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Clinical, Journal: Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity. (Pubmed Central) - Jul 7, 2020
P1
This study illustrates how DILIsym, a computational representation of liver injury, was able to reproduce species differences in liver toxicity due to PF-04895162 (ICA-105665)...Modeling even higher PF-04895162 liver exposures than were measured in the rat safety studies aggravated mitochondrial toxicity but did not result in rat hepatotoxicity due to insufficient accumulation of cytotoxic bile acid species. This investigative study highlights the potential for combined in vitro and computational screening methods to identify latent hepatotoxic risks and paves the way for similar and prospective studies.
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Biomarker, P1 data, Clinical Trial,Phase I, Journal: Phase I study of PF-04895162, a Kv7 channel inhibitor, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis. (Pubmed Central) - Apr 16, 2019
P1
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 (NCT01691274)...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.
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Trial termination: A Study to Investigate the Effect of ICA-105665 in Photosensitive Epilepsy Patients (clinicaltrials.gov) - Sep 26, 2012
P2, N=13, Terminated,
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. Completed --> Terminated; The study was terminated on September 12, 2010 per protocol following a serious adverse event that occurred with the first subject dosed at 600 mg.
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