Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y₁₂ Receptor Antagonist Selatogrel in Healthy Subjects

Background and objectives: Selatogrel is a potent, reversible, and selective antagonist of the platelet P2Y₁₂ receptor currently developed for the treatment of acute myocardial infarction (AMI). In the completed Phase I/II studies, selatogrel was subcutaneously (s.c.) administered as a lyophilizate-based formulation by syringe by a healthcare professional. In the Phase III study, selatogrel will be self-administered s.c. as a liquid formulation with an autoinjector at the onset of AMI symptoms to shorten treatment delay. This clinical bridging study compared the pharmacokinetics (PK) of selatogrel between the different formulations.

Methods: This was a single-center, randomized, open-label, three-period, cross-over Phase I study in 24 healthy subjects. In each period, a single subcutaneous dose of 16 mg selatogrel was administered as (1) a Phase III liquid formulation by autoinjector (Treatment A), (2) a Phase III liquid formulation by prefilled syringe (Treatment B), or (3) a Phase I/II reconstituted lyophilizate-based formulation by syringe (Treatment C). PK parameters including area under the plasma concentration-time curve from zero to infinity (AUC_0-∞), maximum plasma concentration (C_max), time to reach C_max(t_max), and terminal half-life (t_1/2) were determined using noncompartmental analysis. Pharmacodynamic (PD) parameters were estimated using PK/PD modeling, including the time of first occurrence of inhibition of platelet aggregation (IPA) ≥ 80% (t_onset), duration of IPA above 80% (t_duration), and responder rate defined as the percentage of subjects with t_onset ≤ 30 min and t_duration ≥ 3 h. Safety and tolerability were also assessed.

Results: Comparing Treatment A to Treatment C, the exposure (AUC_0-∞) was bioequivalent with a geometric mean ratio (GMR) (90% confidence interval) of 0.95 (0.92-0.97) within the bioequivalence range (0.80-1.25). Absorption following Treatment A was slightly slower with a t_max occurring approximately 30 min later and a 20% lower C_max. The autoinjector itself had no impact on the PK of selatogrel, as similar values of C_max and AUC_0-∞ were determined after administration as a Phase III liquid formulation by autoinjector or by prefilled syringe (i.e., GMR [90% confidence interval] of 1.06 [0.97-1.15] and 0.99 [0.96-1.03] for C_max and AUC_0-∞, respectively). PK/PD modeling predicted that the median t_onset will occur slightly later for Treatment A (7.2 min) compared to Treatment C (4.2 min), while no relevant differences in t_duration and responder rate were estimated between the two treatments. Selatogrel was safe and well tolerated following all three treatments.

Conclusions: PK and simulated PD effects of selatogrel were similar across treatments.

Clinical trial registration: NCT04557280.