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

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Abstract

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 (AUC0–∞), maximum plasma concentration (Cmax), time to reach Cmax(tmax), and terminal half-life (t1/2) 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% (tonset), duration of IPA above 80% (tduration), and responder rate defined as the percentage of subjects with tonset ≤ 30 min and tduration ≥ 3 h. Safety and tolerability were also assessed.

Results

Comparing Treatment A to Treatment C, the exposure (AUC0–∞) 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 tmax occurring approximately 30 min later and a 20% lower Cmax. The autoinjector itself had no impact on the PK of selatogrel, as similar values of Cmax and AUC0–∞ 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 Cmax and AUC0–∞, respectively). PK/PD modeling predicted that the median tonset will occur slightly later for Treatment A (7.2 min) compared to Treatment C (4.2  min), while no relevant differences in tduration 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.

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Acknowledgements

The authors thank Mark Enzler from Swiss BioQuant AG, Reinach, Switzerland for the bioanalytical conduct of this study and Beya Khouildi, Anne-Sophie Guern, and Anna Kaufmann for their dedicated support in the conduct of this study.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland

    Isabelle Zenklusen, Chih-Hsuan Hsin, Uta Schilling, Andreas Krause, Mike Ufer & Jasper Dingemanse

  2. Altasciences Clinical, Inc. 10103 Metcalf Avenue, Overland Park, KS 66212, USA

    Martin Kankam

Authors
  1. Isabelle Zenklusen
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  2. Chih-Hsuan Hsin
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  3. Uta Schilling
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  4. Martin Kankam
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  5. Andreas Krause
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  6. Mike Ufer
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  7. Jasper Dingemanse
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Corresponding author

Correspondence to Isabelle Zenklusen.

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Funding

The study was funded by Idorsia Pharmaceuticals Ltd.

Conflict of interest

During the conduct of this study, IZ, CH, US, AK, MU, and JD were full-time employees of Idorsia Pharmaceuticals Ltd and MK was the principal investigator.

Ethics approval

The protocol was approved by the Midlands Independent Review Board, USA. This study was performed according to Good Clinical Practice and in accordance with the principles of the Declaration of Helsinki.

Consent to participate

All participants provided written informed consent prior to the initiation of study-related procedures.

Consent for publication

Not applicable (no personal data were reported).

Data availability

Datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The model codes are available upon request.

Author contributions

IZ wrote the manuscript, CH and AK conducted the PK/PD modeling, US, MU, and JD designed and analyzed the study, and MK was the principal investigator of the study. All authors revised the manuscript critically for important intellectual content and approved the version to be submitted.

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Zenklusen, I., Hsin, CH., Schilling, U. et al. Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y12 Receptor Antagonist Selatogrel in Healthy Subjects. Clin Pharmacokinet 61, 687–695 (2022). https://doi.org/10.1007/s40262-021-01097-9

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  • DOI: https://doi.org/10.1007/s40262-021-01097-9

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