A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study.
BACKGROUND
Ferroquine (SSR97193) is a candidate anti-malarial currently undergoing clinical trials for malaria. To better understand its pharmacokinetic (PK) and pharmacodynamic (PD) parameters the compound was tested in the experimentally induced blood stage malaria infection model in volunteers.


METHODS
Male and non-pregnant female aged 18-50 years were screened for this phase II, controlled, single-centre clinical trial. Subjects were inoculated with ~1800 viable Plasmodium falciparum 3D7A-infected human erythrocytes, and treated with a single-dose of 800 mg ferroquine. Blood samples were taken at defined time-points to measure PK and PD parameters. The blood concentration of ferroquine and its active metabolite, SSR97213, were measured on dry blood spot samples by ultra-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Parasitaemia and emergence of gametocytes were monitored by quantitative PCR. Safety was determined by recording adverse events and monitoring clinical laboratory assessments during the course of the study.


RESULTS
Eight subjects were enrolled into the study, inoculated with infected erythrocytes and treated with 800 mg ferroquine. Ferroquine was rapidly absorbed with maximal exposure after 4-8 and 4-12 h exposure for SSR97213. Non-compartmental PK analysis resulted in estimates for half-lives of 10.9 and 23.8 days for ferroquine and SSR97213, respectively. Parasite clearance as reported by parasite reduction ratio was 162.9 (95 % CI 141-188) corresponding to a parasite clearance half-life of 6.5 h (95 % CI: 6.4-6.7 h). PK/PD modelling resulted in a predicted minimal parasiticidal concentration of 20 ng/mL, and the single dosing tested in this study was predicted to maintain an exposure above this threshold for 454 h (37.8 days). Although ferroquine was overall well tolerated, transient elevated transaminase levels were observed in three subjects. Paracetamol was the only concomitant treatment among the two out of these three subjects that may have played a role in the elevated transaminases levels. No clinically significant ECG abnormalities were observed.


CONCLUSIONS
The parameters and PK/PD model derived from this study pave the way to the further rational development of ferroquine as an anti-malarial partner drug. The safety of ferroquine has to be further explored in controlled human trials. Trial registration anzctr.org.au (registration number: ACTRN12613001040752), registered 18/09/2013.
QIMR Berghofer Medical Research Institute, Brisbane, Australia.|University of Queensland, Brisbane, Australia.
James S
JS
McCarthy
Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Geneva, Switzerland.
Thomas
T
Rückle
Sanofi Aventis Recherche Développement, Chilly-Mazarin, France.
Elhadj
E
Djeriou
Sanofi Aventis Recherche Développement, Vitry Alfortville, France.
Cathy
C
Cantalloube
Sanofi Aventis Recherche Développement, Chilly-Mazarin, France.
Daniel
D
Ter-Minassian
Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Geneva, Switzerland.|Novartis Consumer Health SA, 2 route de l'Etraz, Case Postale 1279, 1260, Nyon, Switzerland.
Mark
M
Baker
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Peter
P
O'Rourke
QIMR Berghofer Medical Research Institute, Brisbane, Australia.|University of Queensland, Brisbane, Australia.|Mater Health Services, Brisbane, Australia.|Q-Pharm Pty Ltd, Brisbane, Australia.
Paul
P
Griffin
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Louise
L
Marquart
Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Geneva, Switzerland.
Rob
R
Hooft van Huijsduijnen
Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Geneva, Switzerland. moehrlej@mmv.org.
Jörg J
JJ
Möhrle
D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001769:Blood / Q000469:parasitology; D001774:Blood Chemical Analysis; D002853:Chromatography, Liquid; D005260:Female; D005296:Ferrous Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D000075163:Metallocenes; D008875:Middle Aged; D059208:Parasite Load; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome; D055815:Young Adult
D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; C479230:ferroquine
Drug discovery; Ferrochloroquine; Ferroquine; Induced blood-stage malaria (IBSM); Malaria; Pharmacokinetic/pharmacodynamic modelling; Plasmodium falciparum; SSR97193; Translational models