The effect of morning versus evening administration of empagliflozin on its pharmacokinetics and pharmacodynamics characteristics in healthy adults: a two-way crossover, non-randomised trial

Abstract

Background: Empagliflozin is an SGLT2 inhibitor approved for use in patients with diabetes mellitus type 2 (DMT2) with or without other cardiovascular disease. Empagliflozin is taken once daily without rationale on the optimal timing for administration. This study aimed to determine the chronopharmacological effects of morning vs evening administration of empagliflozin (10 mg) in healthy Egyptian adults, by investigating the pharmacokinetics and pharmacodynamics parameters of empagliflozin depending on the intake time. Methods: An open label, sequential, two-way crossover trial comprised of two periods with a washout period of 7 days. All participants received a single oral dose of empagliflozin (JARDIANCE ®; 10 mg film coated tablet) in the evening, and after a seven-day washout period, the morning. Pharmacokinetics parameters (primary endpoints: t max (h), C max (ng/ml), AUC 0-t (ng.h/ml); secondary endpoints: AUC 0 to ∞(ng.h/ml)) were assessed. Method validation was done prior to injection in LC/MS/MS and samples were processed by Liquid-Liquid extraction. The pharmacodynamic profile (UGE 0-24) was determined after method validation (glucose hexokinase method). Results: T max increased by 35% in the evening phase compared to the morning phase, while C max decreased by -6.5% in the evening dose compared to the morning dose. Additionally, AUC 0 to ∞ increased in the evening phase by 8.25% compared to the morning phase. The mean cumulative amount of glucose excreted (UGE ( 0-24)) increased by 43% in the evening dose compared to the morning dose Conclusion: Despite the difference in pharmacokinetics parameters between evening and morning doses, C max, AUC 0-t, AUC 0-∞, didn't differ on the bioequivalence level. In addition, as UGE ( 0-24) didn't statistically differ, thus, we can conclude that there is no statistical significance between the morning and evening doses. Trial registration: Clinal Trials.gov, ID: NCT03895229 (registered on 29 th March 2019).

Keywords: Bioequivalence; Chronopharmacology; Circadian rhythm.; Diabetes Mellitus; Empagliflozin 10 mg; Pharmacodynamic; Pharmacokinetics; evening dose; morning dose.

Conflict of interest statement

No competing interests were disclosed.

Copyright: © 2021 ElDash RM et al.

Figures

Figure 1.. Flow chart of the study design of the effect of morning vs evening administration of empagliflozin (Jardiance® 10mg film coated tablet; manufactured by Boehringer Ingelheim Pharma Gmbh & Co, Germany) on its pharmacokinetics and pharmacodynamics.

Figure 2.. Cumulative amount of glucose excreted for the evening (phase 1) and morning (phase 2) after administration of empagliflozin 10 mg.

Figure 3.. Cumulative amount of glucose excreted over the 24 h for phase 1 and phase 2 after administration of single oral dose of empagliflozin 10 mg.

Figure 4.. Linear (left panel) and semi-logarithmic plot (right panel) for average empagliflozin 10 mg plasma concentration (ng/ml) after evening (phase 1) and morning (phase 2) doses.