Chemical formula: C₂₅H₃₄F₂O₅ Molecular mass: 452.531 g/mol PubChem compound: 9868491
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.
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.
After once daily administration of one drop of unpreserved tafluprost 0.0015% eye drops 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.
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.
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.
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.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, systemic repeated dose toxicity, genotoxicity and carcinogenic potential. As with other PGF2 agonists, repeated dose topical ocular administration of tafluprost to monkeys produced irreversible effects on iris pigmentation and reversible enlargement of the palpebral fissure.
Increased contraction of rat and rabbit uteri in vitro was observed at tafluprost acid concentrations that exceeded 4 to 40 times, respectively, the maximum plasma concentrations of tafluprost acid in humans. Uterotonic activity of tafluprost has not been tested in human uterus preparations.
Reproduction toxicity studies were performed in the rat and rabbit with intravenous administration. In rats, no adverse effects on fertility or early embryonic development were observed at systemic exposure over 12,000 times the maximum clinical exposure based on Cmax or greater than 2,200 times based on AUC.
In conventional embryo-foetal development studies, tafluprost caused reductions in foetal body weights and increases in post-implantation losses. Tafluprost increased the incidence of skeletal abnormalities in rats as well as the incidence of skull, brain and spine malformations in rabbits. In the rabbit study, plasma levels of tafluprost and its metabolites were below the level of quantification.
In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offspring at tafluprost doses greater than 20 times the clinical dose.
The experiments in rats with radiolabelled tafluprost showed that around 0.1% of the topically applied dose on eyes was transferred into milk. As the half-life of active metabolite (tafluprost acid) in plasma is very short (not detectable after 30 minutes in humans), most of the radioactivity probably represented metabolites with little, or no pharmacologic activity. Based on metabolism of the drug and natural prostaglandins, the oral bioavailability is expected to be very low.
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