A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study
| Autor: | Paul M. Griffin, James S. McCarthy, Elhadj Djeriou, Rob Hooft van Huijsduijnen, Cathy Cantalloube, Mark Baker, Thomas Rückle, Daniel Ter-Minassian, Jörg J. Möhrle, Peter O'Rourke, Louise Marquart |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Adolescent Ferrochloroquine Metallocenes Plasmodium falciparum SSR97193 030106 microbiology Biology Pharmacology Pharmacokinetic/pharmacodynamic modelling Real-Time Polymerase Chain Reaction Parasite Load Antimalarials Young Adult 03 medical and health sciences Pharmacokinetics Tandem Mass Spectrometry Gametocyte medicine Humans Ferrous Compounds Malaria Falciparum Adverse effect Active metabolite Ferroquine Induced blood-stage malaria (IBSM) Drug discovery Research Middle Aged biology.organism_classification medicine.disease Healthy Volunteers Malaria 3. Good health Clinical trial Blood Treatment Outcome Infectious Diseases Pharmacodynamics Aminoquinolines Translational models Female Parasitology Blood Chemical Analysis Chromatography Liquid |
| Zdroj: | Malaria Journal |
| ISSN: | 1475-2875 |
| Popis: | 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 Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1511-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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