Analytical approach to characterize the intratumoral pharmacokinetics and pharmacodynamics of gefitinib in a glioblastoma model.

Sharma J, Lv H, Gallo JM.
Journal   J Pharm Sci.
Species  
Analytes Measured  
Matrix Tested   Tumor xenograft lysates
Year   2012
Volume   101
Page Numbers   4100-4106
Application   Phosphoproteins
Abstract
Heterogeneity in brain tumors can result in variable drug distribution and possibly drug response; however, there are no readily accessible means to obtain regional pharmacokinetic (PK)/pharmacodynamic (PD) information in preclinical tumor models that typically rely on average drug concentration measurements. On the basis of a novel serial brain tumor sectioning protocol, sensitive and robust methods were developed to characterize the intratumoral PK [liquid chromatography with tandem mass spectrometry detection (LC/MS/MS)] and PD (phosphorylated extracellular-signal-regulated kinase, antibody-based detection) of gefitinib in small amounts of glioblastoma tumor samples obtained from mice bearing intracerebral tumors administered 150 mg/kg of gefitinib. LC/MS/MS method was accurate (±15%) and precise (coefficient of variation ≤15%). For PD analysis, two antibody-based assay systems [enzyme-linked immunosorbent assay and meso scale discovery (MSD)] were compared and the more sensitive method (MSD) was selected. Gefitinib concentrations showed up to 2.4 ± 0.7-fold intratumoral variability in PK and 1.5 ± 0.20-fold variability in PD. The methods are sufficiently accessible and could be applied to other anticancer drugs and tumor models to obtain greater resolution of intratumoral PKs and PDs.

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