Cilostazol absorption and pharmacokinetics were simulated using GastroPlus™ 6.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental and Transit (ACAT) model described the absorption of the drug, while pharmacokinetics was simulated with physiologically-based pharmacokinetics (PBPK) model. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™ module. Tissue/plasma partition coefficients were calculated using a modified Rodgers (2007) & Lukacova (2008) 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 (Hiratsuka 2007) combined with built-in in vitro values for the distribution of 3A4 in gut (Paine 1997) and the average expressions of all four enzymes in liver (Inoue 2006). The resultant model accurately reproduced human in vivo plasma concentration-time profiles for solid oral doses ranging from 25 to 300 mg. Simulations with doses from 10 to 1000 mg showed a nonlinear dose dependency of bioavailability with maximum at ~50 mg dose. For lower doses, the predicted fraction absorbed (Fa) was nearly 100 %, with predicted bioavailability affected mainly by saturable first pass extraction (FPE). The predicted bioavailability increased by ~5 % from 10 to 50 mg. Limited solubility caused a decrease in Fa with increasing dose. This decrease in Fa was more significant than the further decrease in FPE, resulting in ~50 % decrease in the predicted bioavailability from 50 to 1000 mg. This study demonstrates that even in the absence of intravenous data, mechanistic simulations of oral doses can help to estimate fraction absorbed and first pass extraction in gut and liver, and to provide information about processes affecting bioavailability which can be used in estimates of drug-drug interactions and/or formulation design.
16th North American ISSX Meeting, October 18-22, 2009, Baltimore, MD
By Viera Lukacova, Michael B. Bolger, J.R. Crison and Walter S. Woltosz