Abstract
This analysis assessed the relationship between the plasma concentrations of loperamide and its N-desmethyl loperamide meta- bolite (M1) and the potential QT interval prolongation at therapeutic and supratherapeutic doses. The exposure-response analysis was performed using the data from healthy adults participating in a randomized, double-blind, single-dose, four-way (placebo; loperamide 8 mg [therapeutic]; loperamide 48 mg [supratherapeutic]; moxifloxacin 400 mg [positive control]) crossover study. The electrocardiographic measurements extracted from 12-lead digital Holter recordings were time-matched to pharmacokinetic sampling of loperamide/M1. The primary response variable was placebo-adjusted change from baseline in Fridericia-corrected QT interval (ΔΔQTcF); the exposure variable was loperamide and/or M1 concentration. A total of 53 participants with 1408 time-matched pharmacokinetic and ΔΔQTcF measurements was analyzed. Hysteresis between both loperamide and M1 concentrations and ΔΔQTcF was observed with supratherapeutic dose. The pre-specified linear concentration-ΔΔQTcF relationship was driven by M1 concentrations in the effect compartment. The model-predicted mean ΔΔQTcF at the geometric mean of the maximum concentration in the effect compartment was -0.526 msec (90% CI, -1.51 to 0.462) following 8-mg dose (2.1 ng/mL) and 6.06 msec (90% CI, 3.86-8.27) following 48-mg dose (14.2 ng/mL). The upper bound of two-sided 90% CI was < 10 msec for both doses. The sensitivity analysis considering loperamide concentrations in the effect compartment instead of M1 as input for the concentration-ΔΔQTcF analysis confirmed these findings. The data showed that loperamide or M1 does not have an effect on cardiac repolarization that exceeds the threshold of regulatory concern in healthy participants at doses of 8 and 48 mg.
Published Version
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