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Food Increased the Bioavailability of BMS‐690514, an Orally Active EGFR/HER2/VEGF Receptor Kinase Inhibitor, in Healthy Subjects
Author(s) -
Vakkalagadda Blisse,
Park JongSoon,
Ahlers Christoph M.,
Dorizio Stephanie,
Has Teresa,
Roongta Vikram,
Heller Kevin N.,
Derbin George M.,
Zhang Steven
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011417826
Subject(s) - bioavailability , vegf receptors , pharmacology , orally active , medicine , kinase , oral administration , chemistry , biochemistry
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.