Pharmacokinetics of a potent soluble epoxide hydrolase inhibitor in three formulations

Abstract

Inhibition of soluble epoxide hydrolase (sEHI) was shown to be potent to reduce the inflammation, lower the blood pressure in hypertension and is being developed for indication of chronic pain treatment. Guiding by in vitro potency screening, pharmacokinetics and in vivo efficacy studies, a potent sEHI (EC5026) is optimized for the followed clinical trials. Besides its own properties, formulation method is an important factor to be considered to reach ideal exposure time span and concentration in vivo, therefore for the efficacy in vivo.Here, we compared three different formulation methods: PEG mixtures, hot melt extrusion (HME), spray‐dried dispersion (SDD) for EC5026 by comparing the pharmacokinetics in Sprague Dawley rats. A sensitive UHPLC/MS/MS method was developed to measure the concentration of EC 5026 in the blood of rats after oral dosing at 3mg/Kg as a single dose. The pharmacokinetics parameters including Cmax, Tmax, AUC were calculated using non‐compartment modeling analysis. The result shows that three different formulations have similar pharmacokinetics properties with the highest Cmax in SDD (1,557 ng/mL) followed by HME (1,432 ng/mL) and PEG mixture (1,329 ng/mL). Tmax are all about the same at 2.5 and 3 hour respectively. The T1/2s are between 75–90 hours.The results above indicates all three formulations are proper for decent exposure of EC5026 with AUC from 6759–8516 ng/mL hr. The similarity among these three formulations allow the translation to the clinical trials using the new formulations (HME/SDD) from the preclinical studies with PEG mixture.Support or Funding InformationSupport or Funding InformationThis work was supported in part by NIEHS grant R35 ES030443, NIEHS Superfund Basic Research Program grant P42 ES04699.