Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study

Jennifer Brown; Ruth Plummer; Todd M Bauer; Stephen Anthony; John Sarantopoulos; Filip De Vos; Mike White; Marco Schupp; Ying Ou; Ulka Vaishampayan

doi:10.1186/s40164-017-0086-1

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study

Exp Hematol Oncol. 2017 Oct 3:6:27. doi: 10.1186/s40164-017-0086-1. eCollection 2017.

Authors

Jennifer Brown¹, Ruth Plummer², Todd M Bauer³, Stephen Anthony⁴, John Sarantopoulos⁵, Filip De Vos⁶, Mike White⁷, Marco Schupp⁸, Ying Ou⁹, Ulka Vaishampayan¹⁰

Affiliations

¹ Beatson West of Scotland Cancer Centre, 1053 Great Western Rd, Glasgow, Scotland G12 0YN UK.
² Sir Bobby Robson Cancer Trials Research Centre, Freeman Hospital, Newcastle, England UK.
³ Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN USA.
⁴ Arizona Oncology, Sedona, AZ USA.
⁵ Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center San Antonio, San Antonio, TX USA.
⁶ Department of Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands.
⁷ Department of Biostatistics, Amgen Inc., South San Francisco, CA USA.
⁸ Department of International Development, Amgen (Europe) GmbH, Zug, Switzerland.
⁹ Department of Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., South San Francisco, CA USA.
¹⁰ Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI USA.

Abstract

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 56 mg/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 AUC_0-last, respectively (27 mg/m² dose); increases at the 56 mg/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.gov NCT01949545; date of registration: September 6, 2013.

Keywords: Advanced malignancy; Carfilzomib; Hepatic impairment; Oncology; Pharmacokinetics; Proteasome inhibitor.

Associated data

ClinicalTrials.gov/NCT01949545