title: Influence of hepatic impairment on lenvatinib pharmacokinetics following single-dose oral administration.
abstract: This open-label, single-dose study assessed lenvatinib pharmacokinetics (PK) in subjects with normal hepatic function (n = 8) and mild, moderate, or severe hepatic impairment (n = 6 each). Subjects received 10 mg oral lenvatinib, except those with severe hepatic impairment (5 mg). Plasma and urine samples were collected over 14 days; free and total lenvatinib and its metabolites were analyzed using validated chromatography/spectrometry. PK parameters were estimated using noncompartmental analysis. There were no clinically meaningful effects of mild or moderate hepatic impairment on lenvatinib PK. Dose-normalized Cmax for free lenvatinib was 7.0, 3.7, 5.7, and 5.6 ng/mL in subjects with normal hepatic function, mild, moderate, and severe hepatic impairment, respectively. There was no consistent trend, although dose-normalized Cmax was lower for all subjects with hepatic impairment. AUCs increased 170% and t1/2 increased (37 versus 23 hours) in subjects with severe hepatic impairment. Changes in exposure based on total plasma concentrations were generally less than those based on free concentrations, suggesting changes in plasma protein binding in subjects with severe hepatic impairment. Lenvatinib was generally well tolerated. Subjects with severe hepatic impairment should begin lenvatinib treatment at a reduced dose of 14 mg versus 24 mg for subjects with normal liver function and subjects with mild or moderate hepatic impairment.
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Shumaker
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Aluri
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Fan
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Gresel
authors.initials: G
authors.lastname: Martinez
authors.affiliation: SAJE Consulting LLC, Baltimore, MD, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Pentikis
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ren
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001711:Biotransformation; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000503:physiopathology*; D008107:Liver Diseases / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology* / Q000652:urine; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D065667:Renal Elimination; D012720:Severity of Illness Index; D053719:Tandem Mass Spectrometry; D014481:United States
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib
keywords: angiogenesis inhibitor; hepatic impairment; lenvatinib; pharmacokinetics; tyrosine kinase inhibitor