Pharmacologic and safety profile of the ocular hypotensive agent cromakalim prodrug 1 (CKLP1), a novel ATP-sensitive potassium channel opener

Abstract

Purpose : To evaluate the pharmacologic and safety parameters of CKLP1 following topical application in hound dog eyes.

Methods : Optimal concentration of CKLP1 for reduction of IOP was established in female hound dogs (n=5) by topical application to the eye with CKLP1 (5-20 mM). Following washout (14 days), the dogs were treated with the optimal dose once daily for 60 consecutive days. IOP was measured 3 times daily (1, 4 and 23 hours post treatment), 3-7 times per week. Blood pressure measurements were recorded using a tail cuff, once daily, 3-5 times per week. For pharmacokinetic studies, both eyes were treated with CKLP1 for 8 consecutive days. Blood samples were collected on days 1, 4 and 8 and concentration of CKLP1 and its parent compound levcromakalim were evaluated in the plasma by LC MS/MS. Necropsy was performed on all animals and systemic effects of drug administration were histologically evaluated in 40 different tissue samples from each animal.

Results : The 10 mM topical dose of CKLP1 was found to provide the best IOP reduction (14.4 ± 4.2 % reduction over 5 days, p=0.02) During the extended treatment regimen, 10 mM CKLP1 significantly lowered IOP by 18.9 ± 1.1 % compared to control eyes (p=0.0002) over the entire course of the study with no significant change in systolic (p=0.05) or diastolic blood pressure (p=0.26). Analysis of dog plasma showed that approximately 10% of CKLP1 was converted to its active compound levcromakalim. Half-life for CKLP1 was 318 minutes with a C_max of 10.4 ng/ml. Area under the curve (AUC) was 5303 ng/ml x minutes. For levcromakalim, half-life was 74 minutes, C_max was 1.2 ng/ml and AUC was 303 ng/ml x minutes. Histologic analysis did not reveal any significant finding related to drug administration.

Conclusions : Extended treatment with the ocular hypotensive agent CKLP1 showed no adverse side effects and an excellent ocular/systemic fluid and tissue safety profile. Results from this study support the use of CKLP1 in phase I clinical trials to treat ocular hypertensive diseases such as glaucoma.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.