TY - JOUR
T1 - Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101, a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent
AU - Chowdhury, Uttio Roy
AU - Pervan-Steel, Cynthia L.
AU - Sheeler, Ryan
AU - Sookdeo, Hemchand K.
AU - Rogers, Brian
AU - Casale, Ralph
AU - Dosa, Peter I.
AU - Htoo, Thurein
AU - Wirostko, Barbara M.
AU - Fautsch, Michael P.
N1 - Publisher Copyright:
©Mary Ann Liebert, Inc.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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 (T1/2) of 5.50–8.82 h and a corresponding time (Tmax) range of 2–12 h in rabbits, and a T1/2 of 3.32–6.18 h with a Tmax range of 1–2 h in dogs. Maximum tissue concentration (Cmax) 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 T1/2 and Tmax were similar to QLS-101, while Cmax 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.
AB - 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 (T1/2) of 5.50–8.82 h and a corresponding time (Tmax) range of 2–12 h in rabbits, and a T1/2 of 3.32–6.18 h with a Tmax range of 1–2 h in dogs. Maximum tissue concentration (Cmax) 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 T1/2 and Tmax were similar to QLS-101, while Cmax 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.
KW - ATP-sensitive potassium channel
KW - CKLP1
KW - glaucoma
KW - intraocular pressure
KW - levcromakalim
KW - prodrug
UR - http://www.scopus.com/inward/record.url?scp=85163899972&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85163899972&partnerID=8YFLogxK
U2 - 10.1089/jop.2022.0184
DO - 10.1089/jop.2022.0184
M3 - Article
C2 - 37200453
AN - SCOPUS:85163899972
SN - 1080-7683
VL - 39
SP - 332
EP - 346
JO - Journal of Ocular Pharmacology and Therapeutics
JF - Journal of Ocular Pharmacology and Therapeutics
IS - 5
ER -