Pharmacokinetics and metabolism of mirogabalin, a novel α₂δ ligand, in rats and monkeys

Abstract

1. The purpose of this study was to investigate the pharmacokinetic behaviour of mirogabalin in rats and monkeys.

2. Pharmacokinetic parameters of mirogabalin after its oral and intravenous administration were determined. Distribution study, mass balance study, and metabolite identification were also conducted after the oral administration of [¹⁴C]mirogabalin.

3. Plasma exposure (C_max and AUC_inf) increased dose-proportionally after the oral administration of mirogabalin at 1, 3, and 10 mg/kg to rats and monkeys. Mean total body clearance (CL_tot) after intravenous administration at 3 mg/kg was 13.5 mL/min/kg in rats and 9.02 mL/min/kg in monkeys, and absolute bioavailability at 3 mg/kg was 97.6% in rats and 85.2% in monkeys. There was a greater recovery of radioactivity in urine than that in faeces after the oral administration of [¹⁴C]mirogabalin. The main radioactive component in the plasma, urine, and faeces was mirogabalin. A204-4455 (lactam form), an oxidised metabolite of mirogabalin, mirogabalin N-glucuronide and O-glucuronide of oxidised A204-4455 were detected as minor components in monkeys and rats.

4. Mirogabalin administered orally was almost completely eliminated via urinary excretion. A small part of the orally administered dose of mirogabalin was metabolised via glucuronidation at the amine and carboxylic acid moiety and oxidation as the primary metabolic pathway.

Keywords:

• Mirogabalin
• pharmacokinetics
• disproportional metabolite
• rat
• monkey

Acknowledgements

The authors thank Hideyuki Shiozawa (Daiichi Sankyo Co., Ltd.) for support with an elucidation of the metabolite structures. The authors also thank Yoshihiro Takahashi, Yuki Ayukawa, and Yoshifumi Kodama (Shin Nippon Biomedical Laboratories, Ltd.) for conducting pharmacokinetic studies on rats and monkeys, Hiroshi Nakai (then of Mitsubishi Chemical Medience Corp.) for conducting mass balance study on monkeys, and Takayuki Miyake (Sekisui Medical Co., Ltd.) for conducting mass balance study, distribution study by autoradiography on rats, and in vitro study using blood and plasma of rats, monkeys, and humans.

Disclosure statement

N. Yamamura, M. Uchiyama, M. Takahashi, T. Honda, and Y. Nishiya are full-time employees of the sponsor, Daiichi Sankyo Co., Ltd.

Additional information

Funding

This work was funded by Daiichi Sankyo Co., Ltd.