Abstract

Purpose: To develop an integrated model for drug absorption from the oral cavity. The model simulates combined absorption of a drug from both the oral cavity and the gastrointestinal tract.

Methods: GastroPlus™ 5.3 with the PBPKPlus™ Module (Simulations Plus, Inc., Lancaster, CA) was used to simulate adult human plasma concentration time (Cp-time) profiles of nifedipine when administered as a 1 mg intravenous (IV) infusion, 10 mg oral capsule (PO), 10 mg oral solution held sublingually (SL) for 7 min and then swallowed, and 10 mg oral solution held sublingually for 20 min and expectorated. A physiologically-based pharmacokinetic model (PBPK) based on adult human physiology was used in all simulations. Tissue/plasma partition coefficients were calculated using in silico physicochemical properties (ADMET Predictor™, Simulations Plus, Lancaster, CA) combined with in vitro measured values where available. Cp-time data from an IV infusion dose were used to fit the systemic clearance model, which was then used in all PO and SL dose simulations. Cp-time profiles after expectorated SL and PO doses were used to calibrate the absorption and first pass extraction of drug from the oral cavity and the gastrointestinal tract, respectively. The combination of these absorption parameters was then used to simulate the SL dose swallowed after 7 min.

10th European Regional ISSX Meeting, May 2008, Vienna, Austria

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