Demonstration of the equivalent pharmacokinetic/pharmacodynamic dosing strategy in a multiple-dose study of gefitinib.

The goals of this investigation were to illustrate the use of pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategies in drug development based on a multiple-dose study of gefitinib in a preclinical tumor model. Mice bearing s.c. LN229-wild-type epidermal growth factor receptor or LN229-EGFRvIII mutant (a sensitizing mutation) tumors were administered gefitinib at oral doses of either 55 mg/kg/d p.o. x 15 days or 30 mg/kg/d p.o. x 15 days, respectively, as dictated by the equivalent PK/PD dosing strategy. In each tumor group, gefitinib plasma and tumor concentrations were quantitated, as well as the tumoral amounts of phosphorylated-extracellular signal-regulated kinase 1/2 (pERK), a selected PD end point, and tumor size. The resultant data provided the basis to develop hybrid physiologically based PK/PD/tumor growth models for each tumor type. It was found that the 1.83-fold dose difference administered to the two tumor groups resulted in analogous pERK profiles on both days 1 and 15, and further induced similar antitumor efficacy based on tumor size. In addition, using brain tumor patient PK data linked to the pERK PD model, simulations were conducted to illustrate potential applications of a target tumor model to patients. The simulations provided insight on the relationships between blood-brain barrier penetration, brain tumor gefitinib concentrations, and the extent of inhibition of pERK. The implementation of the PK/PD equivalent dosing strategy offers a new approach to drug development.