Clinical drug investigation · 2018
Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin.
Клиническое исследование I фазыСтатьяНазвание и аннотация: Перевод в очереди
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Duchin Kenneth, Senaldi Giorgio, Warren Vance, Marbury Thomas, Lasseter Kenneth, Zahir Hamim
Аннотация
BACKGROUND AND OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.