Evaluation of the Effect of Loperamide on the Cardiac Repolarization Interval Using Exposure-Response Analysis
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…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 53 participants or records.
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