PI-057 - AN INVESTIGATION INTO THE DOSE-DEPENDENT FOOD-EFFECT FOR DRUGS.

A. Yu¹, Y. Pithavala²; ¹UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, United States of America, ²Pfizer, Inc., San Diego, CA, United States.

Background: Food-effect studies on the pharmacokinetics (PK) of a drug are typically evaluated at the highest labeled dose, and the magnitude of change in drug exposure with food is usually assumed to be independent of the dose. However, there are situations where the change in exposure with food has been different across tested doses for the same drug. The intent of this analysis was to conduct a literature search for drugs that demonstrate dose-dependent food-effects, and to further evaluate the potential reasons for this.

Methods: A literature search was conducted (PubMed), with articles filtered for appropriate key words. Data was gathered on dose strength and drug exposure (AUCinf, and Cmax) in the fasted and fed states. The specific type of food administered for the fed state (e.g, high-fat, high-calorie, etc.) was recorded. Additional data on dose-proportionality, Biopharmaceutics Classification System (BCS) class, absorption characteristics, and drug solubility (mg/mL at pH 7) was extracted from United States Prescribing Information (USPI) labels and multi-discipline reviews at the Drugs@FDA database. The change in AUCinf and Cmax between fed and fasted states at each dose, and the fraction of dose soluble in 250 mL were estimated.

Results: Eight drugs were found to have dose-dependent food-effects, with dose strengths ranging from 3 to 900 mg and number of participants in the studies ranging from 12 to 122. The magnitude of change in AUC varied with drug/dose, e.g., 38.7% increase in AUC at the 10 mg rivaroxaban dose and little change (-1.2%) at the 20 mg dose. Drug solubility at pH 7 data ranged from 0.0000042 to 0.0183 mg/mL, and the estimated percent of dose soluble in 250 mL varied from 0.0002625 to 25%.

Conclusion: Of the 8 drugs found to have dose-dependent food-effects, all were BCS Class II or IV drugs. Surprisingly, all 8 drugs demonstrated linear dose-proportionality across the doses at which food-effect was evaluated. All 8 drugs were found to have a small fraction of dose in solution (250 mL) suggesting a predominant reason for differing magnitude of food effect seen across different doses of the same drug.