Results from in vitro and in vivo studies evaluating the bioavailability, effects of food, and administration as crushed tablet suspension on vericiguat pharmacokinetics

Abstract

Abstract Objective This article describes in vitro and in vivo studies that aimed to further characterize the biopharmaceutical properties and pharmacokinetic (PK) profile of vericiguat and to guide dosing recommendations. Methods Five open-label, phase I studies characterized the biopharmaceutical aspects of vericiguat, including absolute bioavailability, bioavailabilities of different formulations, dose proportionality, and food effect. Area under the curve (AUC) and maximum plasma concentrations (C max), determined by a noncompartmental analysis, were compared by analysis of variance, and a mixed-effects power model was used to assess dose proportionality. The effect of food on the dissolution of vericiguat was evaluated in vitro using media simulating the gastrointestinal tract under fed and fasted conditions. In vitro dissolution of intact vs crushed vericiguat tablet was assessed in quality control medium (HCl at pH 2), acetate buffer at pH 4.5, and phosphate buffer at pH 6.8. Results Dissolution of vericiguat increased under fed conditions. In healthy subjects, exposure (AUC and C max) increased ~ 40% with food vs fasted state (10 mg intact tablet) confirming a food effect on vericiguat bioavailability. Interindividual variability in exposure decreased ~ 20%, irrespective of meal type. Absolute bioavailability of vericiguat 10 mg (intact tablets, fed) was 93%. Vericiguat 2.5–10 mg demonstrated dose proportionality (intact tablets, fed) in healthy subjects. Dissolution studies showed no differences between the formulations, and this was confirmed with in vivo studies. Conclusion Vericiguat tablets should be administered with food and may be crushed for patients who have difficulty swallowing. Graphical Abstract

Keywords

• Crushed
• Dissolution
• Heart failure
• Dose proportionality
• Bioavailability