RT Journal Article A1 Fautsch, Michael P A1 Kudgus, Rachel A1 Rinkoski, Tommy A1 Hann, Cheryl A1 Bahler, Cindy A1 Holman, Bradley A1 Reid, Joel A1 Dosa, Peter A1 Roy Chowdhury, Uttio T1 Pharmacologic and safety profile of the ocular hypotensive agent cromakalim prodrug 1 (CKLP1), a novel ATP-sensitive potassium channel opener JF Investigative Ophthalmology & Visual Science JO Invest. Ophthalmol. Vis. Sci. YR 2019 VO 60 IS 9 SP 3772 OP 3772 SN 1552-5783 AB To evaluate the pharmacologic and safety parameters of CKLP1 following topical application in hound dog eyes. 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. 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 Cmax of 10.4 ng/ml. Area under the curve (AUC) was 5303 ng/ml x minutes. For levcromakalim, half-life was 74 minutes, Cmax 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. 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. RD 3/4/2021