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.

• Authors: Christian Supan, Ghyslain Mombo-Ngoma, Matthias P Dal-Bianco, Carmen L Ospina Salazar, Saadou Issifou, Florent Mazuir, Aziz Filali-Ansary, Christophe Biot, Daniel Ter-Minassian, Michael Ramharter, Peter G Kremsner, Bertrand Lell
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 6 Pg. 3165-73 (Jun 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22430976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoquinolines
• Antimalarials
• Ferrous Compounds
• Metallocenes
• ferroquine
• 4-aminoquinoline

Topics

• Adolescent
• Adult
• Aminoquinolines (pharmacokinetics, therapeutic use)
• Antimalarials (pharmacokinetics, therapeutic use)
• Clinical Trials, Phase I as Topic
• Ferrous Compounds (pharmacokinetics, therapeutic use)
• Humans
• Malaria, Falciparum (drug therapy)
• Male
• Metallocenes
• Models, Statistical
• Plasmodium falciparum (drug effects, pathogenicity)
• Young Adult