Evaluating In Vitro Dosing of Tyrosine Kinase Inhibitors for Clinical Repositioning: A Systematic Review
Open Access
- Author:
- Brown, Donovan
- Millennium Scholars Program:
- Biology (BIOL)
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisor:
- Justin R Pritchard, Thesis Supervisor
Stephen Wade Schaeffer, Advisor - Keywords:
- drug development
pharmacokinetics
systematic review - Abstract:
- In vitro experimentation plays an essential role in the early stages of drug development, though its environments vary greatly from physiological systems. Poor success in recent clinical trials suggests a systematic overestimation of preclinical drug efficacy, possibly due to inadequate consideration for the physiological effects influencing drug concentrations. For example, the pharmacologic activity of kinase inhibitors, a class of targeted cancer therapies, is influenced by plasma protein binding and other interactions less impactful in in vitro environments than physiologically. This study employs a systematic review of the preclinical literature comparing clinically relevant kinase inhibitor concentrations with those being applied in vitro. Additionally, we evaluate how these concentrations are justified and discussed in the literature with respect to pharmacokinetics and physiological interactions. Our results show little consideration for clinical pharmacokinetics in the published discussion of in vitro results. Median in vitro concentrations for all six kinase inhibitors in the study’s focus were also found to be greater than their effective mean plasma concentrations, with heightened disparities when publications fail to reference pharmacokinetic parameters. These results present crucial evidence of preclinical reports communicating kinase inhibitor efficacy at clinically unrealistic concentrations; such reports likely drawing attention to drug repositioning efforts with poor prospects for clinical success. Despite recent efforts in the scientific community to improve standards for basic science experimentation, further consideration may be necessary to accurately reconcile clinical observations with methods of in vitro drug profiling.