{"doi":"10.1089/jop.2022.0184","title":"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 (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.","journal":"Journal of Ocular Pharmacology and Therapeutics","year":2023,"id":368581,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9363,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1127416,"name":"Cynthia L. Pervan-Steel","orcid":null,"position":2,"is_corresponding":false},{"id":1127417,"name":"Ryan Sheeler","orcid":null,"position":4,"is_corresponding":false},{"id":1127418,"name":"H Sookdeo","orcid":null,"position":5,"is_corresponding":false},{"id":1127419,"name":"Brian Rogers","orcid":null,"position":6,"is_corresponding":false},{"id":1127420,"name":"Ralph Casale","orcid":null,"position":7,"is_corresponding":false},{"id":387857,"name":"Peter I. Dosa","orcid":"0000-0002-0081-3867","position":8,"is_corresponding":false},{"id":1127421,"name":"Thurein Htoo","orcid":null,"position":9,"is_corresponding":false},{"id":386672,"name":"Barbara Wirostko","orcid":null,"position":10,"is_corresponding":false},{"id":528702,"name":"Michael P. Fautsch","orcid":"0000-0002-9115-2485","position":11,"is_corresponding":false},{"id":753988,"name":"Uttio Roy Chowdhury","orcid":null,"position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-19T01:15:24.517012Z","pmid":"37200453","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}