Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin

Abstract

Mirogabalin is an α2δ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where hepatic impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or moderate hepatic impairment alters the pharmacokinetics of mirogabalin. Serial blood samples were collected for determination of maximum observed concentration, time to maximum concentration, and area under the concentration-time curve until the last quantifiable concentration of the active free form (A200-700) and inactive lactam metabolite (A204-4455) of mirogabalin. The A200-700 maximum observed concentration was similar in subjects with mild hepatic impairment but lower in subjects with moderate hepatic impairment vs. control subjects. The A204-4455 maximum observed concentration was lower in subjects with mild and moderate hepatic impairment vs. control groups. The A200-700 area under the concentration-time curve until the last quantifiable concentration was slightly lower in subjects with mild hepatic impairment and slightly higher in subjects with moderate hepatic impairment vs. control subjects. Peak A204-4455 levels were approximately 22% and 31% lower for subjects with mild and moderate hepatic impairment vs. control individuals, respectively. Exposure to A204-4455 was approximately 37% lower in subjects with mild hepatic impairment but unaffected in subjects with moderate hepatic impairment vs. control groups. Two subjects in the mild hepatic impairment group reported a treatment-emergent adverse event of mild somnolence. No serious or severe treatment-emergent adverse events, discontinuations as a result of treatment-emergent adverse events, or deaths were reported. Mild hepatic impairment resulted in lower A200-700 and A204-4455 exposure, while moderate hepatic impairment did not affect A200-700 exposure. Overall, mild-to-moderate hepatic impairment did not have a significant effect on mirogabalin exposure. A single 15-mg dose of mirogabalin was well tolerated by subjects with mild or moderate hepatic impairment.