title: Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients.
abstract: Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single-dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 × 10(9) /L and 150 × 10(9) /L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Jack G
authors.initials: JG
authors.lastname: Shi
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Emm
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Ryan F
authors.initials: RF
authors.lastname: McGee
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lo
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Landman
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Naresh G
authors.initials: NG
authors.lastname: Punwani
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: William V
authors.initials: WV
authors.lastname: Williams
authors.affiliation: Incyte Corp., Wilmington, DE, USA.
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
keywords: hepatic impairment; pharmacodynamics; pharmacokinetics; renal impairment; ruxolitinib