ICA-105665 (PF-04895162) is a potent and orally active neuronal Kv7.2/7.3 and Kv7.3/7.5 potassium channels opener. ICA-105665 had low cytotoxic potential in human hepatocytes but inhibited liver mitochondrial function and bile salt export protein (BSEP) transport (IC50 of 311 μM). ICA-105665 can penetrate the central nervous system (CNS) and has antiseizure effects[1][2][3][4].

ICA-105665 (PF-04895162) does not exhibit strong cytotoxic properties in THLE and HepG2 cell lines (IC 50 ~192 μM and 130 μM after 72 hours, respectively) or in human hepatocytes (AC 50 for cell loss at 48 hours was >125 μM based on results in three assessments in two different human hepatocyte lots (LBN and HU4165) [1]. Mitochondrial respiratory reserve is compromised in human hepatocytes treated with ICA-105665 (PF-04895162) at concentrations >11 μM for 25 minutes [1].

For ICA-105665 (PF-04895162), dose-dependent alanine aminotransferase (ALT) elevations were observed in a 7-day rat toxicity study which is potentially indicative of liver toxicity. However, no histological evidence of liver injury was identified, and ALT elevations were not confirmed in a repeat 7-day study. Moreover, 28 day and 6 month toxicity studies in rats were negative for transaminase elevations and liver toxicity, and toxicity studies up to 9 months duration in cynomolgus monkeys were also negative [2]. ICA-105665 (PF-04895162) has demonstrated broad spectrum antiseizure activity in multiple animal models including maximal electroshock, 6 Hz seizures, pentylenetetrazole, and electrical kindling at doses from <1 to 5 mg/kg [3].