title: Dose-Dependent Effect of Piragliatin, a Glucokinase Activator, on the QT Interval Following Short-Term Multiple Doses in Patients With Type 2 Diabetes Mellitus.
abstract: To determine the effect of piragliatin on the QTcS (QT-corrected study-specific) interval, a double-blind, double-dummy, placebo-controlled, active-comparator, 4-period, 4-treatment, 4-sequence randomized crossover trial was performed in 42 patients with type 2 diabetes mellitus who received 100 and 200 mg piragliatin twice daily, placebo, and 400 mg moxifloxacin (on day 1 and day 5 only) for 5 days. In the categorical analyses, piragliatin did not have a clinically significant effect on the QTcS interval at either dose, and the majority of patients were categorized with low risk for maximum change from baseline (≤30 milliseconds) and a maximum postbaseline QTcS interval as normal (≤450 milliseconds). However, in the analysis of variance model, both piragliatin doses crossed the 10-millisecond threshold (100 mg twice daily on day 5, hour 1; 200 mg twice daily on days 1 and 5, hours 1 and 2) with P values indicating statistical significance. Headache and mild hypoglycemia were the most frequent adverse events associated with piragliatin treatment. There appeared that the effect of piragliatin treatment on the QTc interval was dose/exposure dependent following short-term multiple doses. Longer-term monitoring of electrocardiograms with pharmacokinetic exposure should continue, especially at conditions for potentially higher pharmacokinetic exposure.
authors.affiliation: Roche Innovation Center New York, New York, NY, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhi
authors.affiliation: Roche Innovation Center New York, New York, NY, USA.
authors.forename: Suoping
authors.initials: S
authors.lastname: Zhai
authors.affiliation: Roche Innovation Center New York, New York, NY, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Boldrin
mesh_terms: D000328:Adult; D000368:Aged; D044482:Benzeneacetamides / Q000008:administration & dosage* / Q000494:pharmacology; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin
chemical_list: D044482:Benzeneacetamides; D024841:Fluoroquinolones; C553963:piragliatin; D000077266:Moxifloxacin
keywords: glucokinase activator; piragliatin; thorough QT