title: 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.affiliation: Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon.
authors.forename: Christian
authors.initials: C
authors.lastname: Supan
authors.forename: Ghyslain
authors.initials: G
authors.lastname: Mombo-Ngoma
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Dal-Bianco
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Ospina Salazar
authors.forename: Saadou
authors.initials: S
authors.lastname: Issifou
authors.forename: Florent
authors.initials: F
authors.lastname: Mazuir
authors.forename: Aziz
authors.initials: A
authors.lastname: Filali-Ansary
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot
authors.forename: Daniel
authors.initials: D
authors.lastname: Ter-Minassian
authors.forename: Michael
authors.initials: M
authors.lastname: Ramharter
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lell
mesh_terms: D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D005296:Ferrous Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D000075163:Metallocenes; D015233:Models, Statistical; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity*; D055815:Young Adult
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; C479230:ferroquine; C001920:4-aminoquinoline