High clearance means the drug is rapidly eliminated from the body, reducing its systemic levels despite a long half-life. This leads to a decreased duration of effective drug concentration, necessitating more frequent dosing to maintain therapeutic levels. Even with a long half-life, if clearance is high, the drug is removed quickly, causing plasma concentrations to fall below the therapeutic range faster. Therefore, frequent dosing compensates for rapid elimination and maintains drug efficacy.

Reference: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Brunton et al., 13th Edition.