Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor
Authors: Basavapathruni, A; Olhava, EJ; Daigle, SR; Therkelsen, CA; Jin, L; Boriack-Sjodin, PA; Allain, CJ; Klaus, CR; Raimondi, A; Scott, MP; Dovletoglou, A; Richon, VM; Pollock, RM; Copeland, RA; Moyer, MP; Chesworth, R; Pearson, PG; Waters, NJ
Biopharmaceutics and Drug Disposition.
HERO ID: 2321106
EPZ-5676 ((2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol) . . .
EPZ-5676 ((2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. In this report, we describe the preclinical pharmacokinetics and metabolism of EPZ-5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following IV and PO administration; EPZ-5676 had moderate to high clearance, low oral bioavailability with a steady-state volume of distribution 2-3 fold higher than total body water. EPZ-5676 showed biexponential kinetics following IV administration, giving rise to terminal t1/2 of 1.1, 3.7 and 13.6 h in mouse, rat and dog respectively. Corresponding in vitro ADME parameters were also studied and utilized for in vitro - in vivo extrapolation purposes. There was good agreement between microsomal clearance and in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to fu-corrected GFR and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ-5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N-dealkylated product (M4) as well as an N-oxide (M6). This article is protected by copyright. All rights reserved.