Abstract
PF06821497 has been identified as an orally available small molecule EZH2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect response model reasonably fit dose-dependent pharmacodynamic responses (H3K27me3 inhibition) with an unbound EC50 of 76 nM while a signal transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (Tsc) of 168 nM. Thus, EC70 for H3K27me3 inhibition was roughly comparable to Tsc, suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also indicated that ~70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC70 estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious plasma concentration of PF06821497 in cancer patients.
SIGNIFICANCE STATEMENT Using a mathematical modeling approach, the quantitative relationships of an orally available anticancer small molecule EZH2 inhibitor, PF06821497, were characterized among pharmacokinetics, pharmacodynamic biomarker inhibition and disease responses in nonclinical xenograft models with diffuse large B-cell lymphoma. The modeling results suggest that >70% H3K27me3 inhibition would be required for tumor stasis (i.e., 100% tumor growth inhibition). Accordingly, we would propose that an EC70 estimate for H3K27me3 inhibition could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.
- anticancer agents
- cancer
- DNA methylation
- drug development
- drug discovery
- oncogenes
- pharmacokinetic / pharmacodynamic modeling
- pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics