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IDN5109, a Taxane with Oral Bioavailability and Potent Antitumor Activity¹

Department of Oncology, Laboratory of Biology and Treatment of Metastasis, Mario Negri Institute for Pharmacological Research, 24125 Bergamo [M. I. N., R. G.]; Department of Oncology, Laboratory of Cancer Pharmacology, Mario Negri Institute for Pharmacological Research, 20157 Milan [T. C., M. Z., M. D.]; Consorzio Mario Negri Sud, 66030 S. Maria Imbaro, Chieti [C. R., C. M., S. S., M. B. D.]; and Indena S.p.A., 20139 Milan [A. R., P. M., E. B.] Italy

IDN5109 is a new taxane, derived from 14ß-hydroxy-10-deacetylbaccatin III, selected for its lack of cross-resistance in tumor cell lines expressing the multidrug resistant phenotype. Because, unlike paclitaxel, IDN5109 is a poor substrate for P-glycoprotein, we hypothesized that IDN5109 given p.o. could improve bioavailability compared with paclitaxel. Here, we studied the p.o. and i.v. pharmacokinetics of IDN5109 together with its antitumor activity. Using a high-performance liquid chromatography method, the bioavailability of IDN5109 was determined to be 48% after oral delivery. IDN5109 given p.o. was highly active against the two human ovarian carcinoma xenografts 1A9 and HOC18 (90–100% tumor regressions) and showed significant activity on the paclitaxel-resistant MNB-PTX1 xenograft (10% tumor regressions). The p.o. administration was as active as the i.v. route at doses reflecting the pharmacokinetic data. IDN5109 is the first taxane with good oral bioavailability and potent antitumor activity and represents a potential candidate for clinical investigation.

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