Pharmacokinetics and Pharmacology of Latanoprost 0.005% without Benzalkonium Chloride Vs Latanoprost 0.005% with Benzalkonium Chloride in New Zealand White Rabbits and Beagles.

Purpose: Many intraocular pressure (IOP)-lowering medications contain benzalkonium chloride (BAK), a preservative associated with unfavorable outcomes.A formulation of latanoprost 0.005% ophthalmic without BAK is approved by the FDA and indicated for reduction of IOP in patients with open-angle glaucoma or ocular hypertension. We present two preclinical studies of latanoprost 0.005% BAK-free vs latanoprost with BAK; one examining plasma and ocular tissue pharmacokinetics (PK) in New Zealand white rabbits, and one comparing in vivo IOP-lowering efficacy in healthy beagles.Methods: In the PK study, one drop of treatment (latanoprost BAK-free or latanoprost with BAK) was instilled into both eyes of rabbits in each treatment group (n = 18). At 0.25, 0.5, 1, 4, 6, and 24 hours postdose, three rabbits per study group underwent terminal blood and tissue collection.In the IOP study, in the first dosing period, both eyes of each beagle received either 1 drop latanoprost BAK-free or latanoprost with BAK, once daily for 10 days. After a 10-day washout period, a second 10-day dosing period was conducted and latanoprost BAK-free or latanoprost with BAK were dosed in the opposite eyes, respectively. IOP measurements were taken at 1, 6, and 12 hours postdose.Results: The maximum plasma concentration for latanoprost BAK-free and latanoprost with BAK occurred 0.25 hours after administration (174.1 vs 217.2 pg/mL, respectively). Area under the concentration time curve from zero to infinity was highest in aqueous humor for latanoprost BAK-free and latanoprost with BAK (133.1 vs 119.6 hr·ng/mL, respectively) and was not estimable in vitreous humor. In beagles, once-daily administration of latanoprost BAK-free or latanoprost with BAK led to a significant reduction in IOP vs baseline (P < .001); there was no difference between groups (P > .05).Conclusions: Latanoprost BAK-free showed comparable activity in reducing IOP, and comparable plasma and ocular PK parameters to latanoprost with BAK.

A Comparative Ocular Pharmacokinetics Study of Preservative-Free Latanoprost Unit-Dose Eye Drops and a Benzalkonium Chloride-Preserved Branded Product Following Topical Application to Rabbits.

Purpose: To evaluate the aqueous humor pharmacokinetics of a preservative-free 0.005% latanoprost unit-dose eye drop (test drug) compared with that of a benzalkonium chloride (BAK)-preserved 0.005% latanoprost branded product (control drug) following topical application to rabbits. Methods: A total of 120 healthy New Zealand albino rabbits were administrated test eye drops (T group) or control eye drops (C group) for a comparative pharmacokinetics study. The aqueous humor was collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after a single dose or multiple doses. Ultraperformance liquid chromatography-tandem quadrupole mass spectrometry was employed to detect latanoprost free acid (LTA, the active metabolite of latanoprost) in the aqueous humor. Results: For the single-dose study, there was no significant difference (t-test, P > 0.05) in the peak concentration (Cmax) of LTA in aqueous humor between the T group (69.0 ± 23.4 ng/mL) and C group (73.8 ± 28.7 ng/mL). The area under the curve values over 12 h (AUC0-12h) of LTA for the 2 groups were 254.4 (ng/mL) × h and 219.5 (ng/mL) × h, respectively. For the multidose study, there was also no significant difference (t-test, P > 0.05) in the Cmax of LTA in the aqueous humor between the T group (86.8 ± 21.2 ng/mL) and C group (70.5 ± 25.9 ng/mL). The AUC0-12h values of LTA for the 2 groups were 274.5 (ng/mL) × h and 256.3 (ng/mL) × h, respectively. Conclusions: The preservative-free 0.005% latanoprost unit-dose eye drops demonstrated similar pharmacokinetic properties to the BAK-preserved branded product following topical application to rabbits.

Effect of Topical Prostaglandin F2α Analogs on Selected Oxidative Stress Parameters in the Tear Film.

Background and Objectives: Topically administered antiglaucoma medications, especially those containing benzalkonium chloride (BAC), may cause local adverse effects and compromise ocular surface. The aim of the study was to assess the effect of topical prostaglandin F2α analogs (PGAs): preservative-free latanoprost, BAC-preserved latanoprost, preservative-free tafluprost, and BAC-preserved bimatoprost, on selected oxidative stress parameters in the tear film. Materials and Methods: The patients were divided into five groups: group C (n = 25) control group-subjects who did not use topical antiglaucoma medications, group L (n = 22)-patients using topical preservative-free latanoprost, group L+BAC (n = 25)-patients using topical BAC-preserved latanoprost, group T (n = 19)-patients using topical preservative-free tafluprost, and group B+BAC (n = 17)-patients using topical BAC-preserved bimatoprost. The oxidative stress markers in the tear film samples were evaluated: total protein (TP) concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl (-SH) groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response (TAR), and Oxidative Stress Index (OSI). Results: The TP concentrations in the groups L, L+BAC, and B+BAC were statistically significantly higher in comparison with group C. The SOD and CAT activities in the groups L+BAC and B+BAC were statistically significantly higher when compared to group C. As compared to group C, AOPP and TOS were statistically significantly higher in all the study groups. OSI was found to be statistically significantly higher in the groups L+BAC, T, and B+BAC in comparison with group C. Conclusion: Use of topical PGAs by the patients with ocular hypertension or primary open-angle glaucoma is associated with increased oxidative stress in the tear film which is additionally exacerbated by the presence of BAC in the formulation.

