CD388 is a novel drug-Fc conjugate designed to function as a long-acting antiviral drug by inhibiting proliferation of the influenza virus. This action results from a dimeric form of zanamivir, a neuraminidase inhibitor, conjugated to an Fc fragment of recombinant human IgG1 through a noncleavable polyethylene glycol-based linker. In this study, we aimed to demonstrate that, although similar to monoclonal antibody-based molecules, CD388 is distinct in that it maintains stability in vivo for an extended period with minimal biotransformation and achieves prolonged exposure in the lungs, the intended site of therapeutic action. For this purpose, rats received a single subcutaneous administration of 146 mg/kg (655 μCi/kg) radiolabeled CD388 which resulted in a maximal plasma concentration at 24 hours and a terminal half-life of 190 hours. Drug-related radioactivity recovery in urine and feces over a 28-day period was 61% and 15% of the dose, respectively, with a total recovery of 96% ± 2% (cage wash, dose site, and carcass included). 14C-CD388-related radioactivity was distributed to most tissues and declined slowly beyond 120 hours, remaining widespread throughout the body during the entire sampling time (840 hours). During the period of absorption, the highest radioactivity was observed in the kidney, lung, cardiac blood, lymph duct, and lymph nodes. Based on liquid chromatography-accurate mass spectrometry data, CD388 was the major circulating component in plasma. Radioactivity observed in urine and feces were primarily metabolites containing unmodified dimeric zanamivir plus linker (abbreviated as di-ZAN). No free zanamivir was identified in the analyzed matrices. SIGNIFICANCE STATEMENT: CD388 is a drug-Fc conjugate in development for prevention of influenza. This study showed wide tissue distribution, prolonged clearance of CD388, and evidence that no zanamivir was cleaved from the drug-Fc conjugate. Catabolism of the Fc domain resulted in formation of metabolites containing the unmodified dimeric zanamivir plus linker. These data support the mode of action of CD388 and demonstrate that the conjugation of zanamivir to the Fc domain is stable, thereby enabling CD388 to maintain its potent antiviral activity.