The Effect of the Once-Daily Human Glucagon-like Peptide 1 Analog Liraglutide on the Pharmacokinetics of Acetaminophen

Introduction: Acetaminophen is a commonly used analgesic and antipyretic drug, and is frequently used to study gastric emptying. Due to its high permeability and high solubility, acetaminophen can be used as a pharmacologic model for medications with similar characteristics. The objective of this study was to assess the effect of liraglutide on the pharmacokinetics (PK) of acetaminophen in patients with type 2 diabetes. Methods: This was a randomized, placebo-controlled, twoperiod crossover trial in which subjects with type 2 diabetes received placebo or liraglutide. After steady state PK of liraglutide 1.8 mg/ placebo were established, a single dose of acetaminophen 1 g was administered at the time of liraglutide Cmax (maximum concentration). The PK profile of acetaminophen was assessed at 18 time points during the 8-hour post-dosing period. Placebo and liraglutide were considered equivalent with respect to area under the curve (AUC)0-∞ and AUC0-480 min of acetaminophen if the 90% CI for the ratio was fully contained within the limits of 0.80 to 1.25. Results: All subjects (n=18; mean [SD] age 59 [7] years, body mass index [BMI] 29.7 [4.2] kg/m2, and glycated hemoglobin [HbA1c] 7.8% [0.6%]) completed the study. Equivalence was demonstrated between liraglutide 1.8 mg at steady state and placebo, with respect to acetaminophen AUC0-∞ (estimated ratio 1.04; 90% CI: 0.97, 1.10) and acetaminophen AUC0-480 min (estimated ratio 0.95; 90% CI: 0.89, 1.01). During liraglutide, a lower Cmax was observed (estimated ratio 0.69; 90% CI: 0.56, 0.85) and the median acetaminophen tmax occurred 15 minutes later compared with placebo. Conclusion: The overall exposure of acetaminophen following a 1 g dose was comparable for subjects taking liraglutide or placebo, and the clinical impact of the lower Cmax and delay in absorption of acetaminophen was considered to be transient and small, and without clinical relevance. No adjustment for acetaminophen is recommended when used concomitantly with liraglutide.