title: Pharmacokinetics of tofacitinib, a janus kinase inhibitor, in patients with impaired renal function and end-stage renal disease.
abstract: The pharmacokinetics (PK) of tofacitinib were assessed in patients with mild (Cockcroft-Gault creatinine clearance >50 and ≤80 mL/min), moderate (≥30 and ≤50 mL/min), and severe (<30 mL/min) renal impairment, and end-stage renal disease (ESRD) requiring dialysis. Six patients each with normal, mild, moderate, or severely impaired renal function, and 12 patients with ESRD, received single tofacitinib doses of 10 mg. PK data were obtained from blood and dialyzate (patients with ESRD only) samples prior and subsequent to dosing and/or hemodialysis (patients with ESRD only). Relative to patients with normal renal function, mean (90% CI) AUC(0-∞) ratios were 137% (97-195), 143% (101-202), and 223% (157-316) in patients with mild, moderate, and severe renal impairment, respectively. Maximum plasma concentrations (Cmax ) were similar across the four treatment groups. Terminal phase half-life (t1/2 ) increased with severity of renal impairment. Mean AUC(0-∞) in patients with ESRD on a non-dialysis day was similar to that in patients with moderate renal impairment and approximately 40% greater than healthy volunteer data. Mean (SD) dialyzer efficiency (ratio of dialyzer clearance/blood flow entering the dialyzer) was 0.73 (0.15). However, due to extensive non-renal clearance, dialysis procedure is unlikely to result in significant elimination of tofacitinib.
authors.affiliation: Pfizer Specialty Care, Groton, CT, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.forename: Vincent
authors.initials: V
authors.lastname: Chow
authors.forename: Mary
authors.initials: M
authors.lastname: Boy
authors.forename: Cunshan
authors.initials: C
authors.lastname: Wang
authors.forename: Gary
authors.initials: G
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D007674:Kidney Diseases / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D006435:Renal Dialysis
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D053612:Janus Kinases
keywords: Janus kinase inhibitor; end-stage renal disease; pharmacokinetics; renal impairment; tofacitinib