title: Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial.
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.
authors: Sophie
authors: S
authors: Le Lamer
authors: Stéphanie
authors: S
authors: Paradis
authors: Hidayat
authors: H
authors: Rahmouni
authors: Corinne
authors: C
authors: Chaimbault
authors: Magali
authors: M
authors: Michaud
authors: Marcel
authors: M
authors: Culcasi
authors: Jean
authors: J
authors: Afxantidis
authors: Mathilde
authors: M
authors: Latreille
authors: Patrick
authors: P
authors: Berna
authors: Alain
authors: A
authors: Berdeaux
authors: Sylvia
authors: S
authors: Pietri
authors: Didier
authors: D
authors: Morin
authors: Yves
authors: Y
authors: Donazzolo
authors: Jean-Louis
authors: JL
authors: Abitbol
authors: Rebacca M
authors: RM
authors: Pruss
authors: Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. sschaller@trophos.com.
authors: Sophie
authors: S
authors: Schaller
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010091:Oximes / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012632:Secosteroids / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D034421:Sus scrofa; D057170:Translational Research, Biomedical
chemical_list: D008081:Liposomes; D010091:Oximes; D012632:Secosteroids; C549911:3,5-seco-4-norcholestan-5-one oxime-3-ol