Model‐Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti–PD‐1 Monoclonal Antibody in Advanced Solid Tumors
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, a...
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| Veröffentlicht in: | CPT: pharmacometrics and systems pharmacology 2017-01, Vol.6 (1), p.49-57 |
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| creator | Ahamadi, M Freshwater, T Prohn, M Li, CH de Alwis, DP de Greef, R Elassaiss‐Schaap, J Kondic, A Stone, JA |
| description | 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. |
| doi_str_mv | 10.1002/psp4.12139 |
| format | Article |
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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.</description><identifier>ISSN: 2163-8306</identifier><identifier>EISSN: 2163-8306</identifier><identifier>DOI: 10.1002/psp4.12139</identifier><identifier>PMID: 27863186</identifier><language>eng</language><publisher>United States: John Wiley & Sons, Inc</publisher><subject><![CDATA[Antibodies, Monoclonal, Humanized - administration & dosage ; Antibodies, Monoclonal, Humanized - pharmacokinetics ; Antigens ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Cancer therapies ; Chemotherapy ; Clinical Trials, Phase I as Topic - statistics & numerical data ; Clinical Trials, Phase III as Topic - statistics & numerical data ; Cytotoxicity ; Dose-Response Relationship, Drug ; Drug dosages ; Humans ; Immunotherapy ; Internationality ; Ligands ; Lung cancer ; Melanoma ; Models, Biological ; Monoclonal antibodies ; Neoplasms - blood ; Neoplasms - diagnosis ; Neoplasms - drug therapy ; Original ; Pharmacokinetics ; Population ; Programmed Cell Death 1 Receptor - antagonists & inhibitors ; Programmed Cell Death 1 Receptor - blood ; Randomized Controlled Trials as Topic - statistics & numerical data ; Studies ; Targeted cancer therapy ; Tumors]]></subject><ispartof>CPT: pharmacometrics and systems pharmacology, 2017-01, Vol.6 (1), p.49-57</ispartof><rights>2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics</rights><rights>2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.</rights><rights>2017. 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| subjects | Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - pharmacokinetics Antigens Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Cancer therapies Chemotherapy Clinical Trials, Phase I as Topic - statistics & numerical data Clinical Trials, Phase III as Topic - statistics & numerical data Cytotoxicity Dose-Response Relationship, Drug Drug dosages Humans Immunotherapy Internationality Ligands Lung cancer Melanoma Models, Biological Monoclonal antibodies Neoplasms - blood Neoplasms - diagnosis Neoplasms - drug therapy Original Pharmacokinetics Population Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - blood Randomized Controlled Trials as Topic - statistics & numerical data Studies Targeted cancer therapy Tumors |
| title | Model‐Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti–PD‐1 Monoclonal Antibody in Advanced Solid Tumors |
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