title: In vitro hemolysis and buffer capacity studies with the novel marine anticancer agent kahalalide F and its reconstitution vehicle cremophor EL/ethanol.
abstract: An in vitro biocompatibility study was performed with the pharmaceutical formulation of the investigational, marine-derived anticancer agent kahalalide F developed for early clinical studies. The pharmaceutical formulation consists of a lyophilized product containing 150 micrograms kahalalide F, 3 mg citric acid, 3 mg polysorbate 80, and 150 mg of sucrose per dosage unit, to be reconstituted with 3 mL of a mixture composed of Cremophor EL, ethanol, and water (5/5/90% v/v/v), resulting in a solution of pH 3 and to be further diluted in normal saline for infusion. The reconstituted product, infusion solutions, and Cremophor/ethanol (CE) vehicle were tested for hemolytic potential and buffer capacity. No significant hemolysis due to the kahalalide F formulation as well as the CE vehicle was found using both a static and dynamic test model. FB-ratio's (ratio of formulation solution (F) and volume of blood simulant (B) necessary to maintain physiological pH) as a measure of the buffer capacity of the kahalalide F infusion solutions examined indicated that no vascular irritation due to pH effects is expected in the intended administration schedule in the forthcoming Phase I study.
authors.affiliation: Slotervaart Hospital/The Netherlands Cancer Institute, Dept. of Pharmacy & Pharmacology, Louwesweg 6, 1066EC Amsterdam, The Netherlands. apbnu@slz.nl
authors.forename: B
authors.initials: B
authors.lastname: Nuijen
authors.forename: M
authors.initials: M
authors.lastname: Bouma
authors.forename: C
authors.initials: C
authors.lastname: Manada
authors.forename: J M
authors.initials: JM
authors.lastname: Jimeno
authors.forename: A
authors.initials: A
authors.lastname: Bult
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001672:Biocompatible Materials; D002021:Buffers; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D047630:Depsipeptides; D000431:Ethanol; D005990:Glycerol / Q000031:analogs & derivatives; D006461:Hemolysis / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D002021:Buffers; D047630:Depsipeptides; D010455:Peptides; D014677:Pharmaceutical Vehicles; D000431:Ethanol; C000515:cremophor EL; C097897:kahalalide F; D005990:Glycerol