Simulation of Food Effect on Cilostazol Exposure in Human

Conference: CRS
Division: Simulations Plus


Introduction: For certain drugs, the time of administration respective to meal times can have a significant impact on exposure. The effect of food is usually attributed to increased solubility/dissolution rate and/or modulation of the intestinal first pass. Administration of the drug with food can also lead to delayed Tmax compared to administration in fasted state. The effect of food on differences in solubility/dissolution rate can be predicted [1, 2] using drug solubilities measured in biorelevant media mimicking the intestinal fluid in fasted and fed state [3]. The current work presents simulations explaining the dose- dependency of food effects on the dissolution and absorption of a Class II drug.

Methods: The PBPKPlus™ module of GastroPlus™ 6.0 (Simulations Plus, Inc.) was used to construct a physiologically-based pharmacokinetic (PBPK) model for simulating cilostazol distribution and clearance. The model was based on the physiology (height, weight, tissue volumes and tissue blood flows) of typical 30-year-old (“30yo”) adult male physiologies from Western and Japanese populations. Tissue/plasma partition coefficients (Kps) were calculated using a modified Rodgers [4, 5] algorithm from in vitro and in silico physicochemical properties (ADMET Predictor™, Simulations Plus, Lancaster, CA). The metabolic clearance of cilostazol in gut and liver was estimated from in vitro enzyme kinetic constants for CYP3A4, 3A5, 2C8 and 2C19 [6] combined with experimental values for the distribution of 3A4 in gut [7] and the average expressions of all four enzymes in liver [8]. Published fasted-state Cp-time profiles were used to calibrate the absorption model [9, 10] by fitting solubility and amount of fluid available for drug dissolution in colon . To model the fed state studies, the solubility was increased to account for the solubilizing effect of higher concentrations of bile acids (by increasing solubility) and the physiological gut parameters were modified to reflect the other physiological changes in fed state (mainly stomach pH, volume and stomach emptying rate represented by stomach transit time).

Controlled Release Society (CRS) Annual Meeting, July 18-22, 2009, Copenhagen, Denmark

By Viera Lukacova, J.R. Crison, Michael B. Bolger and Walter S. Woltosz