Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy

Abstract

Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

A Class of Tricyclic Compounds Blocking Malaria Parasite Oocyst Development and Transmission

“…Ketotifen has been extensively tested in animals for safety and toxicity (38,40). Large doses have been tested in rats and rabbits with minimum side effects, including during pregnancy.…”

“…The terminal elimination half-life is 2 to 27 h, with a mean half-life of 12 h. Approximately 60 to 70% of a dose of ketotifen is eliminated in the urine within 48 h, with the remainder excreted in the feces; ϳ50% is recovered as ketotifen-N-glucuronide and ϳ10% as norketotifen (38). In a recent study evaluating antimalarial activity, both ketotifen and its metabolite norketotifen were shown to be active against schizonts and liver-stage Plasmodium berghei parasites, and the plasma drug concentration was maintained above the IC 50 for approximately 8 h for ketotifen and over 24 h for norketotifen (38,40). The form of ketotifen metabolite(s) that is active against the sexual stages of the malaria parasite is still unknown.…”

“…Ketotifen may prevent further relapses if a similar treatment regimen is given. Indeed, ketotifen and its metabolite, norketotifen, have recently been shown to be active against the liver stage of P. berghei; no evidence of live parasites was detected after treatment with both drugs at 160 mg/kg/day for 3 days (40).…”

Cytochrome P450 2D-mediated metabolism is not necessary for tafenoquine and primaquine to eradicate the erythrocytic stages of Plasmodium berghei

“…To probe this relationship, an established murine P. berghei challenge model was utilized involving an intravenous (IV) P. berghei sporozoite inoculation on day 0 that results in a hepatic infection followed by subsequent erythrocytic infection on day 3 [16, 17]. Vehicle control mice are generally deceased or euthanized due to morbidity within a week.…”

“…Vehicle control mice are generally deceased or euthanized due to morbidity within a week. The utility of this model has also been demonstrated for non-8-aminoquinoline structural motifs [16]. As shown in Table 1, administering drugs days −1, 0, and/or +1 versus day +4 post infection allows for the direct comparison of hepatic causal prophylactic activity versus anti-erythrocytic activity within the same challenge model.…”