title: Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K.
abstract: Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage. The syndrome was reproduced in only 1 male mouse after continuous dietary dosing, and TMC125 was demonstrated to affect coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [APTT], clotting factors II, VII and XI), particularly in males. This was counteracted by vitamin K supplementation, supporting the hypothesis that the effects were mediated via a vitamin K deficiency. It is therefore concluded that the observed cardiac changes were not caused by a direct cardiotoxic effect but occurred after a state of disabled clotting ability with subsequent effects on mouse cardiac muscle. Therefore, clotting times can be used as adequate safety biomarkers in clinical trials. To date, no changes have been observed at therapeutic doses of TMC125, following human monitoring of PT and APTT. One other NNRTI, Efavirenz (Sustiva), has been reported to cause prolongation of coagulation times in rats and monkeys.
authors: Johnson & Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. sdjonghe@prdbe.jnj.com
authors: Sandra
authors: S
authors: De Jonghe
authors: Johan
authors: J
authors: Verbeeck
authors: Petra
authors: P
authors: Vinken
authors: Lieve
authors: L
authors: Lammens
authors: Sofie
authors: S
authors: Starckx
authors: Sophie
authors: S
authors: Lachau-Durand
authors: Marie-Paule
authors: MP
authors: Bouche
authors: Bart
authors: B
authors: Willems
authors: Werner
authors: W
authors: Coussement
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D009202:Cardiomyopathies / Q000209:etiology* / Q000517:prevention & control; D004032:Diet; D005260:Female; D006321:Heart / Q000187:drug effects; D006474:Hemorrhagic Disorders / Q000209:etiology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D009570:Nitriles; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011724:Pyridazines / Q000633:toxicity*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D020107:Troponin T / Q000097:blood; D014812:Vitamin K / Q000627:therapeutic use*; D014813:Vitamin K Deficiency / Q000209:etiology* / Q000517:prevention & control
chemical_list: D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D020107:Troponin T; C451734:etravirine; D014812:Vitamin K