Concentration of Milataxel (MAC-321, TL-139) and its major metabolite (M-10) in xenograft tumors from mice dosed orally and intravenously

512 Milataxel is a novel taxane that has shown substantial anti-tumor activity versus taxane-sensitive and taxane-resistant human tumors in mouse xenograft models. Milataxel has entered phase II clinical studies. Mice implanted with human xenograft tumors (SKMES-lung, HCT-15-colon and A-375 melanoma) were treated with oral and a non-cremophor milataxel IV formulation. Concentrations of milataxel and its major metabolite, M-10, were measured using HPLC-UV-βRAM and LC/MS. Levels for parent and metabolite were found to be different when measuring 14 C labeled species in tumor. M-10 levels were typically 50% higher than parent in tumors from non-Pgp cell lines when milataxel was administered either orally or IV. Measurable levels of parent drug and metabolite persisted for 10 days post dosing. In-vitro IC50 evaluation of Milataxel and M-10 show both to be potent cytotoxics, but M-10 was shown to be a substrate for Pgp. Oral Milataxel has completed a phase I study and plasma levels of M-10 and parent were measured.