title: Population Pharmacokinetics and Exposure-Response Relationship of Carfilzomib in Patients With Multiple Myeloma.
abstract: A population pharmacokinetic (PK) model and exposure-response (E-R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m2(20 mg/m2in cycle 1 and, if tolerated, escalated to 56 mg/m2on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant. Despite inclusion of different populations (relapsed or relapsed/refractory), treatments (carfilzomib monotherapy or combination therapy), infusion lengths (2 to 10 minutes or 30 minutes), and different doses, the E-R analysis of efficacy showed that after adjusting for baseline characteristics, higher area under the concentration-time curve was associated with improved overall response rate (ORR), from 15 to 20/56 mg/m2. No positive relationships between maximum concentration and ORR were identified, indicating that ORR would not be expected to be impacted by infusion length. For safety end points, no statistically significant relationship between exposure and increasing risk of adverse events was identified. The results of an E-R analysis provided strong support for a carfilzomib dose at 20/56 mg/m2as a 30-minute infusion for monotherapy and combination therapy. This article illustrates an example of application of E-R analysis to support labeling dose recommendation in the absence of extensive clinical data.
authors.affiliation: Amgen, South San Francisco, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Amgen, South San Francisco, CA, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Doshi
authors.affiliation: Amgen, South San Francisco, CA, USA.
authors.forename: Anh
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Pharsight, a Certara company, St. Louis, MO, USA.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jonsson
authors.affiliation: Amgen, South San Francisco, CA, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Amgen, South San Francisco, CA, USA.
authors.forename: Kanya
authors.initials: K
authors.lastname: Rajangam
authors.affiliation: National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: University of Maryland, Baltimore, MD, USA.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Badros
authors.affiliation: South Texas Accelerated Research Therapeutics, San Antonio, TX, USA.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: John Theurer Cancer Center, Hackensack, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.affiliation: Mount Sinai Medical Center, New York, NY, USA.
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.affiliation: Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Niesvizky
authors.affiliation: Amgen, South San Francisco, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Graham
authors.affiliation: Amgen, South San Francisco, CA, USA.
authors.forename: Jenn
authors.initials: J
authors.lastname: Visich
mesh_terms: D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D009842:Oligopeptides; C524865:carfilzomib
keywords: carfilzomib; dosing; exposure-response; multiple myeloma; population PK