Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 91–96 | Cite as

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

  • Nathalie RiouxEmail author
  • Amy Kim
  • Darrell Nix
  • Todd Bowser
  • Markus Warmuth
  • Peter G. Smith
  • Joanne Schindler
Original Article
  • 81 Downloads

Abstract

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

H3B-6527 FGFR4 inhibitor Phase I Pharmacokinetics Food-effect 

Notes

Acknowledgements

The authors are grateful to the study volunteers, and the investigators and team at the study site. The authors want to thank the H3B-6527 team at H3 Biomedicine and Eisai for fruitful discussions.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflicts of interest.

References

  1. 1.
    Pinyol R, Nault JC, Quetglas IM, Zucman-Rossi J, Llovet JM (2014) Molecular profiling of liver tumors: classification and clinical translation for decision making. Semin Liver Dis 34:363–375CrossRefPubMedGoogle Scholar
  2. 2.
    Jones S (2008) Mini-review: endocrine actions of fibroblast growth factor 19. Mol Pharm 5:42–48CrossRefPubMedGoogle Scholar
  3. 3.
    French DM et al (2012) Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One 7(5):e36713CrossRefPubMedGoogle Scholar
  4. 4.
    Joshi JJ, Coffey H, Corcoran E, Tsai J, Huang CL, Ichikawa K, Prajapati S, Hao MH, Bailey S, Wu J, Rimkunas V, Karr C, Subramanian V, Kumar P, MacKenzie C, Hurley R, Satoh T, Yu K, Park E, Rioux N, Kim A, Lai WG, Yu L, Zhu P, Buonamici S, Larsen N, Fekkes P, Wang J, Warmuth M, Reynolds DJ, Smith PG, Selvaraj A (2017) H3B-6527 is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer Res 77:6999–7013CrossRefPubMedGoogle Scholar
  5. 5.
    GBD 2013 Mortality and Causes of Death Collaborators (2015) Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385:117–171CrossRefGoogle Scholar
  6. 6.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMedGoogle Scholar
  7. 7.
    US Department of Health and Human Services Food and Drug Administration (2002) Guidance for industry: food-effect bioavailability and fed bioequivalence studies. In: (CDER) CfDEaR (ed) Office of training and communications. Division of Drug Information, Rockville, HFD–H240Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.H3 Biomedicine IncCambridgeUSA

Personalised recommendations