A definitive QT study incorporating step-wise dose escalation to steady-state

Abstract

Background Controversy exists surrounding the optimal study design to evaluate a drug's effect on the QT interval. Confounding issues include drug interactions, presence of metabolites, and tolerability at high dosages. These issues impacted a QT evaluation of duloxetine. Methods An initial study assessed the rate and feasibility of adaptive step-wise dose escalations to steady-state at supratherapeutic dosages and the linearity of the dose-exposure relationship. A second study measured exposures during maximal inhibition of drug metabolism. ECGs were collected per ICH draft guidelines. Results The final design was a randomized, double-blind, placebo-controlled, two-way crossover study in healthy females, with a single dose of moxifloxacin as a positive control. Duloxetine was dosed per preliminary studies, which defined tolerability of a step-wise dosing scheme to exposures approximating those after maximal inhibition of 2D6 and 1A2 (5X the recommended dosage). Replicate ECGs were collected at baseline and compared with time-matched ECGs during placebo, duloxetine, and positive control periods at 4 separate times during the 12h-dosing interval. The primary endpoint was Fridericia's corrected QT interval with a sample size to detect a 7.5 msec change from baseline due to drug. Conclusions Tolerability issues and confounding pharmacodynamic factors can complicate study designs for QTc assessment. Preliminary studies can define limitations and maximize efficiency of study design. Clinical Pharmacology & Therapeutics (2005) 77, P12–P12; doi: 10.1016/j.clpt.2004.11.049