Compatibility and stability of the investigational polypeptide marine anticancer agent kahalalide F in infusion devices

Kahalalide F is a novel marine-derived antitumor agent isolated from the ma rine mollusk Elysia rufescens, an organism living in the seas near Hawaii. The compound has shown highly selective in vitro activity against prostate tumors and phase I trials in patients with androgen independent prostate tu mors incorporating a daily times five and weekly schedule have been initiat ed. Kahalalide F is pharmaceutically formulated as a lyophilized product co ntaining 150 mug active substance per dosage unit. Prior to i.v. administra tion it is reconstituted with a solution composed of Cremophor EL, ethanol absolute and Water for Injection (CEW, 5/5/90% v/v/v) with further dilution in 0.9% w/v sodium chloride for infusion. The aim of this study was to inv estigate the compatibility and stability of kahalalide F with different inf usion systems prior to the start of clinical trials with the compound. Due to the presence of Cremophor EL in the infusion solution, leaching of dieth ylhexyl phthalate (DEHP) from polyvinyl chloride infusion containers (PVC, Add-a-Flex(R)) was found. Loss of kahalalide F as a consequence of sorption to contact surfaces was shown with an infusion container composed of low d ensity polyethylene (LD-PE, Miniflac(R)). We conclude that kahalalide F mus t be administered in a 3-h infusion in concentrations of 0.5 mug/mL to 14.7 mug/mL using an administration set consisting of a glass container and a l ow-extrables, DEHP-free extension set. Kahalalide F 150 mug/vial powder for infusion reconstituted with 5/5/90% v/v/v CEW is stable in the original co ntainer for at least 24 h at room temperature (+20-25 degreesC) and ambient light conditions. Infusion solutions stored in glass infusion containers a t either room temperature (+20-25 degreesC, in the dark) or refrigerated co nditions (+2-8 degreesC, in the dark) are stable for at least 5 days after preparation.