English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

Attrition risk related to efficacy is still a major reason why new chemical entities fail in clinical trials despite recently increased understanding of translational pharmacology. Pharmacokinetic-pharmacodynamic (PKPD) analysis is key to translating in vivo drug potency from nonclinical models to patients by providing a quantitative assessment of in vivo drug potency with mechanistic insight of drug action. The pharmaceutical industry is clearly moving toward more mechanistic and quantitative PKPD modeling to have a deeper understanding of translational pharmacology. This paper summarizes an anticancer drug case study describing the translational PKPD modeling of crizotinib, an orally available, potent small molecule inhibitor of multiple tyrosine kinases including anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (MET), from nonclinical to clinical development. Overall, the PKPD relationships among crizotinib systemic exposure, ALK or MET inhibition, and tumor growth inhibition (TGI) in human tumor xenograft models were well characterized in a quantitative manner using mathematical modeling: the results suggest that 50% ALK inhibition is required for &gt;50% TGI whereas &gt;90% MET inhibition is required for &gt;50% TGI. Furthermore, &gt;75% ALK inhibition and &gt;95% MET inhibition in patient tumors were projected by PKPD modeling during the clinically recommended dosing regimen, twice daily doses of crizotinib 250 mg (500 mg/day). These simulation results of crizotinib-mediated ALK and MET inhibition appeared consistent with the currently reported clinical responses. In summary, the present paper presents an anticancer drug example to demonstrate that quantitative PKPD modeling can be used for predictive translational pharmacology from nonclinical to clinical development.

Translational Pharmacokinetic-Pharmacodynamic Modeling from Nonclinical to Clinical Development: A Case Study of Anticancer Drug, Crizotinib