Pharmacological and pharmacokinetic profile of the novel ocular hypotensive prodrug CKLP1 in Dutch-belted pigmented rabbits

Abstract

Elevated intraocular pressure is the only treatable risk factor for glaucoma, an eye disease that is the leading cause of irreversible blindness worldwide. We have identified cromakalim prodrug 1 (CKLP1), a novel water-soluble ATP-sensitive potassium channel opener, as a new ocular hypotensive agent. To evaluate the pharmacokinetic and safety profile of CKLP1 and its parent compound levcromakalim, Dutch-belted pigmented rabbits were treated intravenously (0.25 mg/kg) or topically (10 mM; 4.1 mg/ml) with CKLP1. Body fluids (blood, aqueous and vitreous humor) were collected at multiple time points and evaluated for the presence of CKLP1 and levcromakalim using a liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) based assay. Histology of tissues isolated from Dutchbelted pigmented rabbits treated once daily for 90 days was evaluated in a masked manner by a certified veterinary pathologist. The estimated plasma parameters following intravenous administration of 0.25 mg/kg of CKLP1 showed CKLP1 had a terminal half-life of 61.8 ± 55.2 min, T max of 19.8 ± 23.0 min and C max of 1968.5 ± 831.0 ng/ml. Levcromakalim had a plasma terminal half-life of 85.0 ± 37.0 min, T max of 61.0 ± 32.0 min and C max of 10.6 ± 1.2 ng/ml. Topical CKLP1 treatment in the eye showed low levels (<0.3 ng/mL) of levcromakalim in aqueous and vitreous humor, and trace amounts of CKLP1 and levcromakalim in the plasma. No observable histological changes were noted in selected tissues that were examined following topical application of CKLP1 for 90 consecutive days. These results suggest that CKPL1 is converted to levcromakalim in the eye and likely to some extent in the systemic circulation.

Association between dietary calcium, potassium, and magnesium consumption and glaucoma

“…Stumpff et al [ 49 ] demonstrated effluxion of K via maxi-K channels could result in trabecular meshwork relaxation. Study has shown that pharmacologic openers of functional K dependent ATP (K ATP ) channel lower the intraocular pressure in normotensive animal models and nonhuman primates [ 50 , 51 ]. The alteration of K current may activate the cell volume regulation in trabecular meshwork that obstructed aqueous humor outflow and further resulted in increased intraocular pressure [ 52 , 53 ].…”

Ocular Hypotensive Properties and Biochemical Profile of QLS-101, a Novel ATP-Sensitive Potassium (KATP) Channel Opening Prodrug

“… 15 The ocular hypotensive properties of topical K ATP channel openers, including levcromakalim, diazoxide, and nicorandil, have been described in human anterior segments and multiple normal and ocular hypertensive animal models. 16 – 20 Studies using knockout mouse models treated with subtype-specific K ATP channel openers have strongly indicated that the ocular hypotensive effect appears to occur through K ir 6.2/SUR2B subunit-containing channels. 19 When applied topically to the eye, K ATP channel openers such as cromakalim prodrug 1 (CKLP1) have been demonstrated to lower IOP by specifically reducing episcleral venous pressure.…”

“… 21 After topical application to the eye, endogenous phosphatases cleave the phosphate group converting CKLP1 to the active metabolite levcromakalim. 16 , 21 , 22 CKLP1 was shown to retain the potent ocular hypotensive properties of levcromakalim and showed additive effects when used in combination with existing IOP-lowering drugs in normotensive animal model systems. 16 , 17 , 21 , 22 …”

“… 16 , 21 , 22 CKLP1 was shown to retain the potent ocular hypotensive properties of levcromakalim and showed additive effects when used in combination with existing IOP-lowering drugs in normotensive animal model systems. 16 , 17 , 21 , 22 …”