Food increased the bioavailability of BMS-690514, an orally active EGFR/HER2/VEGF receptor kinase inhibitor, in healthy subjects

J Clin Pharmacol. 2012 Sep;52(9):1350-6. doi: 10.1177/0091270011417826. Epub 2011 Oct 26.

Abstract

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS-690514. Two open-label, randomized, single-dose, 2-treatment, 2-period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a high-fat meal, and in study 2 (N = 17), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)), area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-690514 increased by 55%, 33%, and 34%, respectively, following a high-fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS-690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS-690514 was increased when given along with a meal, probably through inhibition of intestinal first-pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS-690514 in the absence and presence of food.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Biological Availability
  • Cross-Over Studies
  • ErbB Receptors / antagonists & inhibitors
  • Female
  • Food
  • Food-Drug Interactions*
  • Humans
  • Male
  • Middle Aged
  • Piperidines / administration & dosage*
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Pyrroles / administration & dosage*
  • Pyrroles / blood
  • Pyrroles / pharmacokinetics*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Triazines / administration & dosage*
  • Triazines / blood
  • Triazines / pharmacokinetics*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • BMS-690514
  • Piperidines
  • Pyrroles
  • Triazines
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • EGFR protein, human
  • ErbB Receptors
  • Receptor, ErbB-2