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
Full Reference: Elassaiss-Schaap, J., S. Rossenu, A. Lindauer, S. P. Kang, R. de Greef, J. R. Sachs, and D. P. de Alwis. “Using Model-Based ‘Learn and Confirm’ to Reveal the Pharmacokinetics-Pharmacodynamics Relationship of Pembrolizumab in the.” CPT: Pharmacometrics & Systems Pharmacology 6, no. 1 (January 2017): 21–28. doi:10.1002/psp4.12132.
Link to full text: http://onlinelibrary.wiley.com/doi/10.1002/psp4.12132/full