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

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.

• Authors: Blisse Vakkalagadda, Jong-Soon Park, Christoph M Ahlers, Stephanie Dorizio, Teresa Has, Vikram Roongta, Kevin N Heller, George M Derbin, Steven Zhang
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 52 Issue 9 Pg. 1350-6 (Sep 2012) ISSN: 1552-4604 [Electronic] England
• PMID: 22031621 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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