Glanatec Mechanism of Action

Pharmacotherapeutic group: Antiglaucoma preparations and miotics.
Pharmacology: Pharmacodynamics: Mechanism of Action: Inhibition of Rho kinase to facilitate aqueous outflow from the conventional outflow pathway via the trabecular meshwork and Schlemm's canal has been suggested as the IOP-lowering mechanism of action by ripasudil.
(1) Ripasudil selectively inhibited human ROCK-1 and ROCK-2, which are isoforms of Rho kinases (in vitro).
(2) After a single instillation of GLANATEC to rabbits, the aqueous outflow rate was significantly increased compared to the group treated with the vehicle.
(3) A single instillation of GLANATEC to rabbits did not affect the volume of uveoscleral outflow or aqueous production.
Pharmacodynamic Effects: After a single instillation of ripasudil hydrochloride hydrate ophthalmic solution at 0.0625% to 0.5% to rabbits and the same solution at 0.1% to 0.4% to monkeys, a concentration-dependent IOP-lowering effect was observed.
Clinical efficacy: Phase 3 Placebo-controlled Double-masked Comparative Study: In Japanese patients with primary open-angle glaucoma or ocular hypertension, placebo or GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily for 8 weeks. Changes in IOP over time and the amount of change in IOP are shown in Figure 1 and Table 1. The study demonstrated a significant IOP-lowering effect in the GLANATEC group compared with the placebo group. (See Figure 1 and Table 1.)

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Phase 3 Combination Study with Latanoprost Ophthalmic Solution: In Japanese patients with primary open-angle glaucoma or ocular hypertension in whom latanoprost ophthalmic solution 0.005% was not adequately effective, placebo or GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily in addition to latanoprost ophthalmic solution 0.005% for 8 weeks. Changes in IOP over time and the amount of change in IOP are shown in Figure 2 and Table 2. (See Figure 2 and Table 2.)

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Phase 3 Combination Study with Timolol Ophthalmic Solution: In Japanese patients with primary open-angle glaucoma or ocular hypertension in whom timolol maleate ophthalmic solution 0.5% was not adequately effective, placebo or GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily in addition to timolol maleate ophthalmic solution 0.5% for 8 weeks. Changes in IOP over time and the amount of change in IOP are shown in Figure 3 and Table 3. The study demonstrated a significant IOP-lowering effect in the GLANATEC group compared with the placebo group. (See Figure 3 and Table 3.)

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Phase 3 Long-term Study: In Japanese patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension, GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily for 52 weeks, either alone or in addition to prostaglandin (PG) analogs, β-blockers, or combination drugs containing them. Changes in IOP over time are shown in Figure 4. The study demonstrated a stable IOP-lowering effect in long-term instillation of GLANATEC and did not show attenuation of the IOP-lowering effect owing to the prolongation of the treatment period, either as monotherapy or in combination therapy. (See Figure 4.)

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Pharmacokinetics: Plasma Concentration and Urinary Excretion: GLANATEC was instilled repeatedly to healthy Japanese male adults at 1 drop/eye dose in both eyes twice daily for 7 days, and the changes of ripasudil and its main metabolite M1 (isoquinoline ring position 1 hydroxylated form) over time in plasma concentrations and their pharmacokinetic parameters are shown in Figure 5 and Table 4. The entry of ripasudil into the systemic circulation and the elimination thereof from the body were rapid. In addition, most of ripasudil and M1 were excreted in the urine by 12 hours after completion of repeated instillation. (See Figure 5 and Table 4.)

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Entry into the Ocular Tissues: After a single dose of GLANATEC (50 μL) was instilled to both eyes of pigmented rabbits, the drug in the cornea and the aqueous humor reached the maximum concentration (68135.4 ng/g and 4126.39 ng/mL, respectively) by 0.25 hour and then was rapidly eliminated. In the lens, the drug reached the maximum concentration (154.37 ng/g) by 0.5 hour and then was slowly eliminated.
After a single dose of ¹⁴C-ripasudil hydrochloride ophthalmic solution 1.0% (50 μL) was instilled to pigmented rabbits, the drug rapidly entered each ocular tissue. In the ocular tissues, a high radioactivity concentration was detected particularly in the iris/ciliary body and the retina/choroid, which are tissues containing melanin. After instillation twice daily for 7 days, the radioactivity concentration in the tissues containing melanin was obviously higher than after the single-dose instillation, and the radioactivity concentration tended to disappear gradually in all tissues.
Toxicology: Preclinical safety data: In the 2.0% (twice daily) group in the 13-week repeated instillation study in rabbits and the 4.0% (4 times daily) group in the 13-week repeated instillation study in dogs, irreversible degeneration of lens fibers with opacification was observed in the suture line of the anterior lens. Such changes in the lens are thought to have been caused by the inhibition of formation of actin stress fibers by the Rho kinase inhibiting effect of GLANATEC, which led to the inhibition of differentiation into the fiber cells of the lens and subsequent extension and migration.