title: Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors.
abstract: Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies. Identified effects of sex, baseline Eastern Cooperative Oncology Group performance status, measures of renal and hepatic function, tumor type and burden, and prior ipilimumab treatment on pembrolizumab exposure were modest and lacked clinical significance. Furthermore, simulations demonstrated the model has robust power to detect clinically relevant covariate effects on clearance. These results support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations.
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ahamadi
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: T
authors.initials: T
authors.lastname: Freshwater
authors.affiliation: Former employee of Merck, currently employed at qPharmetra, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Prohn
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Li
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: de Alwis
authors.affiliation: Former employee of Merck, currently employed at Quantitative Solutions, a Certara company, Oss, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: de Greef
authors.affiliation: Former employee of Merck, currently employed at PD-Value, Houton, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Elassaiss-Schaap
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kondic
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Stone
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D004305:Dose-Response Relationship, Drug; D006801:Humans; D038622:Internationality; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000097:blood; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab