Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of the P2Y12 receptor antagonist selatogrel

Publication: Clinical and Translational Science


Selatogrel is a potent and selective reversible P2Y12 receptor antagonist in development for early treatment of acute myocardial infarction via subcutaneous (s.c.)self-injection. Selatogrel is almost exclusively eliminated via the hepatobiliaryroute. Hepatic impairment is associated with reduced drug clearance and primaryhemostasis. This single-center, open-label study investigated the effect of mild andmoderate hepatic impairment on pharmacokinetics (PK) and pharmacodynamics(PD) of a single s.c. dose of selatogrel (16 mg). The study included groups of eightsubjects with mild and moderate hepatic impairment, and matched healthy con-trol subjects. Compared to healthy subjects, exposure to selatogrel in subjects withmild and moderate hepatic impairment was 30% and 108% (maximum plasmaconcentration [Cmax]) and 47% and 212% (area under the concentration-time curvefrom zero to infinity [AUC 0–­∞]) higher, respectively. Hepatic impairment was as-sociated with lower clearance and volume of distribution, whereas plasma proteinbinding was not affected. Marked inhibition of platelet aggregation (IPA > 80%)was attained within 30 min in all subjects and hepatic impairment prolonged IPAduration. Area under the effect curve was 60% and 160% higher in subjects withmild and moderate hepatic impairment, respectively. PK/PD modeling identified achange in the relationship between exposure and IPA, with a steeper concentration-effect relationship in healthy subjects compared to subjects with hepatic impair-ment. The combination of higher exposure and lower half- maximum inhibitoryconcentration resulted in longer lasting effect. In conclusion, hepatic impairmentalters the PK/PD relationship leading to prolonged effects. Therefore, dose adjust-ments may be warranted in subjects with moderate hepatic impairment.

By Uta Schilling, Chih-Hsuan Hsin, Stephane Delahaye, Andreas Krause, Hauke Sebastian Wülfrath, Atef Halabi, Jasper Dingemanse