Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, prostaglandin analogues

ATC code: S01EE05

Mechanism of action
Tafluprost is a fluorinated analogue of prostaglandin F2α. Tafluprost acid, the biologically active metabolite of tafluprost, is a highly potent and selective agonist of the human prostanoid FP receptor. Tafluprost acid has a 12-fold higher affinity for the FP receptor than latanoprost. Pharmacodynamic studies in monkeys indicate that tafluprost reduces intraocular pressure by increasing the uveoscleral outflow of aqueous humour.

Pharmacodynamic effects
The experiments in normotensive and ocular hypertensive monkeys showed that tafluprost is an effective IOP-lowering compound. In the study investigating IOP- reducing effect of tafluprost metabolites only tafluprost acid reduced IOP significantly.

When rabbits were treated for 4 weeks with a tafluprost 0.0015% ophthalmic solution once daily, the optic nerve head blood flow was significantly (15%) increased compared to baseline when measured by the laser speckle flowgraphy on Days 14 and 28.

Clinical efficacy
Reduction of intraocular pressure starts between 2 and 4 hours after the first administration and maximum effect is reached at around 12 hours after instillation.
The duration of effect is maintained for at least 24 hours. Pivotal studies with a tafluprost formulation containing the preservative benzalkonium chloride have demonstrated that tafluprost is effective as monotherapy and has an additive effect when administered as adjunctive therapy to timolol: In a 6-month study, tafluprost showed a significant IOP lowering effect of 6 to 8 mmHg at different time points of the day as compared to 7 to 9 mmHg with latanoprost. In a second 6-month clinical study, tafluprost reduced IOP by 5 to 7 mmHg as compared to 4 to 6 mmHg with timolol. The IOP lowering effect of tafluprost was maintained in the extension of these studies up to 12 months. In a 6-week study, the IOP-lowering effect of tafluprost was compared with its vehicle when used adjunctively with timolol. Compared to baseline values (measured after a 4-week run in on timolol), the additional IOP-lowering effects were 5 to 6 mmHg in the timolol-tafluprost group and 3 to 4 mmHg in the timolol-vehicle group. The preserved and the non-preserved formulations of tafluprost showed a similar IOP-lowering effect of over 5 mmHg in a small cross-over study with a 4-week treatment period.
Furthermore, in a 3-month study in the US comparing the non-preserved formulation of tafluprost with the non-preserved formulation of timolol, the IOP-lowering effect of tafluprost was between 6.2 and 7.4 mmHg at different timepoints whereas that of timolol varied between 5.3 and 7.5 mmHg.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
After once daily ocular administration of one drop of unpreserved tafluprost 0.0015% eye drops in single-dose container to both eyes for 8 days, plasma concentrations of tafluprost acid were low and had similar profiles on days 1 and 8. The plasma concentrations peaked at 10 minutes after dosing and declined to below the lower limit of detection (10 pg/ml) before one hour after dosing. Mean Cmax (26.2 and 26.6 pg/ml) and AUC0-last (394.3 and 431.9 pg*min/ml) values were similar on days 1 and 8, indicating that a steady drug concentration was reached during the first week of ocular dosing. No statistically significant differences in the systemic bioavailability between the preserved and unpreserved formulation were detected.

In a rabbit study, the absorption of tafluprost into the aqueous humour was comparable after a single ocular instillation of unpreserved or preserved tafluprost 0.0015% ophthalmic solution.


Distribution
In monkeys, there was no specific distribution of radiolabelled tafluprost in the iris- ciliary body or choroid including retinal pigment epithelium, which suggested low affinity for melanin pigment. In a whole body autoradiography study in rats, the highest concentration of radioactivity was observed in the cornea followed by the eyelids, sclera and the iris. Outside the eye radioactivity was distributed to the lacrimal apparatus, palate, oesophagus and gastrointestinal tract, kidney, liver, gall bladder and urinary bladder.

The binding of tafluprost acid to human serum albumin in vitro was 99% at 500 ng/ml tafluprost acid.

Biotransformation
The principal metabolic pathway of tafluprost in human, which was tested in vitro, is the hydrolysis to the pharmacologically active metabolite, tafluprost acid, which is further metabolized by glucuronidation or beta-oxidation. Products of beta-oxidation, 1,2-dinor and 1,2,3,4-tetranor tafluprost acids, which are pharmacologically inactive, may be glucuronidated or hydroxylated. Cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid. Based on the study in rabbit corneal tissue and with purified enzymes, the main esterase responsible for the ester hydrolysis to tafluprost acid is carboxyl esterase. Butylcholine esterase but not acetylcholine esterase may also contribute to the hydrolysis.

Elimination
Following once daily administration of 3H-tafluprost (0.005% ophthalmic solution; 5 μl/eye) for 21 days to both eyes in rats, approximately 87% of the total radioactive dose was recovered in the excreta. Percent of the total dose excreted in urine was approximately 27-38% and approximately 44-58% of the dose was excreted in the feces.