Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial

Journal of Translational Medicine

Sophie Schaller³  Rebacca M Pruss³  Jean-Louis Abitbol³  Yves Donazzolo¹  Didier Morin⁴  Sylvia Pietri²  Alain Berdeaux⁴  Patrick Berna³  Mathilde Latreille¹  Jean Afxantidis³  Marcel Culcasi²  Magali Michaud³  Corinne Chaimbault³  Hidayat Rahmouni²  Stéphanie Paradis⁴  Sophie Le Lamer³ 

[1] Optimed Lyon, Pavillon 4 N 4O, Centre hospitalier Lyon sud 69 310, Pierre Bénite-France;Aix-Marseille Université, CNRS UMR 7273, Sondes Moléculaires en Biologie & Stress Oxydant, Institut de Chimie Radicalaire, Faculté des Sciences de Saint Jérôme, case 522, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France;Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France;INSERM U955, Equipe 3, Université Paris Est, Faculté de Médecine, Créteil 94000, France

关键词: Phase I clinical trial;    Mitochondrial permeability transition pore;    Functional recovery;    Acute myocardial infarction;   

Others  :  820890
DOI  :  10.1186/1479-5876-12-38

 received in 2013-10-09, accepted in 2014-01-28,  发布年份 2014

【 摘 要 】

Background

Although reperfusion injury has been shown to be responsible for cardiomyocytes death after an acute myocardial infarction, there is currently no drug on the market that reduces this type of injury. TRO40303 is a new cardioprotective compound that was shown to inhibit the opening of the mitochondrial permeability transition pore and reduce infarct size after ischemia-reperfusion in a rat model of cardiac ischemia-reperfusion injury.

Methods

In the rat model, the therapeutic window and the dose effect relationship were investigated in order to select the proper dose and design for clinical investigations. To evaluate post-ischemic functional recovery, TRO40303 was tested in a model of isolated rat heart. Additionally, TRO40303 was investigated in a Phase I randomized, double-blind, placebo controlled study to assess the safety, tolerability and pharmacokinetics of single intravenous ascending doses of the compound (0.5 to 13 mg/kg) in 72 healthy male, post-menopausal and hysterectomized female subjects at flow rates from 0.04 to 35 mL/min (EudraCT number: 2010-021453-39). This work was supported in part by the French Agence Nationale de la Recherche.

Results

In the vivo model, TRO40303 reduced infarct size by 40% at 1 mg/kg and by 50% at 3 and 10 mg/kg given by intravenous bolus and was only active when administered before reperfusion. Additionally, TRO40303 provided functional recovery and reduced oxidative stress in the isolated rat heart model.

These results, together with pharmacokinetic based allometry to human and non-clinical toxicology data, were used to design the Phase I trial. All the tested doses and flow rates were well tolerated clinically. There were no serious adverse events reported. No relevant changes in vital signs, electrocardiogram parameters, laboratory tests or physical examinations were observed at any time in any dose group. Pharmacokinetics was linear up to 6 mg/kg and slightly ~1.5-fold, hyper-proportional from 6 to 13 mg/kg.

Conclusions

These data demonstrated that TRO40303 can be safely administered by the intravenous route in humans at doses expected to be pharmacologically active. These results allowed evaluating the expected active dose in human at 6 mg/kg, used in a Phase II proof-of-concept study currently ongoing.

【 授权许可】

   
2014 Le Lamer et al.; licensee BioMed Central Ltd.

【 图 表 】

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