Session Speaker

Development and Validation of a Physiologically Based Pharmacokinetic (PBPK) Model of Tamiflu^® for the Rat
Francis C.P. Law, Gao Guanghua and Mildred S. Yang
Canada

Introduction: Tamiflu® is the drug of choice for the treatment and prevention of avian influenza. A PBPK model of the rat was developed and validated for Tamiflu® and its metabolite, oseltamivir carboxylate (OC).

Methods: Male Sprague-Dawley rats weighing 220-250 g were administered a single dose of Tamiflu® (10 mg/kg or 50 mg/kg) orally. Three rats were sacrificed at pre-determined time points. Blood and tissue samples were collected from the rat and analyzed for Tamiflu® and OC using LC/MS/MS. The PBPK model which consisted of a Tamiflu® and an OC sub-models, was developed using the 10 mg/kg study data. The model was validated with the data of the 50 mg/kg study. Tissue/plasma partition coefficients were derived from the areas under the curves of Tamiflu® and OC in the tissues and plasma. Tamiflu® metabolism was limited to the liver compartment and described by the Michaelis-Menten constants (Km and Vmax) which also provided a link between the Tamiflu® and OC sub-models.

Results: Model-simulated results closely described the concentration-time profiles of Tamiflu® and OC observed experimentally. The experimental data also provide valuable inputs for parameter estimation and validation of the PBPK model (Supported by a Hong Kong RFCID/HHSRF/HSRF/HCPF research grant).