title: The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor.
abstract: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration-time profile from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment-emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment.
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Nervin
authors.initials: N
authors.lastname: Lawendy
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Lamba
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Chan
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Christine W
authors.initials: CW
authors.lastname: Alvey
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005431:Florida; D005838:Genotype; D006801:Humans; D000075242:Janus Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008107:Liver Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index
chemical_list: D000075242:Janus Kinase Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: clinical pharmacology; hepatic impairment; janus kinase inhibitor; pharmacokinetics; tofacitinib