title: A thorough QTc study demonstrates that olmesartan medoxomil does not prolong the QTc interval.
abstract: Two studies (ROADMAP and ORIENT) evaluating the renoprotective effects of olmesartan medoxomil (OM) in patients with type 2 diabetes suggested OM is associated with increased cardiovascular mortality. We conducted a thorough QTc study to evaluate the effects of OM on cardiac repolarization. A randomized, double-blind, phase 1 study was conducted per E14 Guidance to assess the effects of single doses of OM therapeutic dose (40 mg), OM supratherapeutic dose (160 mg), placebo, or moxifloxacin (MOXI; 400 mg) on QTc in 56 healthy subjects. The primary endpoint was the baseline-adjusted, placebo-corrected QTc interval using Fridericia's formula (ΔΔQTcF) for OM and MOXI. Assay sensitivity was concluded if lower limit of 1-sided 95%CI > 5 milliseconds of ΔΔQTcF for MOXI. No threshold pharmacologic effect for OM was concluded if upper limit of 1-sided 95%CI <10 milliseconds for ΔΔQTcF at any timepoint. Pharmacokinetics, ECGs, and safety were assessed. Assay sensitivity was demonstrated. The largest upper limit of the 1-sided 95%CI for ΔΔQTcF was <5 milliseconds for OM. No clinically significant changes were observed in ECGs. Pharmacokinetics and safety profile were consistent with previous data. Therapeutic and supratherapeutic OM doses had no clinically significant effect on cardiac repolarization and were well tolerated.
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mendell
authors.affiliation: Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Matsushima
authors.affiliation: Celerion Pharma Services, Tempe, AZ, USA.
authors.forename: Terry E
authors.initials: TE
authors.lastname: O'Reilly
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D064368:Healthy Volunteers; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000068557:Olmesartan Medoxomil / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000068557:Olmesartan Medoxomil
keywords: QTc interval; angiotensin receptor blocker; cardiac safety; olmesartan