Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity

Pharmacol Res Perspect. 2019 Oct 9;7(6):e00523. doi: 10.1002/prp2.523. eCollection 2019 Dec.

Abstract

Many compounds that appear promising in preclinical species, fail in human clinical trials due to safety concerns. The FDA has strongly encouraged the application of modeling in drug development to improve product safety. 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). PF-04895162, a drug in development for the treatment of epilepsy, was terminated after transaminase elevations were observed in healthy volunteers (NCT01691274). Liver safety concerns had not been raised in preclinical safety studies. DILIsym, which integrates in vitro data on mechanisms of hepatotoxicity with predicted in vivo liver exposure, reproduced clinical hepatotoxicity and the absence of hepatotoxicity observed in the rat. Simulated differences were multifactorial. Simulated liver exposure was greater in humans than rats. The simulated human hepatotoxicity was demonstrated to be due to the interaction between mitochondrial toxicity and bile acid transporter inhibition; elimination of either mechanism from the simulations abrogated injury. The bile acid contribution occurred despite the fact that the IC50 for bile salt export pump (BSEP) inhibition by PF-04895162 was higher (311 µmol/L) than that has been generally thought to contribute to hepatotoxicity. 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.

Keywords: DILIsym; PBPK; PF‐04895162; QSP; QST; bile acid transporters; drug‐induced liver injury; mechanistic; mitochondria; species translation.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / metabolism
  • Administration, Oral
  • Adolescent
  • Adult
  • Animals
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / toxicity*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / pathology*
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / standards
  • Epilepsy / drug therapy
  • HEK293 Cells
  • Healthy Volunteers
  • Hepatocytes
  • Humans
  • Inhibitory Concentration 50
  • Liver / drug effects
  • Liver / pathology
  • Male
  • Middle Aged
  • Mitochondria / drug effects
  • Models, Biological*
  • Quinazolines / administration & dosage
  • Quinazolines / toxicity*
  • Rats
  • Species Specificity
  • Taurocholic Acid / metabolism
  • Young Adult

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • Anticonvulsants
  • PF-04895162
  • Quinazolines
  • Taurocholic Acid

Associated data

  • ClinicalTrials.gov/NCT01691274