This study is the first trial to develop a PK/PD model for an antiglaucoma agent using an indirect response and the relationship between IOP and aqueous humor flow.
We have established an ocular pharmacokinetic/pharmacodynamic (PK/PD) model for a b b-adrenergic antagonist, timolol, after instillation into rabbits. Timolol concentrations were determined by HPLC in the tear fluid, aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber of the eye in rabbits. In addition, intraocular pressure (IOP) measurement was performed after instillation of timolol by a telemetry system, which was able to obtain detailed IOP data automatically. The PK/PD parameters were estimated by fitting the concentration-time profiles and the ocular hypotensive effect-time profiles using MULTI (RUNGE) program. The PK model consisted of six compartments and the PD model included aqueous humor dynamics based on an action mechanism of timolol, which causes lowering of IOP by suppressing aqueous humor production. The PK/PD model described well the concentration-time profiles and the ocular hypotensive effect-time profiles after instillation of timolol. This study is the first trial to develop an ocular PK/PD model for timolol after instillation. This model can predict both the drug concentrations in various ocular tissues and the ocular hypotensive effect after instillation of timolol.
The current mainstay of glaucoma treatment is topical medications of ocular hypotensive effect drugs in controlling intraocular pressure (IOP) and preserving visual field. IOP is mainly determined by the aqueous humor dynamics, which is the coupling of aqueous humor formation in the ciliary body and its drainage through the uveoscleral route and the trabecular meshwork route.1) The action mechanisms of anti-glaucoma drugs are well known and classified into several action mechanisms 2,3) : b-adrenergic antagonists (e.g., timolol, betaxolol), carbonic anhydrase inhibitors (e.g., dorzolamide), and a 2 -adrenergic agonists (e.g., apraclonidine, brimonidine) that suppress aqueous humor formation; prostaglandin FP receptor agonists (e.g., latanoprost, travoprost), prostamides (e.g., bimatoprost), and a 1 -adrenergic antagonists (bunazosin), which promote aqueous humor outflow through the uveoscleral route; and cholinomimetics (e.g., pilocarpine) responsible for promoting aqueous humor outflow through the trabecular meshwork route as a result of contraction of the ciliary muscle.It is also a common practice to use multiple anti-glaucoma drugs in combination to achieve target IOP lowering when a favorable response is not obtained by monotherapy. 4) In order to comprehend the result of multidrug treatment, some comparative studies on the combined effects of drugs were reported. 4,5) However, in multidrug therapy, without experiments it has been impossible to determine the strength and duration of the ocular hypotensive effect quantitatively.Pharmacokinetic/pharmacodynamic (PK/PD) models allow us to predict quantitatively both the drug concentration and pharmacological effect after administration of drugs. In the previous reports, we have succeeded in developing two ocular PK/PD models for anti-glaucoma drugs after instillation into rabbits. One is the model for an a 1 -adrenergic antagonist, bunazosin, 6) and the other is for a b-adrenergic antagonist, timolol, 7) but no ocular PK/PD model for multidrug therapy for the eye has been devised. The models for bunazosin and timolol each include aqueous humor dynamics based on each action mechanism, which are different from one another; therefore, a combined ocular PK/PD model after instillation of a combination of multiple drugs must be able to be constructed by including each action mechanism.In the present study, we constructed a new combined ocular PK/PD model by including both the action mechanisms of bunazosin and timolol, and simulated the theoretical drug concentrations and ocular hypotensive effects after instillation of a combination of bunazosin and timolol into rabbits using the combined model and PK/PD parameters for each drug. In addition, to verify the reliability of the combined model, we confirmed the drug concentrations and ocular hypotensive effects measured by a telemetry system after instillation of the drug combination. The PD parameters for bunazosin were recalculated from the ocular hypotensive effects measured by the telemetry system in order to obtain...
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