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

Abstract

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. Pharmacokinetic summary - Dry Powder vs. Lipid Suspension Capsules Parameters 100 mg MP-470 Dry Powder Average (CV, n=12) 90 mg MP-470 Lipid Suspension Average (CV, n=12) Average % Increase* (95% CI) Cmax (ng/mL) 23.2 (71%) 132.6 (55%) 635% (420%, 851%) Tmax (h) 4.1 (44%) 1.7 (54%) - AUClast (ng·h/mL) 253 (54%) 488 (40%) 131% (85%, 177%) Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B209.

Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers

“…This article summarizes the results from the three clinical pharmacology studies undertaken in healthy adult subjects to evaluate the systemic exposure of amuvatinib after oral administration of amuvatinib DPC and amuvatinib LSC: a food-eVect study using amuvatinib DPC (Study A [13]), a single-dose study comparing amuvatinib DPC to amuvatinib LSC (Study B [10,14]), and a multipleascending-dose study using amuvatinib LSC (Study C).…”