PII-043

Y. Lau, T. Lin, D. Song, J. Gu, R. Yu, A. Joe; Novartis Pharmaceuticals Corporation, East Hanover, NJ

BACKGROUND: Two open-label, randomized, two-period crossover studies were conducted to examine the influence of meal type (low-fat, high-fat and light snack) on the pharmacokinetics (PK) of ceritinib in healthy subjects.
METHODS: In the first study, subjects (N=28) received a single 500 mg oral dose of ceritinib following one of the three treatments during each period (fasted state, low-fat meal (330 calories, 9 grams of fat), or high-fat meal (1000 calories, 58 g of fat)). In the second study, subjects (N=12) received a single 750 mg oral dose of ceritinib following one of the two treatments during each period (fasted state, or light snack (100-300 calories, 1.5 g of fat)). A wash-out of 2 weeks was used between periods. Plasma samples were assayed by LC/MS/MS. PK analysis was determined by non-compartmental analysis.
RESULTS: Compared with the fasted state, Cmax (90% CI) and AUCinf (90% CI) of ceritinib were increased by 43% (21%, 71%) and 58% (34%, 86%), respectively, after the intake of a low-fat meal, by 41% (18%, 68%) and 73% (46%, 105%), respectively, after the intake of a high-fat meal, and by 45% (15%, 82%) and 54% (19%, 99%), respectively, after the intake of a light snack. Ceritinib was well tolerated in both studies.
CONCLUSION: A light snack and a low-fat meal increased ceritinib PK to a similar extent, suggesting that a meal with even a very low fat content could lead to a clinically meaningful increase in PK (> 30%). The differential bioavailability was apparent only with a high-fat meal, which resulted in a 15-19% higher AUC compared to a light snack or low-fat meal. Based on these findings, it is essential to avoid any type of meal during dosing of ceritinib as intake of food may result in systemic exposure exceeding that of a 750 mg labeled dose taken once daily fasted, and may increase adverse drug reactions.