TY - JOUR
T1 - Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment
T2 - An open-label, single-arm, phase 1 study
AU - Brown, Jennifer
AU - Plummer, Ruth
AU - Bauer, Todd M.
AU - Anthony, Stephen
AU - Sarantopoulos, John
AU - Vos, Filip
AU - White, Mike
AU - Schupp, Marco
AU - Ou, Ying
AU - Vaishampayan, Ulka
N1 - Funding Information:
The authors wish to thank all of the patients, families, caregivers, research nurses, study coordinators, and support staff who contributed to this study. J. Brown acknowledges Medicine Centres, funded by Cancer Research UK, Department of Health (England) and the Chief Scientist Office, Scotland. J. Sarantopoulos acknowledges the Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, San Antonio, TX (Cancer Center Support Grant P30CA054174). This study was supported by Amgen Inc. Medical writing and editorial assistance was provided by BlueMomentum, an Ashfield Company, part of UDG Healthcare PLC, and funded by Amgen Inc.
PY - 2017/10/3
Y1 - 2017/10/3
N2 - Background: Carfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function. Methods: Patients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles. The primary objective was to assess the influence of hepatic impairment on carfilzomib PK following 27 and 56mg/m2 doses. Results: The majority of patients enrolled in this study had solid tumors (n=44) vs. MM (n=2) since patients with multiple myeloma do not tend to have severe hepatic impairment in the same way as patients with solid tumors. A total of 11 normal and 17 mild, 14 moderate, and 4 severe hepatic impairment patients were enrolled. Compared with patients with normal hepatic function, patients with mild and moderate hepatic impairment had 44 and 26% higher carfilzomib AUC0-last, respectively (27mg/m2 dose); increases at the 56mg/m2 dose were 45 and 21%, respectively. Considerable PK variability (% coefficient of variation in AUC ≤100%) was discerned and no consistent trend of increasing exposure resulting from increasing hepatic impairment severity (moderate vs. mild) was seen. The observed adverse event (AE) profile in patients of mostly solid tumors was consistent with the known safety profile of carfilzomib, with the exception of an increased frequency of AEs consistent with hepatic function abnormalities. Conclusions: In this population of primarily advanced solid tumor patients, patients with mild and moderate hepatic impairment had approximately 20-50% higher carfilzomib AUC vs. normal hepatic function patients. These increases are unlikely to be clinically significant, in light of the intrinsic PK variability and exposure-response relationship of carfilzomib. Trial registration http://clinicaltrials.govNCT01949545; date of registration: September 6, 2013
AB - Background: Carfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function. Methods: Patients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles. The primary objective was to assess the influence of hepatic impairment on carfilzomib PK following 27 and 56mg/m2 doses. Results: The majority of patients enrolled in this study had solid tumors (n=44) vs. MM (n=2) since patients with multiple myeloma do not tend to have severe hepatic impairment in the same way as patients with solid tumors. A total of 11 normal and 17 mild, 14 moderate, and 4 severe hepatic impairment patients were enrolled. Compared with patients with normal hepatic function, patients with mild and moderate hepatic impairment had 44 and 26% higher carfilzomib AUC0-last, respectively (27mg/m2 dose); increases at the 56mg/m2 dose were 45 and 21%, respectively. Considerable PK variability (% coefficient of variation in AUC ≤100%) was discerned and no consistent trend of increasing exposure resulting from increasing hepatic impairment severity (moderate vs. mild) was seen. The observed adverse event (AE) profile in patients of mostly solid tumors was consistent with the known safety profile of carfilzomib, with the exception of an increased frequency of AEs consistent with hepatic function abnormalities. Conclusions: In this population of primarily advanced solid tumor patients, patients with mild and moderate hepatic impairment had approximately 20-50% higher carfilzomib AUC vs. normal hepatic function patients. These increases are unlikely to be clinically significant, in light of the intrinsic PK variability and exposure-response relationship of carfilzomib. Trial registration http://clinicaltrials.govNCT01949545; date of registration: September 6, 2013
KW - Advanced malignancy
KW - Carfilzomib
KW - Hepatic impairment
KW - Oncology
KW - Pharmacokinetics
KW - Proteasome inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85030536155&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030536155&partnerID=8YFLogxK
U2 - 10.1186/s40164-017-0086-1
DO - 10.1186/s40164-017-0086-1
M3 - Article
AN - SCOPUS:85030536155
VL - 6
JO - Experimental Hematology and Oncology
JF - Experimental Hematology and Oncology
SN - 2162-3619
IS - 1
M1 - 27
ER -