Absorption, distribution, metabolism and excretion of the P2Y12 receptor antagonist selatogrel after subcutaneous administration in healthy subjects

Abstract

1. The P2Y12 receptor antagonist selatogrel which exhibits rapid inhibition of platelet aggregation following subcutaneous administration is in development for the treatment of acute myocardial infarction.

2. This human ADME study was performed in six healthy male subjects to determine the routes of elimination and to identify/quantify the metabolites of selatogrel at a therapeutically relevant dose of 16 mg [¹⁴C]-radiolabelled selatogrel.

3. The median t_max and t_1/2 of selatogrel was 0.75 h and 4.7 h, respectively. It was safe and well tolerated based on adverse event, ECG, vital sign and laboratory data.

4. Geometric mean total recovery of [¹⁴C]-radioactivity was 94.9% of which 92.5% was recovered in faeces and 2.4% in urine.

5. Selatogrel was the most abundant entity in each matrix. In plasma, no major metabolite was identified. In excreta, the glucuronide M21 (14.7% of radioactivity) and the mono-oxidized A1 (6.2%) were the most abundant metabolites in urine and faeces, respectively.

6. Overall, none of the metabolic pathways contributed to a relevant extent to the overall elimination of selatogrel, i.e. by more than 25% as defined per regulatory guidance. Hence, no pharmacokinetic interaction studies with inhibitors or inducers of drug-metabolizing enzymes are warranted for clinical development of selatogrel.

Keywords:

• Mass balance
• metabolite profiling
• P2Y12 receptor
• acute myocardial infarction
• ADME

Acknowledgements

Margaux Boehler and Racheal Rowles are acknowledged for their scientific and operational support of this study. Susanne Globig is acknowledged for her support regarding bioanalytical aspects.

Disclosure statement

Mike Ufer, Christine Huynh, Eva Caroff and Jasper Dingemanse are full-time employees of Idorsia Pharmaceuticals Ltd.

Additional information

Funding

Idorsia Pharmaceuticals Ltd provided funding for this clinical trial.