RT Journal Article
SR Electronic
T1 Translational Pharmacokinetic-Pharmacodynamic Modeling for an Orally Available Novel Inhibitor of Epigenetic Regulator Enhancer of Zeste Homolog 2
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 220
OP 229
DO 10.1124/jpet.119.263491
VO 373
IS 2
A1 Shinji Yamazaki
A1 Hovhannes J. Gukasyan
A1 Hui Wang
A1 Sean Uryu
A1 Shikhar Sharma
YR 2020
UL http://jpet.aspetjournals.org/content/373/2/220.abstract
AB PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 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 [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC50 of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (Tsc) of 168 nM. Thus, effective concentration for 70% of maximal effect (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 suggested 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 concentration of PF06821497 in cancer patients.SIGNIFICANCE STATEMENT Using a mathematical modeling approach, the quantitative relationships of an orally available anticancer small-molecule enhancer of zeste homolog 2 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% histone H3 on lysine 27 (H3K27) me3 inhibition would be required for tumor stasis (i.e., 100% tumor growth inhibition). Accordingly, we would propose that an effective concentration for 70% of maximal effect estimate for H3K27me3 inhibition could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.