Abstract A135: Physiologically-based pharmacokinetic modeling to support clinical investigation of the EZH2 inhibitor, tazemetostat (EPZ-6438) in INI1-deficient pediatric tumors
Authors: Rioux Nathalie , Keilhack Heike , Thomson Blythe , Chesworth Richard , Copeland Robert A. , Hedrick Eric , Ho Peter , Waters Nigel J. 
Published: May 2016

Abstract
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2, which has been implicated in the pathogenesis of a variety of malignancies, including B-cell non-Hodgkin lymphoma and INI1-deficient tumors. INI1-negative malignant rhabdoid tumors, for instance, occur mainly in young children.
Tazemetostat pharmacokinetic (PK) data from the first in human phase I clinical study (CT.gov: NCT01897571), across the dose range of 100 mg (suspension) and 100, 200, 400, 800 and 1600 mg (tablet) p.o. twice daily (BID), together with in vitro data including plasma protein binding, blood partitioning, metabolic stability and P450 phenotyping were used to simulate adult exposures by physiologically-based PK (PBPK) modeling (GastroPlus™ 8.5, Simulations Plus, Inc.). A model fit of the adult exposures (n = 24) that, based on visual inspection, adequately described the time-concentration profiles of tazemetostat resulted in prediction of mean steady-state AUC0-t and oral clearance (CL/F) within ±30% of the observed results across the dose range. In addition, mean steady-state Cmax were predicted ≤2-fold of the observed values, for both suspension and tablet formulations. The resultant model was then used to simulate tazemetostat steady-state exposures in discrete pediatric age ranges (6 month to 1 year (yr), &gt;1-2 yrs, &gt;2-6 yrs, &gt;6-12 yrs, &gt;12-18 yrs) following BID administration of an oral suspension. In addition to pediatric physiology, the simulations accounted for ontogeny in hematocrit, plasma protein levels and CYP expression. Using this exposure-based analysis, pediatric doses which afforded the target AUC (80% of adult steady-state AUC0-t at 800 mg or 390 mg/m2 BID) were identified.
On a body surface area normalized basis, the projected doses were comparable across the age range (1 to 18 yrs), from 270 to 305 mg/m2 BID, with a slightly lower projected dose of 230 mg/m2BID, for the 6 month to 1 yr old group. As the projected doses by age were comparable, population simulations were performed to determine the corresponding exposures for each age range, at a fixed 300 mg/m2 BID dose. At this dose, mean steady-state AUC0-t values ranged from approximately 80% to 100% of that observed in adults at 800 mg BID. Mean steady-state Cmax was projected to range between 895 and 1550 ng/mL (110% to 190% of Cmax,ss at 800 mg BID in adult), but within the safe and efficacious exposure range defined in adult at doses up to 1600 mg BID.
This study demonstrates the prospective application of PBPK early in clinical development to support clinical trial design in special populations, and has provided dosing recommendations for future tazemetostat trials in pediatric patients, ages 6 months to 18 years.
Citation Format: Nathalie Rioux, Heike Keilhack, Blythe Thomson, Richard Chesworth, Robert A. Copeland, Eric Hedrick, Peter Ho, Nigel J. Waters. Physiologically-based pharmacokinetic modeling to support clinical investigation of the EZH2 inhibitor, tazemetostat (EPZ-6438) in INI1-deficient pediatric tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A135.