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J Pharmacokinet Pharmacodyn. 2017 Oct;44(5):403-414. doi: 10.1007/s10928-017-9528-y. Epub 2017 Jun 1.

Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response.

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Food and Drug Administration, Silver Spring, MD, USA.
Merck & Co., Inc., Kenilworth, NJ, USA.
Quantitative Solutions, A Certara Company, Oss, The Netherlands.
Food and Drug Administration, Silver Spring, MD, USA.
Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA.


Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately Imax or exactly eImax - 1), the time to reach Imax/2 (TI50), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of Imax.


Best overall response; Immunotherapy; Monoclonal antibody; Oncology; PD-1; Pembrolizumab; Time dependent pharmacokinetics; Time varying clearance

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