Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment<sup/>.
This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUClast; unbound) in mild, moderate, and severe cohorts was 4.1-, 9.8-, 13.4-fold higher, respectively. Terminal half-life trended slightly longer in moderately and severely impaired subjects, but risk of accumulation on repeated dosing appears negligible as half-life did not exceed 10 h. Based on observed effects on exposure, reduced doses are recommended for patients with mild and moderate liver impairment (Child-Pugh Class A and B), whereas 140 mg is considered too high for severely impaired patients (Class-C). A single dose of 140 mg was well tolerated in this study (NCT01767948).
a Janssen Research & Development , San Diego , CA , USA.
Jan
J
de Jong
b Janssen Research & Development , Raritan , NJ , USA.
Donna
D
Skee
c Janssen Research & Development , Beerse , Belgium.
Peter
P
Hellemans
b Janssen Research & Development , Raritan , NJ , USA.
James
J
Jiao
c Janssen Research & Development , Beerse , Belgium.
Ronald
R
de Vries
c Janssen Research & Development , Beerse , Belgium.
Dominique
D
Swerts
d Texas Liver Institute, University of Texas Health Science Center San Antonio , TX , USA.
Eric
E
Lawitz
e Orlando Clinical Research Center , Orlando , FL , USA.
Thomas
T
Marbury
f New Orleans Center for Clinical Research , Knoxville , TN , USA.
William
W
Smith
g Pharmacyclics LLC , Sunnyvale , CA , USA.
Juthamas
J
Sukbuntherng
c Janssen Research & Development , Beerse , Belgium.
Erik
E
Mannaert
D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D015994:Incidence; D008107:Liver Diseases / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000453:epidemiology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index
D015415:Biomarkers; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine
Hepatic impairment; ibrutinib; pharmacokinetic; safety