Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists

Abstract

Background: The P2Y12 receptor antagonist selatogrel is being developed for subcutaneous self-administration with a ready-to-use autoinjector at the onset of acute myocardial infarction (AMI) symptoms. The unique pharmacological profile of selatogrel (fast, potent, and short-acting) can bridge the time gap between the onset of AMI and first medical care. A clinical Phase 1 study showed a time-dependent pharmacodynamic interaction between selatogrel and loading doses of clopidogrel and prasugrel. As treatment switching is a common clinical practice, the assessment of subsequent switching from a clopidogrel loading dose to the first maintenance dose of oral P2Y12 receptor antagonists is highly relevant. Objectives: Model-based predictions of inhibition of platelet aggregation (IPA) for the drugs triggering pharmacodynamic interactions were to be derived to support clinical guidance on the transition from selatogrel to oral P2Y12 receptor antagonists. Methods: Scenarios with selatogrel 16 mg administration or placebo followed by a clopidogrel loading dose and, in turn, prasugrel or ticagrelor maintenance doses at different times of administration were studied. Population pharmacokinetic/pharmacodynamic modeling and simulations of different treatment scenarios were used to derive quantitative estimates for IPA over time. Results: Following selatogrel/placebo and a clopidogrel loading dose, maintenance treatment with ticagrelor or a prasugrel loading dose followed by maintenance treatment quickly achieved sustained IPA levels above 80%. Prior to maintenance treatment, a short time span from 18 to 24 h was identified where IPA levels were predicted to be lower with selatogrel than with placebo if clopidogrel was administered 12 h after selatogrel or placebo. Predicted IPA levels reached with placebo alone and a clopidogrel loading dose at 4 h were consistently lower than with selatogrel administration, followed by a clopidogrel loading dose at 12 h. If a clopidogrel loading dose is administered at 12 h, selatogrel maintains higher IPA levels up to 16 h. IPA levels are subsequently lower than on the placebo until the administration of the first maintenance dose. Conclusions: Model-based predictions informed the transition from selatogrel subcutaneous administration to oral P2Y12 therapy. The application of modeling techniques illustrates the value of employing pharmacokinetic and pharmacodynamic modeling for the simulation of various clinical scenarios of switching therapies.