Compatibility and stability of aplidine, a novel marine-derived depsipeptide antitumor agent, in infusion devices, and its hemolytic and precipitation potential upon i.v. administration

Aplidine is a novel marine-derived antitumor agent isolated from the Medite rranean tunicate Aplidium albicans, The compound is pharmaceutically formul ated as a lyophilized product containing 500 mu g active substance per dosa ge unit. Prior to i.v. administration it is reconstituted with a solution c omposed of Cremophor EL, ethanol absolute and Water for Injection (15/15/70 % v/v/v) with further dilution in 0.9% w/v sodium chloride for infusion (no rmal saline). The aim of this study was to investigate the compatibility of aplidine infusion solutions with polyvinyl chloride (PVC)-containing and P VC-free administration sets, and to determine the stability of aplidine aft er reconstitution and further dilution in infusion solutions, Furthermore, in vitro biocompatibility studies to estimate the hemolytic and precipitati on potential of aplidine infusion solutions upon i.v. administration were c onducted. In this study we show that sorption of aplidine to PVC and to a l esser extent to PVC-free administration set materials occurs. Also, most pr obably due to the presence of Cremophor EL in the infusion solution, signif icant leaching of diethylhexyl phtalate (DEHP) from the PVC administration set occurs. After reconstitution and dilution the drug is stable for at lea st 24 and 48 h, respectively, in glass containers when stored at room tempe rature (20-25 degrees C) and ambient light conditions. We found that aplidi ne should be administered in infusion concentrations equal or above 28.8 mu g/ml using a PVC-free administration set consisting of a glass container a nd PVC-free infusion tubing, After reconstitution it must be diluted furthe r with normal saline within 24 h after preparation and subsequently adminis tered to the patient within 48 h. Additionally, results from the biocompati bility studies show that neither hemolysis nor precipitation of aplidine is expected upon i.v. administration. [(C) 1999 Lippincott Williams & Wilkins .].