Corneal and scleral permeability of Desmoteplase in different species

Abstract

Objective Intraocular fibrin clots caused by severe uveitis can be a sight‐threatening condition that needs to be resolved quickly and reliably. Intracameral injection of tissue‐plasminogen activator (tPA) is commonly used to resolve intraocular fibrin. However, the drug does not reach fibrinolytic concentrations after topical application. Desmoteplase (DSPA) is a structurally similar but smaller fibrinolytic agent with a higher fibrin selectivity, a longer half‐life, and better biocompatibility compared with tPA. This study was designed to evaluate the corneal and scleral permeability of DSPA in rabbits, pigs, dogs, horses, and humans ex vivo. Procedures Corneal and scleral tissues (n = 5 per group) were inserted into Franz‐type diffusion chambers and exposed to 1.4 mg/mL DSPA for 30 minutes. Drug concentrations on the receiver side were determined by liquid chromatography‐tandem mass spectrometry. Results Concentrations of DSPA after corneal and scleral permeation through fresh tissues ranged from 0.0 to 16.3 µg/mL and 0.0 to 11.4 µg/mL (rabbits), 0.3 to 5.6 µg/mL and 3.1 to 9.2 µg/mL (dogs), 2.1 to 14.9 µg/mL and 4 to 8.7 µg/mL (horses), and 0.6 to 3 µg/mL and 2.9 to 18.1 µg/mL (pigs), respectively. A concentration of 0.07‐12.9 µg/mL DSPA was detectable after diffusion through tissue culture preserved human donor bank corneas (Table 1). Conclusions Desmoteplase has the ability to permeate both cornea and sclera ex vivo in all species tested. Implications of the ex vivo permeability of DSPA suggest that in vivo permeability may be possible, and if so, it could lead to a novel topical application for lysing fibrin.

Clinical Pharmacokinetics and Pharmacodynamics of Desmoteplase

“…Recently, a Russian review mentioned desmoteplase as one of the latest modified variants of a tissue plasminogen activator with a prolonged clearance time, high fibrin-selectivity, and bolus delivery, to be used in acute ischemic stroke treatment [ 45 ]. Moreover, Deborah et al [ 46 ] tested the corneal and scleral permeability of desmoteplase ex vivo both in different animal species and in humans. The rationale behind this study was mainly the documented failure of rtPA to reach fibrinolytic concentrations that are capable of resolving intraocular fibrin.…”

“…Results of this study have reported a higher ability of desmoteplase to permeate both cornea and sclera ex vivo in all the species tested, ranging, respectively, from 0.0 to 16.3 µg/mL and 0.0 to 11.4 µg/mL in rabbits, 0.3 to 5.6 µg/mL and 3.1 to 9.2 µg/mL dogs, 2.1 to 14.9 µg/mL and 4 to 8.7 µg/ml in horses, and 0.6 to 3 µg/mL and 2.9 to 18.1 µg/mL in pigs. Preserved human corneas showed concentrations ranging from 0.07 to 12.9 µg/mL of desmoteplase after diffusion through tissue culture, suggesting that in vivo permeability may be possible [ 46 ].…”