Rajashree Joshi-Hangal

Abstract B209: A self‐emulsifying lipid suspension formulation enhances oral bioavailability of MP‐470 in a randomized two‐way crossover study in healthy male subjects

Background: MP‐470 is an orally bioavailable multi‐targeted tyrosine kinase inhibitor specifically designed to be a potent inhibitor of mutant c‐Kit and PDGFR. MP‐470 is also active as an inhibitor of DNA repair following chemotherapy. MP‐470 has shown significant synergistic activity with DNA damaging chemotherapy in several xenograft models and in a phase I combination study. Oral bioavailability of this agent is limited by its solubility but not permeability. An in vitro/in vivo iterative approach was utilized preclinically for formulation selection. In the Beagle dog model, the oral bioavailability of MP‐470 is enhanced to a maximum of 4–5‐fold by formulating it in tocopherols and lipidic surfactants with self‐emulsification ability (5%, dry powder vs. 20%, lipid suspension). Results presented herein are from a randomized two‐way crossover pharmacokinetic (PK) study evaluating two formulations in healthy human subjects. Methods: Twelve healthy male subjects 18–45 years with a body mass index of 18–35 kg/m2 were randomized in a 1:1 ratio to receive either a 100 mg dry powder capsule or 90 mg (3 × 30 mg) lipid suspension capsules in a fasted condition with 240 mL of water. Subjects receiving MP‐470 90 mg lipid suspension capsules ingested all three capsules within one minute. The alternate formulation was administered after a 14 day washout. Plasma for PK assessments was collected and evaluated at pre‐dose through hour 48 post MP‐470 administration. Results: Comparative PK results from twelve subjects are summarized below. Additional information will be summarized in the final presentation. Conclusions: Solubility of the drug in the formulation vehicle alone plays a limited role in bioavailability enhancement; rather the ability of the formulation to keep the drug in solution after dilution in the GI tract seems critical. It is also possible that physiological mechanisms such as active transport or metabolism contribute to the enhanced absorption of MP‐470 in the tocopherol‐based vehicles. Consistent with preclinical Beagle dog data, the lipid suspension formulation offers an enhanced oral bioavailability over the dry powder formulation in healthy human subjects. The lipid suspension formulation will be utilized in future MP‐470 clinical studies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B209.

Abstract A190: In vivo activity of SGI‐110, a novel hypomethylating agent for treatment in hematology and solid malignancies

SGI‐110 is a second generation hypomethylating agent being developed for treatment in myelodysplastic syndrome (MDS) and solid tumor malignancies. In previous work, SGI‐110 has demonstrated potent in vivo activity in a number of tumor types, including non‐hematological cell lines. Current efforts are underway to optimize formulation and delivery of SGI‐110 for first‐in‐human (FIH) studies. In animals, SGI‐110 is well‐tolerated across multiple species utilizing multiple routes of drug delivery. Tolerability studies have been performed in mouse, rat, and rabbit models with multiple dose routes and schedules. Myelosuppression is an observed toxicity endpoint for hypomethylating agents. Hence, myelotoxic effects were investigated by comparing RBCs and bone marrow cellularity of mice treated with and without SGI‐110. Mice dosed with SGI‐110 for five consecutive days showed a significant decrease in RBCs at the end of the dosing period and a continued decrease one week after dosing. Bone marrow cellularity also showed a decrease at the end of dosing, but recovered to near normal levels one week later. Interestingly, RBCs from SGI‐110 treated mice were elevated in the bone marrow after the dosing period. Pyrosequencing methylation analysis of colon samples was also evaluated in this study. A significant decrease in B1 methylation was observed in colon samples of treated mice, indicating global DNA methylation is being inhibited. Decreased levels in several hematology parameters and decreases in bone marrow cellularity were also observed in rat and rabbit studies after five consecutive days of SGI‐110 dosing. Increased dosing frequency, while maintaining the same total dose per week, appears to result in increased toxicity. Previous pharmacokinetic studies have shown that SGI‐110 rapidly metabolizes to decitabine, an FDA‐approved drug for MDS. Multiple formulations and different routes of delivery were examined to determine the optimal dose form to be used in FIH studies. Subcutaneous dosing results in bioavailability that is similar to that of intravenous dosing. Subcutaneous dosing appears to reduce the Cmax while maintaining similar AUC values when compared to intravenous dosing. Similar results in pharmacokinetic parameters are observed when the delivery vehicle is changed from an aqueous to non‐aqueous formulation. SGI‐110 is a novel hypomethylating agent that is well‐tolerated in rodent models, provides excellent PK exposure, and demonstrates inhibition of DNA methylation in a mouse model. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A190.