Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

During a randomized Phase 1 clinical trial the drug candidate, PF ‐04895162 ( ICA ‐105665), caused transaminase elevations (≥grade 1) in six of eight healthy subjects treated at 300 mg twice daily for 2‐weeks ( NCT 01691274). This was unexpected since studies in rats ( < 6 months) and cynomolgus monkeys ( < 9 months) treated up to 100 mg/kg/day did not identify the liver as a target organ. Mechanistic studies showed PF ‐04895162 had low cytotoxic potential in human hepatocytes, but inhibited liver mitochondrial function and bile salt export protein ( BSEP ) transport. Clinical relevance of these postulated mechanisms of liver injury was explored in three treated subjects that consented to analysis of residual pharmacokinetic plasma samples. Compared to a nonresponder, two subjects with transaminase elevations displayed higher levels of mi RNA 122 and total/conjugated bile acid species, whereas one demonstrated impaired postprandial clearance of systemic bile acids. Elevated taurine and glycine conjugated to unconjugated bile acid ratios were observed in two subjects, one before the onset of elevated transaminases. Based on the affinity of conjugated bile acid species for transport by BSEP , the profile of plasma conjugated/unconjugated bile acid species was consistent with inhibition of BSEP . These data collectively suggest that the human liver injury by PF ‐04895162 was due to alterations in bile acid handling driven by dual BSEP /mitochondrial inhibition, two important risk factors associated with drug‐induced liver injury in humans. Alterations in systemic bile acid composition were more important than total bile acids in the manifestation of clinical liver injury and may be a very early biomarker of BSEP inhibition.