Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial. - Archive ouverte HAL Access content directly
Journal Articles Journal of Translational Medicine Year : 2014

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

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Sophie Le Lamer
  • Function : Author
  • PersonId : 952774
Hidayat Rahmouni
  • Function : Author
  • PersonId : 952776
Corinne Chaimbault
  • Function : Author
  • PersonId : 952777
Magali Michaud
  • Function : Author
  • PersonId : 952778
Marcel Culcasi
Jean Afxantidis
  • Function : Author
  • PersonId : 952780
Mathilde Latreille
  • Function : Author
  • PersonId : 952781
Patrick Berna
  • Function : Author
  • PersonId : 952782
Alain Berdeaux
  • Function : Author
  • PersonId : 860422
Sylvia Pietri
  • Function : Author
  • PersonId : 952783
Didier Morin
  • Function : Author
  • PersonId : 864860
Yves Donazzolo
  • Function : Author
  • PersonId : 952784
Jean-Louis Abitbol
  • Function : Author
  • PersonId : 952785
Rebacca Pruss
  • Function : Author
  • PersonId : 952786
Sophie Schaller
  • Function : Correspondent author
  • PersonId : 872901

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Abstract

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.
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Dates and versions

inserm-00946700 , version 1 (14-02-2014)

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Sophie Le Lamer, Stéphanie Paradis, Hidayat Rahmouni, Corinne Chaimbault, Magali Michaud, et al.. Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial.. Journal of Translational Medicine, 2014, 12 (1), pp.38. ⟨10.1186/1479-5876-12-38⟩. ⟨inserm-00946700⟩
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