Background and Objective <p>Landiolol, an ultra-short-acting β-blocker, is commonly used to manage tachyarrhythmias, including critically ill patients requiring renal replacement therapy (RRT). Pharmacokinetic (PK) data for landiolol in these patients are lacking. This study aimed to evaluate the PK and dialytic clearance of landiolol and its metabolite, M1, in septic shock patients receiving RRT, with the goal of guiding dosing optimization to ensure safe and effective treatment in this high-risk population.</p> Methods <p>This pre-defined PK sub-study was embedded within the Landi-SEP trial, which randomized patients with septic shock and persistent tachycardia to receive standard care or standard care with landiolol. Patients from two centers undergoing RRT were included in the sub-study. PK parameters, including dialytic and total clearance and area under the concentration–time curve (AUC), were determined based on plasma concentrations of landiolol and M1. Pharmacodynamic data, including heart rate (HR) and blood pressure (BP), were assessed concurrently.</p> Results <p>Six patients were included in the final analysis. Mean dialytic clearance was 39.3&#xa0;mL/min for landiolol and 42.3&#xa0;mL/min for M1. Dialysis accounted for 2.4% of total landiolol clearance and 50.9% of M1 clearance. HR and BP remained stable throughout the sub-study and no adverse events related to hypotension or bradycardia were reported.</p> Conclusion <p>Dialysis minimally affected landiolol clearance but removed a substantial proportion of M1. These exploratory data align with current dosing recommendations in patients with renal impairment and suggest that no dose adjustment is required during RRT. Individualized dosing and hemodynamic monitoring remain essential.</p> Trial Registration <p>EU Clinical Trial Register; EudraCT Number: 2017-002138-22</p>