Jones, Hannah, Chen, Yuan, Gibson, Christopher, Heimbach, Tycho, Parrott, Neil, Peters, Sheila, Snoeys, Jan, Upreti, Vijay, Zheng, Ming and Hall , Stephen (2015) Physiologically Based Pharmacokinetic Modelling in Drug Discovery and Development: A Pharmaceutical Industry Perspective. Clinical Pharmacology and Therapeutics.

Abstract

Physiologically based pharmacokinetic (PBPK) models are employed broadly throughout the pharmaceutical industry to provide quantitative, integrated analyses of drug absorption and disposition in pre-clinical species and humans. A group comprising of industrial scientists with expertise in PBPK modelling was assembled under the umbrella of the Innovation and Quality (IQ) Drug Metabolism and Clinical Pharmacology Leadership Groups. The focus of this group has been to develop a united view on PBPK best practice and application in the pharmaceutical industry. The first position paper on PBPK modelling that represents the collective view of PBPK experts from 10 leading global pharmaceutical companies will be published.In this unique industry wide collaboration, we describe the principles that underlie the utility and value of PBPK modelling in drug discovery and development. Through detailed case studies and an extensive compilation of ~ 80 examples we exemplify the diverse opportunities for efficiency gains provided by PBPK modelling. The case studies demonstrating PBPK impacts from early discovery through late development will be shared: a) Pediatric PBPK modelling for formulation selection and informing PIP, b) Organ impairment modelling c) PBPK modelling for DDI predictions using reversible and time dependent inhibition, d) ACAT modelling for absorption of preclinical species, e) Recent PBPK model-based FDA approvals with “lessons learned”. The perspective on the confidence and challenges with these different applications are also described and presented in a table. While the confidence level is relatively high for PK and CYP-based DDI prediction, major challenges remain in the prediction of transporter and non-CYP enzyme based DDI, ontogeny of enzymes and transporters proteins and changes in enzyme/transporter abundance in disease populations of interest. We highlight the new opportunities arising as global regulatory agencies recognize that well-planned and well-designed PBPK modeling may not only optimize preclinical or clinical studies throughout the course of the development of the molecule but also support new product labels. Industry best practices for implementation and validation of PBPK models are also presented.

Item Type:	Article
Keywords:	PBPK, Simcyp, GastroPlus, special populations, pediatrics, food effects, human PK predictions, AHD, BCS, BDDCS, DDI, preclinical PK, translation.
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/23072