Efficacy of the combination of carteolol hydrochloride + latanoprost in the treatment of glaucoma and ocular hypertension.

INTRODUCTION: The only evidence-based mechanism for prevention and treatment of glaucomatous optic neuropathy is decreasing the intraocular pressure (IOP). Prescribing multiple ocular hypotensive agents, such as the combination of carteolol and latanoprost, may synergistically improve IOP; however, doing so may increase the complexity of a medication regimen, in turn, impairing patient adherence. Fixed-combination glaucoma medications offer convenience and effectiveness. New to this class of glaucoma medication is fixed combination carteolol-latanoprost (FCCL). Area covered: This review intends to give the reader a better understanding of the efficacy of the combination of carteolol and latanoprost separately, and where FCCL fits into the vast medical arsenal of IOP drops. Furthermore, it outlines the particular pharmacologic mechanisms targeted, the pharmacokinetics, effectiveness, the advantages of fixed-combination administration, and tolerability. Expert opinion: The combination of carteolol and latanoprost, separately or in a fixed-combination, is more effective than either drug alone. Given the early stage in development of FCCL, it has yet to be determined how FCCL compares to other fixed-combination medications. However, pending further approval, fixed-combination carteolol-latanoprost may represent a reasonable alternative for a patient whose IOP is inadequately controlled on a prostaglandin analog alone and for whom a simplified combination is preferred.

New Human Organotypic Corneal Tissue Model for Ophthalmic Drug Delivery Studies.

Purpose: The purpose of the current work was to develop a physiologically relevant, in vitro human three-dimensional (3D) corneal epithelial tissue model for use in ophthalmic drug development. Methods: Normal human corneal epithelial cells were cultured at the air-liquid interface to produce the 3D corneal tissue model. Corneal barrier was determined by measuring transepithelial electrical resistance (TEER). Quantitative PCR arrays were utilized to investigate expression of 84 phase I/II metabolizing enzymes and 84 drug transporter genes. Permeability was evaluated using model compounds with a wide range of hydrophobicity, molecular weight, and excipients. Finally, different formulations of latanoprost and bimatoprost were administered and drug absorption and tissue viability and integrity were investigated. Results: Histologic assessment and TEER of the corneal tissue model revealed tissue structure, thickness, and barrier formation (1000 ± 146 Ω·cm2) comparable to native human corneal epithelium. The 3D corneal tissue expressed tight junctions, mucins, and key corneal epithelial detoxification enzymes. Drug-metabolizing enzyme and transporter gene expression in 3D corneal tissue and excised human corneal epithelium were highly correlated (r2 = 0.87). Coefficients of permeation for model drugs in the tissue model and excised rabbit corneas also showed a high correlation (r2 = 0.94). As expected, latanoprost and bimatoprost free acids had much lower permeability (Papp = 1.2 × 10-6 and 1.9 × 10-6) than the corresponding prodrugs (Papp = 2.5 × 10-5 and 5.6 × 10-5), respectively. The presence of 0.02% benzalkonium chloride in ophthalmic formulations significantly affected tissue barrier and viability. Conclusions: The newly developed 3D corneal tissue model appears to be very useful for evaluation of corneal drug permeability and safety during ophthalmic drug development.

Pharmacokinetic Analysis of Intraocular Penetration of Latanoprost Solutions with Different Preservatives in Human Eyes.

PURPOSE: To investigate the effect of excipients on latanoprost penetration into the aqueous humor with clinically available 6 products with different solutions mainly in the types and concentrations of preservatives. METHODS: In 363 patients with cataracts, we instilled 1 latanoprost drop in 1 eye before surgery. The drop was randomly selected by brand name product (A) and 5 generic products (B-F) composed with different excipients. B contains similar excipients to A. C and D contain lower concentrations of benzalkonium chloride than A. E includes sodium benzoate, and F contains no preservatives. At 0.5-1, 3, and 6 h after instillation, samples of aqueous humor were collected to determine the latanoprost free acid by mass spectrometry. The time course of intraocular concentration and the areas under the aqueous humor latanoprost free acid concentration-time curves (AUCs) were calculated. RESULTS: At 0.5-1 h, the aqueous humor concentration of latanoprost free acid was 8.5 ± 1.0 ng/mL for C, which was significantly higher (P < 0.01) than that of A (3.4 ± 0.5 ng/mL). At 3 and 6 h, however, no significant difference was noted in the concentrations of latanoprost free acid between the brand name and generic products. For each of the generic products, the peak free acid concentration was above the known threshold concentration for biological activity. At 6 h postdose, however, the levels of latanoprost free acid were below the threshold for Products C, E, and F. Comparisons of AUC0-6h and AUC0-24h values showed that these parameters were the greatest with A, and E was significantly inferior to A (P < 0.05). CONCLUSIONS: Currently available latanoprost solutions with different preservatives showed sufficient intraocular concentration to activate the FP receptor, but different pharmacokinetic profiles of absorption or elimination.