Affiliation:
1. School of Engineering University of Warwick Coventry UK
2. MSD London UK
3. Limina Clinical Pharmacology Warrington UK
Abstract
AbstractTyrosine kinase inhibitors (TKIs) are routinely prescribed for the treatment of non‐small cell lung cancer (NSCLC). As with all medications, patients can experience adverse events due to TKIs. Unfortunately, the relationship between many TKIs and the occurrence of certain adverse events remains unclear. There are limited in vivo studies which focus on TKIs and their effects on different regulation pathways. Many in vitro studies, however, that investigate the effects of TKIs observe additional changes, such as changes in gene activations or protein expressions. These studies could potentially help to gain greater understanding of the mechanisms for TKI induced adverse events. However, in order to utilize these pathways in a pharmacokinetic/pharmacodynamic (PK/PD) framework, an in vitro PK/PD model needs to be developed, in order to characterize the effects of TKIs in NSCLC cell lines. Through the use of ordinary differential equations, cell viability data and nonlinear mixed effects modeling, an in vitro TKI PK/PD model was developed with estimated PK and PD parameter values for the TKIs alectinib, crizotinib, erlotinib, and gefitinib. The relative standard errors for the population parameters are all less than 25%. The inclusion of random effects enabled the model to predict individual parameter values which provided a closer fit to the observed response. It is hoped that this model can be extended to include in vitro data of certain pathways that may potentially be linked with adverse events and provide a better understanding of TKI‐induced adverse events.
Reference50 articles.
1. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer
2. Targeted therapy for non‐small cell lung cancer: current standards and the promise of the future;Chan BA;Transl Lung Cancer Res,2015
3. Angiogenesis inhibition as a therapeutic strategy in non‐small cell lung cancer (NSCLC);Hall Richard D;Transl Lung Cancer Res,2015
4. Epidermal growth factor receptor family in lung cancer and premalignancy
5. Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches
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