Effect of Mild or Moderate Hepatic Impairment on the Pharmacokinetics of Avacopan, a Small-Molecule Complement C5a Receptor Antagonist, for the Treatment of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Autor: Miao S; Amgen Inc., Thousand Oaks, CA, USA., Suso P; Clinical Pharmacology of Miami, Inc., Hialeah, FL, USA., Furst JA; Prosoft Clinical, Chesterbrook, PA, USA., Hudson MG; Prosoft Clinical, Chesterbrook, PA, USA., Trivedi A; Amgen Inc., Thousand Oaks, CA, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2024 Sep; Vol. 13 (9), pp. 1000-1010. Date of Electronic Publication: 2024 Jul 11.
DOI: 10.1002/cpdd.1444
Abstrakt: Avacopan is currently approved in several regions of the world as an oral treatment in combination with standard therapy, including glucocorticoids, for adult patients with severe active antineutrophil cytoplasmic autoantibody-associated vasculitis. In vitro and clinical studies have established that avacopan is primarily eliminated through cytochrome P450 3A4 metabolism. This Phase 1, open-label, single-dose study (ClinicalTrials.gov identifier: NCT06004934) was conducted to evaluate the effect of mild (n = 8) or moderate (n = 8) hepatic impairment compared with normal hepatic function (n = 8) on the pharmacokinetics, safety, and tolerability of a single oral dose of 30 mg of avacopan in patients without active antineutrophil cytoplasmic autoantibody-associated vasculitis. Relative to participants with normal hepatic function, in participants with mild or moderate hepatic impairment, the avacopan area under the plasma concentration-time curve from time 0 to infinity geometric mean ratios (90% confidence intervals) were 1.3 (0.9-2.0) and 1.1 (0.6-2.0), respectively, and the avacopan maximum plasma concentration geometric mean ratios (90% CIs) were 1.0 (0.8-1.3) and 0.8 (0.6-1.1), respectively. The geometric mean ratios of metabolite M1 also revealed no pharmacokinetically relevant increase in the peak exposure of M1 in participants with mild or moderate hepatic impairment. Thus, no avacopan dosage adjustment is necessary for patients with mild or moderate hepatic impairment.
(© 2024, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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