Bioequivalence Study of Pegylated Doxorubicin Hydrochloride Liposome (PEGADRIA) and DOXIL® in Ovarian Cancer Patients: Physicochemical Characterization and Pre-clinical Studies

Objective:To develop Pegylated Doxorubicin Hydrochloride Liposome (PEGADRIA) and compare its physicochemical properties, preclinical safety and efficacy, clinical pharmacokinetic and safety profiles with those of the reference product, Doxil®. Methods: PEGADRIA was prepared and the structure morphology, lamellarity, size, shape, drug loading, lipid bilayer and Peg layer thickness were determined. Safety studies were conducted in mice and rats and efficacy study was conducted in a P-388 leukemia mouse model. To evaluate the pharmacokinetic profile of PEGADRIA, a multicenter, open label, balanced, randomized, two-treatment, two-period, two-sequence, single dose cross-over bioequivalence study was conducted with Doxil® in ovarian cancer patients whose disease had progressed or reoccurred after platinum based chemotherapy under fasting conditions. The pharmacokinetic parameters were determined based on the concentration-time profiles of doxorubicin, whereas the concentration was determines using LC-MS/MS methods. Results: PEGADRIA was similar to Doxil® in terms of general morphology, lamellarity, size, shape, drug loading, lipid bilayer and Peg layer thickness. PEGADRIA and Doxil® showed comparable survival benefit in leukemic mice. The toxicity profiles of PEGADRIA in both mice and rats were comparable to those of Doxil®. Plasma concentrations of doxorubicin from cancer patients were measured to determine the pharmacokinetics profile. The geometric mean ratios (90% confidence intervals) of PEGADRIA /Doxil® for free doxorubicin and encapsulated doxorubicin were similar. Conclusion: PEGADRIA was found to have similar physicochemical profile compared to Doxil®. In addition, it was safe and bioequivalent to Doxil® in ovarian cancer patients.