Absorption, distribution, metabolism, and excretion of an antiviral drug-Fc conjugate CD388 following subcutaneous administration of 14C-CD388 in the rat

CD388 is a novel drug-Fc conjugate (DFC) designed to function as 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 non-cleavable polyethylene glycol-based linker. In this study we aimed to demonstrate that, while 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). 14 C-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 (di-ZAN). No free zanamivir was identified in the analyzed matrices.