Using Model‐Based "Learn and Confirm" to Reveal the Pharmacokinetics‐Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE‐001 Trial. (8th November 2016)

• Record Type: Journal Article
• Authors: Elassaiss‐Schaap, J; Rossenu, S; Lindauer, A; Kang, SP; de Greef, R; Sachs, JR; de Alwis, DP
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 6:Number 1(2017)
• Page Start: 21
• Page End: 28
• Publication Date: 2016-11-08
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.12132
• Languages: English
• ISSNs: 2163-8306

Abstract

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.