A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study

Malaria Journal

Research

Thomas Rückle¹  Rob Hooft van Huijsduijnen¹  Jörg J. Möhrle¹  Mark Baker²  Peter O’Rourke³  Louise Marquart³  James S. McCarthy⁴  Paul Griffin⁵  Elhadj Djeriou⁶  Daniel Ter-Minassian⁶  Cathy Cantalloube⁷ 

[1] Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Geneva, Switzerland;Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Geneva, Switzerland;Novartis Consumer Health SA, Case Postale 1279, 2 route de l’Etraz, 1260, Nyon, Switzerland;QIMR Berghofer Medical Research Institute, Brisbane, Australia;QIMR Berghofer Medical Research Institute, Brisbane, Australia;University of Queensland, Brisbane, Australia;QIMR Berghofer Medical Research Institute, Brisbane, Australia;University of Queensland, Brisbane, Australia;Mater Health Services, Brisbane, Australia;Q-Pharm Pty Ltd, Brisbane, Australia;Sanofi Aventis Recherche Développement, Chilly-Mazarin, France;Sanofi Aventis Recherche Développement, Vitry Alfortville, France;

关键词: Induced blood-stage malaria (IBSM);    Drug discovery;    Ferroquine;    Malaria;    Plasmodium falciparum;    Pharmacokinetic/pharmacodynamic modelling;    Translational models;    SSR97193;    Ferrochloroquine;   

DOI  :  10.1186/s12936-016-1511-3

 received in 2016-03-23, accepted in 2016-08-31,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundFerroquine (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.MethodsMale 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.ResultsEight 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.ConclusionsThe 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

【 授权许可】

CC BY   
© The Author(s) 2016