Pharmacokinetics of ferroquine, a novel 4-aminoquinoline, in asymptomatic carriers of Plasmodium falciparum infections

Abstract

Ferroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomatic Plasmodium falciparum infection were administered a single oral dose (n = 40) or a repeated oral dose (n = 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (n = 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([C(max)] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study, C(max) and overall cumulated exposure to ferroquine (AUC(cum)) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (t(max)) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.

Fig 1

Pathways of ferroquine metabolism. FQ is metabolized via a major dealkylation pathway (>50% of global FQ metabolism) into N-desmethyl-ferroquine (DMFQ) and then into N-di-desmethyl-ferroquine (di-DMFQ). Another pathway results in the formation of 7-chloroquinolin-4-amine. Cytochromes identified to be involved in FQ metabolism are CYP2C9, CYP3A, and CYP2D6.

Fig 2

Ferroquine single-dose study mean (standard deviation) blood concentration-time profile at doses of 400, 800, 1,200, 1,400, and 1,600 mg over a 24-h period.

Fig 3

Food interaction study: mean blood concentration-time profile over a 24-h period after administration of 100 mg of ferroquine as an oral single dose under fasted and fed conditions.

Fig 4

Metabolite/parent compound ratio for the two main metabolites of FQ, DMFQ and di-DMFQ, after administration of a single dose of FQ in a dose range from 400 mg to 1,600 mg. Values are geometric mean.

Fig 5

Pharmacokinetic profile of ferroquine, its active metabolite, DMFQ, and di-DMFQ over 60 days after administration of 400 and 800 mg of ferroquine once daily for 3 days. Ferroquine IC₉₉s obtained from in vitro studies (9) are overlaid.

Fig 6

Pharmacokinetic profile of ferroquine and its main active metabolite, DMFQ, and di-DMFQ over 62 days after administration of 400 mg of ferroquine once daily for 3 days. Ferroquine IC₉₉s obtained from in vitro studies (9) are overlaid.