Effect of a high-fat meal on the relative bioavailability of H3B-6527, a novel FGFR4 inhibitor, in healthy volunteers

Cancer Chemother Pharmacol. 2019 Jan;83(1):91-96. doi: 10.1007/s00280-018-3708-3. Epub 2018 Oct 27.


Purpose: This Phase I study estimated the effect of a high-fat meal on the pharmacokinetics (PK) of H3B-6527, a covalent inhibitor of the fibroblast growth factor receptor (FGFR) 4 in clinical development for hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

Methods: In this randomized, single center, single-dose, open-label, 2-period crossover study 12 healthy male volunteers, aged 18-55 years old, received a single 200-mg dose of H3B-6527 (capsule) following an overnight fast or a high-fat breakfast. PK samples were collected serially up to 36 h postdose. H3B-6527 concentrations were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. PK data were analyzed using a noncompartmental approach based on a mixed-effects model. The safety and tolerability of H3B-6527 were also assessed.

Results: H3B-6527 plasma exposure increased after a high-fat meal with fed/fasted ratios of the geometric means (90% confidence interval) of 174% (102-298%) for Cmax and 246% (146-415%) for AUC0-t. Food delayed and prolonged absorption of H3B-6527, with a fed/fasted ratio for tmax of 200% (137-263%). PK variability was lower under the fed condition, as illustrated by the CV% for Cmax and AUC0-t of 41.9-54.5% (fed) versus 64.3-70.4% (fasted).

Conclusions: A single 200 mg dose of H3B-6527 was safe and generally well tolerated when administered to healthy adult males. A high-fat meal significantly increased exposure to H3B-6527, from 1.5- to 2.5-fold in the systemic circulation, compared to administration under fasted conditions. Food delayed and prolonged absorption of H3B-6527. In general, lower inter-subject variability was observed in the fed state in healthy volunteers.

Trial registration: ClinicalTrials.gov.: NCT03424577.

Keywords: FGFR4 inhibitor; Food-effect; H3B-6527; Pharmacokinetics; Phase I.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Area Under Curve
  • Biological Availability
  • Cross-Over Studies
  • Diet, High-Fat*
  • Food-Drug Interactions
  • Healthy Volunteers
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage*
  • Heterocyclic Compounds, 4 or More Rings / blood*
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors*
  • Tissue Distribution
  • Young Adult


  • H3B-6527
  • Heterocyclic Compounds, 4 or More Rings
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4

Associated data

  • ClinicalTrials.gov/NCT03424577