Taflotan Mechanism of Action

Pharmacology: Pharmacodynamics: Intraocular Pressure (IOP) Lowering Effect: Ocular administration of tafluprost ophthalmic solutions ranged from 0.00002% to 0.005% in a single dose to monkeys showed the IOP lowering effect in a concentration-dependent manner. The effect was statistically significant in the groups of the concentration of 0.0005% and higher, compared with the vehicle group. In a repeated-dose study in monkeys of tafluprost ophthalmic solutions ranged from 0.001% to 0.005% once daily for 5 days, IOP lowering effect at every concentration was stable and did not attenuate during the administration period.
Mechanism of action: Tafluprost acid form, an active metabolite, 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.
Effect on ocular blood flow: 1) A repeated instillation of this product into rabbit eyes once daily for 28 days significantly increased the blood flow in the optic nerve head, measured with laser speckle method.
2) A single dose instillation of this product into eyes of healthy adults significantly increased the blood flow rate in the paraoptic nerve head retinal artery and the blood flow at the paraoptic nerve head retina.
Clinical Studies: In a randomized blind comparative study in 109 patients with primary open angle glaucoma or ocular hypertension using latanoprost ophthalmic solution as a comparator, the decrease in intraocular pressure (IOP) for this product was 6.6 mmHg (95% confidence interval: 5.8-7.3 mmHg), which demonstrated non inferiority to the comparator. (See Table 2.)

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In a randomized blind comparative study in 94 patients with normal tension glaucoma using placebo ophthalmic solution as a comparator, the decrease in IOP for this product was 4.0 mmHg (95% confidence interval: 3.5-4.5 mmHg), which showed significant IOP lowering effect compared with placebo. (See Table 3.)

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In a long-term administration study in 351 patients with open angle glaucoma including normal tension glaucoma, or patients with ocular hypertension, the decrease in IOP for this product remained between 4.9 and 5.7 mmHg for 52 weeks, which demonstrated stable IOP lowering effect in long-term administration. IOP decrease was 6.0-6.9 mmHg in cohort 1* and 3.4-4.0 mmHg in cohort 2 over 52 weeks.
*Cohort 1: 22-34 mmHg at baseline.
Cohort 2: 16-21 mmHg at baseline. (See Figure.)

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Pharmacokinetics: Plasma Concentrations: When 0.0025% or 0.005% tafluprost ophthalmic solution was instilled one drop once daily for 7 days in both eyes of 7 healthy adult volunteers, the plasma concentrations of tafluprost and its active metabolite, tafluprost acid form, were below the quantitation limits (tafluprost; 0.2 ng/mL, tafluprost acid form; 0.1 ng/mL) at every time point, except in one volunteer of the 0.0025% group at 15 minutes after instillation on Day 1, with the concentration of tafluprost acid form being 0.144 ng/mL.
(Note: The concentration of this product is 0.0015%.)
Ocular tissue distribution in animal (monkeys): Following a single ocular instillation of 0.005% ³H-tafluprost ophthalmic solution to monkeys, the radioactivity was distributed in the ocular tissues rapidly and reached the maximum radioactive concentration in the cornea and conjunctiva at 5 to 15 minutes after instillation; in the aqueous humor, iris, ciliary body and lens at 2 hours after instillation, and was eliminated rapidly.