title: Using Model-Based "Learn and Confirm" to Reveal the Pharmacokinetics-Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE-001 Trial.
abstract: Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at <0.3 mg/kg every 3 weeks, but linear in the clinical dose range. Saturation of ex vivo target engagement in blood began at ≥1 mg/kg every 3 weeks, and a steady-state dose of 2 mg/kg every 3 weeks was needed to reach 95% target engagement, supporting examination of 2 mg/kg every 3 weeks in ongoing trials in melanoma and other advanced cancers.
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.|PD-Value, Houten, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Elassaiss-Schaap
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.|Janssen Pharmaceuticals, Beerse, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Rossenu
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.|SGS Exprimo NV, Mechelen, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Lindauer
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Kang
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium.|Quantitative Solutions, a Certara company, Oss, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: de Greef
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Sachs
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: de Alwis
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D005500:Follow-Up Studies; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000097:blood; D038622:Internationality; D008954:Models, Biological; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007376:Interleukin-2; C582435:pembrolizumab