Figure 4
The preclinical pharmacokinetics of EPZ-5676 determined in mouse and rat. (A) Table of EPZ-5676 pharmacokinetic parameters as determined in mouse and rat. All values reported as mean ± standard deviation (SD) with exception of mouse IP and rat IV infusion study where nonserial, sparse blood sampling was used. In this case, all values are means. Pharmacokinetic data analysis was performed using noncompartmental analysis and WinNonlin Phoenix v6.2 software. Calculated pharmacokinetic parameters show high clearance (CL) in both species with low oral bioavailability and high intraperitoneal bioavailability in mouse (the latter calculated using the IV area under the curve [AUC] from CD-1 mouse). Volume of distribution at steady state (VDss) was greater than total body water of 0.7 L/kg in both species. Terminal half-lives (t1/2) ranged from 1 to 5 hours depending on the route of administration, whereas mean residence times (MRT) were short, ranging from 0.35 to 0.84 hours. Cmax, the maximum plasma concentration, is determined at time tmax. AUC0-t and AUC0-inf are the areas under the curve to the last measurable data point and extrapolated to infinity, respectively. Data are shown graphically as (B) concentration vs time profile of mean ± SD (n = 3) plasma concentrations following IV bolus (5 mg/kg, red line) and PO (20 mg/kg, blue line) administrations to CD-1 mouse as well as IP (20 mg/kg, black line) administration to NCr nu/nu mouse (all formulated in 10% ethanol:90% saline). The dotted line represents the EPZ-5676 concentration required to completely block proliferation of MV4-11 cells in vitro (Fig. 2C); (C) concentration vs time profile of mean ± SD (n = 3) plasma concentrations following IV bolus (1 mg/kg formulated in 0.4% hydroxypropyl-β-cyclodextrin in saline) administration to Sprague-Dawley rat; (D) concentration vs time profile of mean ± SD (n = 3) plasma concentrations following IV infusion (4.7 mg/kg per day for 7 days formulated in 10% PEG400:90% saline) administration to Sprague-Dawley rat (elimination phase data after 168 hours not shown for clarity). F, absolute bioavailability.

The preclinical pharmacokinetics of EPZ-5676 determined in mouse and rat. (A) Table of EPZ-5676 pharmacokinetic parameters as determined in mouse and rat. All values reported as mean ± standard deviation (SD) with exception of mouse IP and rat IV infusion study where nonserial, sparse blood sampling was used. In this case, all values are means. Pharmacokinetic data analysis was performed using noncompartmental analysis and WinNonlin Phoenix v6.2 software. Calculated pharmacokinetic parameters show high clearance (CL) in both species with low oral bioavailability and high intraperitoneal bioavailability in mouse (the latter calculated using the IV area under the curve [AUC] from CD-1 mouse). Volume of distribution at steady state (VDss) was greater than total body water of 0.7 L/kg in both species. Terminal half-lives (t1/2) ranged from 1 to 5 hours depending on the route of administration, whereas mean residence times (MRT) were short, ranging from 0.35 to 0.84 hours. Cmax, the maximum plasma concentration, is determined at time tmax. AUC0-t and AUC0-inf are the areas under the curve to the last measurable data point and extrapolated to infinity, respectively. Data are shown graphically as (B) concentration vs time profile of mean ± SD (n = 3) plasma concentrations following IV bolus (5 mg/kg, red line) and PO (20 mg/kg, blue line) administrations to CD-1 mouse as well as IP (20 mg/kg, black line) administration to NCr nu/nu mouse (all formulated in 10% ethanol:90% saline). The dotted line represents the EPZ-5676 concentration required to completely block proliferation of MV4-11 cells in vitro (Fig. 2C); (C) concentration vs time profile of mean ± SD (n = 3) plasma concentrations following IV bolus (1 mg/kg formulated in 0.4% hydroxypropyl-β-cyclodextrin in saline) administration to Sprague-Dawley rat; (D) concentration vs time profile of mean ± SD (n = 3) plasma concentrations following IV infusion (4.7 mg/kg per day for 7 days formulated in 10% PEG400:90% saline) administration to Sprague-Dawley rat (elimination phase data after 168 hours not shown for clarity). F, absolute bioavailability.

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