Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101,a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent

Abstract

Purpose:

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.

Methods:

Dutch belted rabbits (n = 85) and beagle dogs (n = 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 (n = 2) following intravenous bolus administrations of QLS-101 (0.05 to 5 mg/kg).

Results:

Plasma analysis following topical dosing of QLS-101 (0.8–3.2 mg/eye/dose) for 28 days indicated an elimination half-life (T_1/2) of 5.50–8.82 h and a corresponding time (T_max) range of 2–12 h in rabbits, and a T_1/2 of 3.32–6.18 h with a T_max range of 1–2 h in dogs. Maximum tissue concentration (C_max) 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_1/2 and T_max were similar to QLS-101, while C_max 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.

Conclusions:

QLS-101 was converted to its active moiety levcromakalim and showed characteristic absorption, distribution, and safety profiles of a well-tolerated prodrug.