Conditional Clinical Pharmacokinetic and Pharmacodynamic Study to Assess Prolongation of Cardiac Repolarization

QTc interval prolongation was assessed in a double-blind, placebo- and positive-controlled three-treatment parallel group, and dose-escalation randomized study of ABC (once-daily oral formulation of a semisynthetic opioid, hydrocodone) in 196 healthy subjects. ABC was administrated as multiple doses (once daily for 3 days), titrated from 20 to 160 mg. A central tendency analysis of the individual corrected QT (QTcI) interval data at steady state demonstrated that the maximum mean (90% upper confidence bound) difference in the QTc interval between ABC and placebo (after baseline correction) at steady state was 6 (9) msec, 7 (10) msec, and 10 (13) msec at ABC doses of 80 mg, 120 mg, and 160 mg, respectively. The largest 90% upper confidence bound for the mean differences at ABC 160 mg and 120 mg was above 10 ms, the threshold for regulatory concern as described in ICH E14 guidelines. The largest lower bound of the two-sided 90% CI for the ΔΔQTcI for moxifloxacin was greater than 5 ms, and the moxifloxacin profile over time was adequately demonstrated, suggesting that the assay sensitivity was established.