Compatibility and Stability of the Investigational Polypeptide Marine Anticancer Agent Kahalalide F in Infusion Devices

Abstract

Kahalalide F is a novel marine-derivedantitumor agent isolated from the marinemollusk Elysia rufescens, an organismliving in the seas near Hawaii. Thecompound has shown highly selective invitro activity against prostate tumors andphase I trials in patients with androgenindependent prostate tumors incorporating adaily times five and weekly schedule have been initiated.Kahalalide F is pharmaceuticallyformulated as a lyophilized productcontaining 150 μg active substance perdosage unit. Prior to i.v. administrationit is reconstituted with a solutioncomposed of Cremophor EL, ethanol absoluteand Water for Injection (CEW, 5/5/90%v/v/v) with further dilution in 0.9% w/vsodium chloride for infusion. The aim ofthis study was to investigate thecompatibility and stability of kahalalide Fwith different infusion systems prior tothe start of clinical trials with thecompound. Due to the presence of CremophorEL in the infusion solution, leaching ofdiethylhexyl phthalate (DEHP) from polyvinylchloride infusion containers (PVC,Add-a-Flex®) was found. Loss ofkahalalide F as a consequence of sorptionto contact surfaces was shown with aninfusion container composed of low densitypolyethylene (LD-PE, Miniflac®). Weconclude that kahalalide F must beadministered in a 3-h infusion inconcentrations of 0.5 μg/mL to14.7 μg/mL using an administration setconsisting of a glass container anda low-extrables, DEHP-free extension set.Kahalalide F 150 μg/vial powder for infusionreconstituted with 5/5/90% v/v/v CEW isstable in the original container for atleast 24 h at room temperature(+20–25 °C) and ambient lightconditions. Infusion solutions stored inglass infusion containers at either roomtemperature (+20–25 °C, in the dark)or refrigerated conditions (+2–8 °C,in the dark) are stable for at least 5 daysafter preparation.