Pharmacokinetics of Ribociclib in Subjects With Hepatic Impairment

Ribociclib is an orally bioavailable, highly selective small-molecule inhibitor of cyclin-dependent kinases 4 and 6. It is currently approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer with a starting dose of 600 mg. Both in vitro and in vivo studies indicate that ribociclib is primarily metabolized in the liver via cytochrome P450 3A4. A phase 1, open-label, multicenter, parallel cohort, single-oral-dose study was conducted to characterize the pharmacokinetics of ribociclib in subjects with varying degrees of hepatic impairment as measured by the Child-Pugh classification. Subjects were divided into 4 cohorts determined by their degree of hepatic impairment: normal, mild, moderate, or severe. Thirty subjects were enrolled and received a single 400 mg dose of ribociclib. Ribociclib exposure was similar in subjects with mild hepatic impairment compared with subjects with normal hepatic function, but was increased by approximately 30% in subjects with moderate and severe hepatic impairment. At a dose of 400 mg, ribociclib was generally well tolerated in all subjects regardless of the level of hepatic impairment. These results indicate that no dose adjustment (recommended dose of ribociclib is 600 mg daily, 3 weeks on and 1 week off) is necessary for patients with mild hepatic impairment but that a reduced dose of 400 mg daily, 3 weeks on and 1 week off in patients with moderate or severe hepatic impairment is recommended.