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Abstract #109316 Published in IGR 24-1
Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101, a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent
Roy Chowdhury U; Pervan-Steel CL; Sheeler R; Sookdeo HK; Rogers B; Casale R; Dosa PI; Htoo T; Wirostko BM; Fautsch MPJournal of Ocular Pharmacology and Therapeutics 2023; 39: 332-346
To evaluate the pharmacokinetic profiles of the ocular hypotensive agent QLS-101, a novel ATP-sensitive potassium channel opening prodrug, and its active moiety levcromakalim, following topical ophthalmic and intravenous dosing of normotensive rabbits and dogs. Dutch belted rabbits ( = 85) and beagle dogs ( = 32) were dosed with QLS-101 (0.16-3.2 mg/eye/dose) or formulation buffer for 28 days. Pharmacokinetic profiles of QLS-101 and levcromakalim were evaluated in ocular tissues and blood by LC-MS/MS. Tolerability was assessed by clinical and ophthalmic examinations. Maximum systemic tolerated dose was evaluated in beagle dogs ( = 2) following intravenous bolus administrations of QLS-101 (0.05 to 5 mg/kg). Plasma analysis following topical dosing of QLS-101 (0.8-3.2 mg/eye/dose) for 28 days indicated an elimination half-life (T) of 5.50-8.82 h and a corresponding time (T) range of 2-12 h in rabbits, and a T of 3.32-6.18 h with a T range of 1-2 h in dogs. Maximum tissue concentration (C) values ranged from 54.8-540 (day 1) to 50.5-777 ng/mL (day 28) in rabbits, and 36.5-166 (day 1) to 47.0-147 ng/mL (day 28) in dogs. Levcromakalim plasma T and T were similar to QLS-101, while C was consistently lower. Topical ophthalmic delivery of QLS-101 was well tolerated in both species, with sporadic mild ocular hyperemia noted in the group treated with the highest concentration (3.2 mg/eye/dose). Following topical ophthalmic dosing, QLS-101 and levcromakalim were found primarily in the cornea, sclera, and conjunctiva. Maximum tolerated dose was determined to be 3 mg/kg. QLS-101 was converted to its active moiety levcromakalim and showed characteristic absorption, distribution, and safety profiles of a well-tolerated prodrug.
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.
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