Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor

Abstract

(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) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. This report describes 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 i.v. and p.o. 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 i.v. administration, giving rise to a terminal elimination half-life (t1/2 ) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro-in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the 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 glomerular filtration rate (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).

Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development

“…A sensitivity analysis of the passive diffusion clearance indicated that a value of 0.0075 mL/min/million hepatocytes gave the best model fit. This was plausible and consistent with the physicochemical properties and preclinical ADME data which showed low permeability in MDCK cell monolayers and a greater than 20-fold higher liver microsomal scaled CL int compared with hepatocyte scaled CL int (Basavapathruni et al, 2014). The adult model simulations and observed data are shown in Fig.…”

“…Preclinically, pinometostat selectively inhibits intracellular histone H3K79 methylation and downstream target gene expression and demonstrated complete tumor regressions in an MLL-r leukemia xenograft model (Daigle et al, 2013). Because of the unmet need of MLL-r in children, we employed a prospective PBPK modeling approach leveraging pinometostat preclinical data (Basavapathruni et al, 2014) and early clinical data from the first-in-human phase I open label study in adult patients with relapsed/refractory leukemia (Stein et al, 2014), to guide dose selection and trial design for a companion pediatric study (Waters et al, 2014;Shukla et al, 2015). A PBPK model describing the concentration-time profile of pinometostat after continuous intravenous administration in adult patients at dose levels of 24-90 mg/m 2 per day was built using Simcyp (Simcyp Ltd., Sheffield, UK).…”

MLL leukemia induction by genome editing of human CD34+ hematopoietic cells

“…[34][35][36][37][38][39][40][41][42][43][44] Small-molecule inhibitors of DOT1L have been developed and are currently undergoing phase 1 clinical trials. [45][46][47][48][49][50] We tested leukemic blast cells explanted from MPAL and AML mice for sensitivity to the DOT1L inhibitor EPZ004777 in comparison with the human MLL-rearranged leukemia cell line MV4-11 and non-MLL-rearranged K562 cells. In CFC assays, the explanted blasts and MV4-11 cells displayed high sensitivity to EPZ004777 in a dose-dependent manner characterized by a decrease of colony number and size, whereas K562 cells showed no significant differences ( Figure 6A-B).…”

Nuclear DNA replication and repair in parasites of the genusLeishmania: Exploiting differences to develop innovative therapeutic approaches

“…In humans, DOT1L seems to play an essential role in leukemic transformation, so many novel studies in the last years have focused on this protein (McLean et al, 2014). A specific and potent inhibitor based on the analogy with DOT1L substrate, S-adenosylmethionine (SAM), has been used in a phase 1 clinical trial for leukemia treatment (Basavapathruni et al, 2007;Stein & Tallman, 2015). If this compound also has the capability to inhibit either trypanosomatid DOT1A and/or DOT1B, this would open new applications as leishmanicidal treatment, besides its use in fighting leukemia.…”