Purpose:To develop a mechanism-based phannacokinetic (PK) and pharmacodynamic (PD) model to describe and predict the intraocular pressure (IOP)-lowering effect of bimatoprost end timolol as a fimction of time, dose, and dosage regimens in subjects with open-angle glaucoma or ocular hypertension.Methods and Results:A mechanism-based model was developed to relate diurnal and drug induced changes of IOP to tbe change of aqueous humor flow dynamics.A circadian aqueous humor production rate model was developed to describe the diumal IOP profile before (baseline, pre-treatment) and during treatment of individual patients.Clinical trial simulations using NONMEM were conducted to illustrate the model properties and its application potentials.Results:Anew class of mechanism-based PK and PD models were developed to describe and predict the IOPlowering effect of drugs of various mechanism of action as a function of time, dose, and dosage regimens in subjects with open-angle glaucoma or ocular hypertension including the following features: 1) relating diurnal and drug induced changes of IOP to the change of aqueous humor flow dynamics; 2) a circadian aqueous humor production rate model describes the diurnal IOP profile before (baseline, pre-treatment) and during trcatnent of individual paticnts; 3) the IOP-lowcring effect of drugs can be modeled by increasing aqueous humor outflow through the trabecular meshwork and or uweoscleral pathway, and reducing aqueous humor production rate.Conclusions: This new class of models are a significant improvement of the classical Goldmann Equation.