Open AccessUsing Model‐Based “Learn and Confirm” to Reveal the Pharmacokinetics‐Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE‐001 Trial
Author(s) -
ElassaissSchaap J,
Rossenu S,
Lindauer A,
Kang SP,
de Greef R,
Sachs JR,
de Alwis DP
Publication year - 2017
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12132
Subject(s) - pembrolizumab , pharmacodynamics , pharmacokinetics , clinical trial , medicine , pharmacology , ex vivo , potency , computer science , medical physics , in vivo , oncology , chemistry , cancer , in vitro , biology , biochemistry , immunotherapy , microbiology and biotechnology
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.