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.
Adult
Animals
Bile Acids and Salts
/ metabolism
Biological Transport
/ drug effects
Chemical and Drug Induced Liver Injury
/ etiology
Double-Blind Method
Hepatocytes
/ drug effects
Homeostasis
Humans
Macaca fascicularis
Male
Mitochondria, Liver
/ drug effects
Rats
Risk Factors
Species Specificity
Transaminases
/ metabolism
Young Adult
BSEP inhibition
PF-04895162 (ICA-105665)
bile acid conjugation status
bile acid homeostasis
hepatotoxicity
Journal
Pharmacology research & perspectives
ISSN: 2052-1707
Titre abrégé: Pharmacol Res Perspect
Pays: United States
ID NLM: 101626369
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
08
11
2018
revised:
11
01
2019
accepted:
13
01
2019
entrez:
21
2
2019
pubmed:
21
2
2019
medline:
16
4
2019
Statut:
ppublish
Résumé
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). 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 miRNA122 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.
Identifiants
pubmed: 30784208
doi: 10.1002/prp2.467
pmc: PMC6370995
doi:
Substances chimiques
Bile Acids and Salts
0
Transaminases
EC 2.6.1.-
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00467Informations de copyright
© 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
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