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
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 In study 1, four patients were withdrawn owing to adverse events.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.
KeywordsDoxorubicin HCl liposome injection Ovarian cancer Bioequivalence Anthracycline
Medical writing support was provided by Claire Aukim-Hastie and Diane Kwiatkoski of IQVIA. Funding for the study and for editorial assistance with this manuscript was provided by Sun Pharmaceutical Industries Limited.
ShB was the clinical lead on this trial, involved in study design, protocol review, and study conduct. SB was the lead formulation development scientist on this trial, involved in product development starting from conceptualization to marketing of the product, and provided the investigational product. KM was a formulation development scientist on this trial and was involved in the development, manufacture, and provision of the investigational product. AC was involved in protocol development and authored the clinical study reports. PS was the clinical pharmacology lead, involved in analytical method development and pharmacokinetic bioanalysis. DJ was the project supervisor with regard to bioanalysis, method validation, and analytical method development. RT was the research and development head, and was involved in product development and provided clinical trial oversight. All authors helped write the manuscript and have read and approved the final manuscript.
Funding for the study and for editorial assistance with this manuscript was provided by Sun Pharmaceutical Industries Ltd.
Compliance with ethical standards
Conflict of interest
All authors were paid employees of Sun Pharmaceutical Industries Ltd. (SPIL) at the time the study was conducted. ShB, SB, KM, PS, and RT are shareholders in SPIL. ShB and KM are salaried employees of Sun Pharma Advanced Research Company (SPARC). KM also owns shares in SPARC.
The studies were approved by the Drug Controller General of India and performed at three (study 1) and five (study 2) sites across India in accordance with the Guidelines for Good Clinical Practice (GCP) and the Declaration of Helsinki. The study 1 protocol and informed consent form were approved by the Institutional Ethics Committee of the MNJ Institute of Oncology and Regional Cancer Center, Hyderabad, India; the Institutional Ethics Committee of Rajah Hospital, Madurai, India; and the Institutional Ethics Committee of the Chittaranjan National Cancer Institute, Kolkata, India. The study 2 protocols and informed consent forms were approved by the Institutional Ethics Committee of the MNJ Institute of Oncology and Regional Cancer Center, Hyderabad, India; the Institutional Ethics Committee of NRR Hospital, Bangalore, Karnataka, India; the Vadodara Ethics Committee of Kailash Cancer Hospital and Research Centre, Goraj, Vadodara, India; the Medical Ethics Committee of Dr. Kamakshi Memorial Hospital, Chennai, India; and the Ethics Committee of Dr. G. Viswanathan Speciality Hospitals, Tamil Nadu, India.
For both studies, all patients provided written informed consent before participating in the study.
This article does not contain any studies with animals performed by any of the authors.
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