Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y12 Receptor Antagonist Selatogrel in Healthy Subjects
© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:61 |
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| Enthalten in: |
Clinical pharmacokinetics - 61(2022), 5 vom: 27. Mai, Seite 687-695 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zenklusen, Isabelle [VerfasserIn] |
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| Links: |
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| Themen: |
6DPK7O4PR7 |
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| Anmerkungen: |
Date Completed 17.05.2022 Date Revised 24.06.2022 published: Print-Electronic ClinicalTrials.gov: NCT04557280 Citation Status MEDLINE |
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| doi: |
10.1007/s40262-021-01097-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM33497755X |
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| 520 | |a © 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: PK and simulated PD effects of selatogrel were similar across treatments | ||
| 520 | |a CLINICAL TRIAL REGISTRATION: NCT04557280 | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Dingemanse, Jasper |e verfasserin |4 aut | |
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