Rapid elimination of suprachoroidally injected small molecule drugs into the systemic blood circulation

Suprachoroidal injections have gained increasing interest in the past years as a promising alternative to intravitreal (IVT) injections for treatment of retinal diseases. This administration route offers a more targeted and less invasive method for delivering drugs to the choroid and the retinal pigment epithelium, whereas IVT injections provide more efficient drug targeting to the vitreous and the inner retina. Although recent studies have provided insights on the pharmacokinetics and tissue distribution of drugs following suprachoroidal administration, the role of choroidal blood flow in the elimination of drugs from the suprachoroidal space has not been systematically quantified. The purpose of this study was to evaluate the pharmacokinetics of suprachoroidally administered beta blocking agents (atenolol, timolol and betaxolol) to enhance understanding of the elimination of small molecular weight drugs. Pharmacokinetic experiments were conducted via both intravenous and suprachoroidal routes in two separate studies utilizing ten New Zealand White rabbits. Blood samples were collected, and drug concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Non-compartmental analysis was applied to the concentration-time profiles to obtain pharmacokinetic parameters. The results indicate very rapid elimination of the drugs into the systemic circulation, with atenolol being eliminated in 12 minutes and timolol and betaxolol in under four minutes. Also, the absolute plasma bioavailability following suprachoroidal administration was determined for the first time. These novel results demonstrate that the administered drugs were rapidly and completely absorbed into the systemic circulation. These findings highlight the critical role of choroidal blood flow in drug clearance and offer valuable insights for the future design of ocular administration routes and dosage forms.