and any drug-refractory forms comprise an increasing proportion of the DNA signal. Recent ex vivo studies suggest that cipargamin does not induce the same refractory forms observed with artemisinin drugs ( 18 ), so the nature of the parasite forms, which persist despite exposure to high cipargamin concentrations, clearly requires further study ( 18 , 19 ). Low-dose primaquine was not given as a rapid gametocytocide in this study because cipargamin was considered to have gametocytocidal activity, but this was insufficient.…”

Generation and characterisation of P. falciparum parasites with a G358S mutation in the PfATP4 Na+ pump and clinically relevant levels of resistance to some PfATP4 inhibitors

“…If parasites with a similar level of resistance to the in vitro selected parasites were to emerge in the field, it is likely that cipargamin would remain effective against them. In clinical trials, cipargamin has been found to reach supramicromolar concentrations in human plasma for sustained periods (28,(35)(36)(37).…”

Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

“…We have previously disclosed studies leading to the discovery of (+)-SJ733 (9), which has recently completed Phase 1 trials (10). (+)-SJ733 is the second inhibitor of PfATP4, a parasite proton-sodium antiporter, that has entered clinical trials -the other being cipargamin (11)(12)(13). We have shown that PfATP4 inhibitors selectively induce eryptosis of infected red blood cells leading to a rapid clearance of infected erythrocytes in vivo (9).…”