J.E.\S. support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ? Pembrolizumab is a potent antibody against the cellular immune switch PD\1 receptor with high activity in the treatment of certain types of advanced cancer. However, an analysis of the population PKs of pembrolizumab in patients with advanced cancer had not yet been performed. WHAT QUESTION DID THIS STUDY ADDRESS? ? The characterization of pembrolizumab PKs and quantification of the effect of its intrinsic and extrinsic factors on exposure. WHAT THIS STUDY ADDS TO OUR KNOWLEDGE ? PK profile is typical for a therapeutic monoclonal antibody with low clearance, limited volume of distribution, and low variability. Intrinsic (e.g., body weight, age, sex, tumor type and burden, and renal and hepatic impairment) and extrinsic (e.g., concomitant medications) factors have no clinically relevant impact on pembrolizumab exposure. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? ? A model\based approach could be used to systematically justify the absence of dose adjustments of pembrolizumab in subpopulations relative to the proposed clinical Rabbit Polyclonal to PAK5/6 (phospho-Ser602/Ser560) dosing regimen. The programmed death 1 (PD\1) receptor pathway represents a major immune control switch, which may be engaged by tumor cells to overcome active T\cell immune surveillance. Many tumors, including melanoma, co\opt the PD\1 pathway by expressing the PD ligand\1 on the cell surface, leading to suppression of tumor\infiltrating cytotoxic T\cell activity.1, 2 Pembrolizumab (MK\3475) is a potent and highly selective antiCPD\1 humanized monoclonal antibody currently approved for the treatment of advanced melanoma and, in the United States, advanced non\small cell lung cancer (NSCLC) previously treated with platinum\doublet chemotherapy and that expresses PD ligand\1. It is in clinical development for treatment of various other advanced cancers. Until recently, the standard\of\care treatment for patients with advanced melanoma was ipilimumab, a fully human, monoclonal antibody that blocks cytotoxic T\lymphocyte antigen\4, another immune checkpoint protein.3, 4 In early preclinical models, the combined blockade of PD\1 and cytotoxic T\lymphocyte antigen\4 achieved more pronounced antitumor activity than blockade of either pathway alone.5, 6 In traditional drug development programs, clinical pharmacology is typically characterized through phase I studies in healthy volunteers with intensive pharmacokinetic (PK) sampling. As in most oncology programs, this approach was not possible in the pembrolizumab program because of a limited ability to administer the drug to healthy subjects. Therefore, population PK analysis of sparse data obtained in patients across multiple trials was the most efficient approach to answer traditional clinical pharmacology development questions, such as the impact of intrinsic and extrinsic factors on PK and the need for dose adjustment. In this study, model\based analysis of pooled data from the KEYNOTE\001, \002, and \006 studies were used to characterize the PK of pembrolizumab in patients with advanced melanoma, NSCLC, and other cancer types. Specific objectives were to characterize serum concentration profiles over time across indications, investigate the effects of potential covariates on pertinent Metyrapone PK parameters, evaluate the impact of selected covariates on exposure to support dose recommendations in subpopulations, and assess the adequacy of a weight\based dosing regimen. Results from this analysis provide an integrated evaluation of the impact of intrinsic and extrinsic factors on the systemic exposure to pembrolizumab, and present evidence for the lacking need for dose adjustment for most subpopulations of patients with advanced solid tumors. METHODS Analysis dataset This analysis was based on pooled data derived from patients from KEYNOTE\001 (ClinicalTrials.gov identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT01295827″,”term_id”:”NCT01295827″NCT01295827), KEYNOTE\002 (ClinicalTrials.gov identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT01704287″,”term_id”:”NCT01704287″NCT01704287), and KEYNOTE\006 (ClinicalTrials.gov identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT01866319″,”term_id”:”NCT01866319″NCT01866319) treated with pembrolizumab in a dose range of 1C10 mg/kg administered as intravenous infusion. The Metyrapone Metyrapone majority of patients included in this analysis were treated.