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Homoharringtonine (HHT) is in clinical development for the treatment of a number of leukemia indications including CML resistant to tyrosine kinase inhibitor therapies, as well as AML and MDS. Initial Phase I and II clinical studies administered HHT intravenously (IV) by short and continuous infusion (CI) schedules. Improved antileukemic results were observed when drug was provided by CI over many days of treatment (e.g. 7 days). Currently, the drug is administered subcutaneously (SC, b.i.d.) to patients in schedules up to 14 days with similar efficacy and toxicity profiles as CI. For either route of administration, HHT, an ester, is rapidly converted in plasma to its acid form. This metabolite has been demonstrated to be less active in vitro. Therefore, sustained presentation of the parent molecule is important. A sustained release system may benefit HHT by maximizing the plasma levels of the active parent molecule. SC dosing has allowed for some sustained release, and recent clinical results demonstrate similar pharmacokinetics for SC and CI administration. While SC dosing allows for greater patient convenience than CI, developing an oral formulation of HHT may further be of value for ease of administration and patient compliance. Moreover, the potential for slow/controlled drug release systems may better mimic the PK profile observed in the CI and SC settings. To test oral formulations for efficacy, we are identifying formulation characteristics to optimize delivery by the oral route (PO) (e.g. compatibility, stability, release kinetic, etc.) in an effort to develop dosage forms for clinical evaluation.

Using the RIF-1 murine tumor growth delay model, we have evaluated the efficacy of HHT after PO delivery with a series of formulation excipients that may be utilized for further preformulation studies. These include aqueous-based solvents, suspension systems, protein, lipid, carbohydrate excipients, and various combinations of these materials. The efficacy of HHT in an aqueous delivery system is similar after either PO or intraperitoneal (IP) administration, suggesting high bioavailability. The use of a protein-based delivery system did not increase efficacy, however HHT in a lipid-based system had a beneficial effect on efficacy, and was not reduced by the use in combination with the protein excipients. Further stability studies, as well as pilot PK assessment is warranted for some of the test formulations. These results suggest that oral formulations for HHT could be developed to increase the ease of administration and patient compliance without sacrificing efficacy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA