Tapcom Mechanism of Action

Pharmacology: Pharmacodynamics: Intraocular pressure (IOP) lowering effect: Ocular administration of this product in a single dose to monkeys showed statistically significant IOP lowering effect. The effect was significantly greater than that of monotherapy containing individual active ingredients (i.e. 0.0015% tafluprost ophthalmic solution and 0.5% timolol ophthalmic solution).
Mechanism of action: Tafluprost carbonic acid, an active form of tafluprost, is an agonist to prostanoid FP receptor, and timolol maleate is a non-selective blocker to β adrenaline receptor. These active ingredients of this product lower IOP by the different modes of action.
Tafluprost acid form, an active metabolite of tafluprost, showed high affinity for the prostanoid FP receptor (Ki=0.40 nM). Aqueous humor dynamics in monkeys was evaluated using fluorophotometry, two-level constant pressure perfusion and ¹²⁵I-¹³¹I labeled albumin perfusion methods following the repeated administration of 0.005% tafluprost ophthalmic solution once daily for 3 to 5 days. Uveoscleral outflow was significantly increased without any change in aqueous production.
Mechanism of action of timolol maleate is not clear but it was suggested that the effect is caused mainly by decreasing aqueous production, which was demonstrated by the fluorophotometry study in monkeys and healthy subjects and the tonography test in glaucoma patients.
Effect on ocular blood flow: A repeated instillation of tafluprost ophthalmic solution 0.0015% into rabbit eyes once daily for 28 days significantly increased the blood flow in the optic nerve head, measured with laser speckle method.
A single dose instillation of tafluprost ophthalmic solution 0.0015% into eyes of healthy adults significantly increased the blood flow rate in the paraoptic nerve head retinal artery and the tissue blood flow at the paraoptic nerve head retina.
Clinical efficacy: In a randomized masked comparison study in 487 patients with primary open angle glaucoma or ocular hypertension, using Tafluprost ophthalmic solution 0.0015% (once daily) (here after Tafluprost group) or concomitant Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily) (here after Concomitant group) as a comparator, after instillation of Tafluprost ophthalmic solution 0.0015% (once daily) during 4 weeks of run-in period and instillation of TAPCOM (once daily) or each control drug in a double-masked manner during 4 weeks of treatment period, the superiority of TAPCOM to Tafluprost group (p<0.001) and the non-inferiority to Concomitant group was confirmed (ANCOVA with baseline IOP as covariate). TAPCOM was confirmed to be non-inferior to Concomitant group in IOP lowering (Table 1 and Figure 1). (See Table 1 and Figure 1.)


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In a randomized masked comparison study in 166 patients with primary open angle glaucoma or ocular hypertension using Timolol ophthalmic solution 0.5% (twice daily) (here after Timolol group) as a comparator, after instillation of Timolol ophthalmic solution 0.5% (twice daily) during 4 weeks of run-in period and instillation of TAPCOM (once daily) or control drug in a double-masked manner during 4 weeks of treatment period, the superiority of TAPCOM to Timolol group was confirmed (p<0.001) (ANCOVA with baseline IOP as covariate) (Table 2 and Figure 2). (See Table 2 and Figure 2.)


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In a long-term administration study in 136 patients with primary open angle glaucoma including normal tension glaucoma or ocular hypertension, TAPCOM was instilled during 52 weeks of treatment period following 4 weeks of run-in period with using Tafluprost ophthalmic solution 0.0015% (once daily), Timolol ophthalmic solution 0.5% (twice daily), or concomitant Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily). In case of switching from Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily), the IOP change from baseline (Week 0) was statistically significant at all measurement points (p<0.001). In case of switching from concomitant Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily), no significant change in IOP was observed throughout the treatment period compared with baseline (Week 0), and the time course of IOP remained stable during the 52 weeks(Figure 3). (See Figure 3.)


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Pharmacokinetics: Plasma concentrations: One drop of TAPCOM ophthalmic solution (once daily), 0.0015% tafluprost ophthalmic solution (once daily), 0.5% timolol ophthalmic solution (twice daily) and a combination of 0.0015% tafluprost ophthalmic solution (once daily)/0.5% timolol ophthalmic solution (twice daily) were instilled to both eyes of 32 healthy adult volunteers for 7 days and plasma concentrations of timolol and tafluprost acid which is an active metabolite of tafluprost were measured.
The C_max of tafluprost acid on the first and seventh day in the repeated instillation of TAPCOM were similar levels to that with the single use of tafluprost and the combination of tafluprost/timolol. The C_max and AUC_inf of timolol on the first and seventh day in the repeated instillation of TAPCOM were similar levels to that with the single use of timolol and the combination of tafluprost/timolol. (See Table 3.)


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Ocular tissue distribution in animals (for reference : Rats): The concentration profiles of tafluprost acid and timolol in aqueous humor following a single ocular instillation of TAPCOM ophthalmic solution to rats were similar to those in combination with a single ocular instillation of 0.5% timolol ophthalmic solution and 0.0015% tafluprost ophthalmic solution with 5-minute interval.