Citation

Poloyac SM, Bertz RJ, McDermott L, Marathe P. J. Neurotrauma 2019; ePub(ePub): ePub.

Affiliation

Bristol-Myers Squibb Pharmaceutical Research and Development, 111059, Department of Metabolism and Pharmacokinetics, Princeton, New Jersey, United States ; punit.marathe@bms.com.

Copyright

(Copyright © 2019, Mary Ann Liebert Publishers)

DOI

10.1089/neu.2018.6295

PMID

30816062

Abstract

The purpose of this review is to highlight the pharmacologic barrier to drug development for traumatic brain injury (TBI) and to discuss best practice strategies to overcome such barriers. Specifically, this article will review the pharmacologic considerations of moving from disease target "hit" to the "lead" compound with drug-like and central nervous system (CNS) penetrant properties. In vitro assessment of drug-like properties will be detailed, followed by preclinical studies to ensure adequate pharmacokinetic and pharmacodynamic characteristics of response. The importance of biomarker development and utilization in both preclinical and clinical studies will be detailed along with importance of identifying diagnostic, pharmacodynamic/response, and prognostic biomarkers of injury type or severity, drug target engagement, and disease progression. This review will detail the important considerations in determining in vivo preclinical dose selection, as well as, cross-species and human equivalent dose selection. Specific use of allometric scaling, pharmacokinetic and pharmacodynamic criteria, as well as, incorporation of biomarker assessments in human dose selection for clinical trial design will be discussed. The overarching goal of this review is to detail the pharmacologic considerations in the drug development process as a method to improve both preclinical and clinical study design as we evaluate novel therapies to improve outcomes in TBI patients.

Language: en

Keywords

BIOMARKERS; METABOLISM; Other; TRAUMATIC BRAIN INJURY