Two multicenter Phase I randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Doxil® or Caelyx® in advanced ovarian cancer

Shravanti Bhowmik, Subhas Bhowmick, Kuntal Maiti, Amaresh Chakra, Pradeep Shahi, Deepak Jain, Thennati Rajamannar

To compare the pharmacokinetic bioequivalence and safety of a generic pegylated liposomal doxorubicin formulation (SPIL DXR hydrochloride liposome injection) with that of the reference products, Caelyx or Doxil. Two open-label, two-way reference crossover studies were conducted in patients with ovarian cancer. Cmax, AUC0 - t, and AUC0-∞, Vd, and Cl for total, free, and encapsulated DXR were evaluated in 18 blood samples taken pre-dose (t = 0), at increasing time intervals over the following 14 days. A washout period of 28 days was observed before crossing over. Studies 1 and 2 were completed by 24/29 and 41/60 patients, respectively. Pharmacokinetic data from 24 patients from each study established bioequivalence for free DXR in study 2, and for total and encapsulated DXR in both studies. Data from 29 and 54 patients, respectively, were included in the safety evaluation. Of these, 37 patients experienced 81 post-dose adverse events (40 related to the test product and 41 related to the reference product). In study 1, four patients were withdrawn owing to adverse events. Eleven patients experienced serious adverse events and one death occurred in study 2. Bioequivalence between the test and the reference products was established for total and encapsulated DXR in both studies, and for free DXR in the study with the larger sample size (study 2). There were no significant differences between the safety profiles of the generic formulation and the reference products. No correlation was found between drug level and adverse events. Study 1 was registered retrospectively; registration number is NCT03055143, dated February 15, 2017. Study 2 registration number is NCT00862355, dated March 13, 2009.