Food increased the bioavailability of BMS-690514, an orally active EGFR/HER2/VEGF receptor kinase inhibitor, in healthy subjects.
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.
Bristol-Myers Squibb, Princeton, NJ 08543, USA.
Blisse
B
Vakkalagadda
Jong-Soon
JS
Park
Christoph M
CM
Ahlers
Stephanie
S
Dorizio
Teresa
T
Has
Vikram
V
Roongta
Kevin N
KN
Heller
George M
GM
Derbin
Steven
S
Zhang
D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D005502:Food; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D014227:Triazines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D066246:ErbB Receptors; D010880:Piperidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A; C552150:BMS-690514; C467484:VEGFA protein, human; C512478:EGFR protein, human