Cancer Chemotherapy and Pharmacology

, Volume 82, Issue 3, pp 521–532 | Cite as

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 BhowmikEmail author
  • Subhas Bhowmick
  • Kuntal Maiti
  • Amaresh Chakra
  • Pradeep Shahi
  • Deepak Jain
  • Thennati Rajamannar
Original Article



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 In study 1, four patients were withdrawn owing to adverse events.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.

Trial registration

Study 1 was registered retrospectively; registration number is NCT03055143, dated February 15, 2017. Study 2 registration number is NCT00862355, dated March 13, 2009.


Doxorubicin 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.

Author contributions

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.

Ethics approval

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.

Informed consent

For both studies, all patients provided written informed consent before participating in the study.

Animal rights

This article does not contain any studies with animals performed by any of the authors.


  1. 1.
    Matsumoto K, Onda T, Yaegashi N (2015) Pharmacotherapy for recurrent ovarian cancer: current status and future perspectives. Jpn J Clin Oncol 45(5):408–410. CrossRefPubMedGoogle Scholar
  2. 2.
    Steinherz LJ, Steinherz PG, Tan CC, Heller G, Murphy M (1991) Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266(12):1672–1677. CrossRefPubMedGoogle Scholar
  3. 3.
    Goorin AM, Chauvenet AR, Perez-Atayde AR, Cruz J, McKone R, Lipshultz SE (1990) Initial congestive heart failure, six to ten years after doxorubicin chemotherapy for childhood cancer. J Pediatr 116(1):144–147CrossRefPubMedGoogle Scholar
  4. 4.
    Benjamin RS, Wiernik PH, Bachur NR (1974) Adriamycin chemotherapy–efficacy, safety, and pharmacologic basis of an intermittent single high-dosage schedule. Cancer 33(1):19–27CrossRefPubMedGoogle Scholar
  5. 5.
    Ali SMSS, Ahmad A, Ahmad MU, Chen P, Paithankar M, Choudhury K, Makadia RD, Kumar A, Velavan K, Satheesh CT, Singh JK, Mamillapalli G, Saptarishi D, Kale P, Patel R, Barkate HV, Ahmad I (2016) Bioequivalence study of pegylated doxorubicin hydrochloride liposome (PEGADRIA) and DOXIL® in ovarian cancer patients: physicochemical characterization and pre-clinical studies. J Nanomed Nanotechnol 7:361. CrossRefGoogle Scholar
  6. 6.
    Vici P, Colucci G, Giotta F, Sergi D, Filippelli G, Perri P, Botti C, Vizza E, Carpino A, Pizzuti L, Latorre A, Giannarelli D, Lopez M, Di Lauro L (2011) A multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM study. J Exp Clin Cancer Res: CR 30:39. CrossRefPubMedGoogle Scholar
  7. 7.
    Broder H, Gottlieb RA, Lepor NE (2008) Chemotherapy and cardiotoxicity. Rev Cardiovasc Med 9(2):75–83PubMedPubMedCentralGoogle Scholar
  8. 8.
    Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97(11):2869–2879. CrossRefPubMedGoogle Scholar
  9. 9.
    Rahman AM, Yusuf SW, Ewer MS (2007) Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation. Int J Nanomed 2(4):567–583Google Scholar
  10. 10.
    Rafiyath SM, Rasul M, Lee B, Wei G, Lamba G, Liu D (2012) Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis. Exp Hematol Oncol 1:10–10. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    van Dalen EC, Michiels EM, Caron HN, Kremer LC (2010) Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev. CrossRefPubMedGoogle Scholar
  12. 12.
    Mayer LD, Tai LC, Ko DS, Masin D, Ginsberg RS, Cullis PR, Bally MB (1989) Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res 49(21):5922–5930PubMedGoogle Scholar
  13. 13.
    O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15(3):440–449CrossRefPubMedGoogle Scholar
  14. 14.
    Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C (2004) Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 22(19):3893–3901. CrossRefPubMedGoogle Scholar
  15. 15.
    Briasoulis E, Pentheroudakis G, Karavasilis V, Tzamakou E, Rammou D, Pavlidis N (2004) Weekly paclitaxel combined with pegylated liposomal doxorubicin (CaelyxTM) given every 4 weeks: dose-finding and pharmacokinetic study in patients with advanced solid tumors. Ann Oncol 15(10):1566–1573. CrossRefPubMedGoogle Scholar
  16. 16.
    Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K, Tkaczuk K, Park YC, Lee LW (2001) Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 19(5):1444–1454CrossRefPubMedGoogle Scholar
  17. 17.
    Schmid P, Krocker J, Jehn C, Michniewicz K, Lehenbauer-Dehm S, Eggemann H, Heilmann V, Kümmel S, Schulz CO, Dieing A, Wischnewsky MB, Hauptmann S, Elling D, Possinger K, Flath B (2005) Primary chemotherapy with gemcitabine as prolonged infusion, non-pegylated liposomal doxorubicin and docetaxel in patients with early breast cancer: final results of a phase II trial. Annals Oncol 16(10):1624–1631. CrossRefGoogle Scholar
  18. 18.
    Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A (2000) Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11(8):1029–1033CrossRefPubMedGoogle Scholar
  19. 19.
    Tuscano JM, Martin SM, Ma Y, Zamboni W, O’Donnell RT (2010) Efficacy, biodistribution, and pharmacokinetics of CD22-targeted pegylated liposomal doxorubicin in a B-cell non-Hodgkin’s lymphoma xenograft mouse model. Clin Cancer Res 16(10):2760–2768. CrossRefPubMedGoogle Scholar
  20. 20.
    Markman M, Kennedy A, Webster K, Peterson G, Kulp B, Belinson J (2000) Phase 2 trial of liposomal doxorubicin (40 mg/m2) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Gynecol Oncol 78(3 Pt 1):369–372. CrossRefPubMedGoogle Scholar
  21. 21.
    Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51(4):691–744PubMedGoogle Scholar
  22. 22.
    Adams SF, Marsh EB, Elmasri W, Halberstadt S, VanDecker S, Sammel MD, Bradbury AR, Daly M, Karlan B, Rubin SC (2011) A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer. Gynecol Oncol 123(3):486–491. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Strauss HG, Hemsen A, Karbe I, Lautenschlager C, Persing M, Thomssen C (2008) Phase II trial of biweekly pegylated liposomal doxorubicin in recurrent platinum-refractory ovarian and peritoneal cancer. Anti-cancer Drugs 19(5):541–545. CrossRefPubMedGoogle Scholar
  24. 24.
    European Medicines Agency (2010) Caelyx doxorubicin hydrochloride. Accessed 10 July 2018
  25. 25.
    Barenholz Y (2012) Doxil(R)--the first FDA-approved nano-drug: lessons learned. J Control Release 160(2):117–134. CrossRefPubMedGoogle Scholar
  26. 26.
    Ait-Oudhia S, Mager DE, Straubinger RM (2014) Application of pharmacokinetic and pharmacodynamic analysis to the development of liposomal formulations for oncology. Pharmaceutics 6(1):137–174. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lionberger R (2015) Pharmaceutical science for generic drugs: the science of equivalence. Accessed 23 Sept 2016
  28. 28.
    Gaspani SM, B (2013) Access to liposomal generic formulations: beyond AmBisome and Doxil/Caelyx. GaBI J 2(2):60–62CrossRefGoogle Scholar
  29. 29.
    Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haidar SH, Patel DT, Yang Y, Yu LX, Woodcock J (2009) Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother 43(10):1583–1597. CrossRefPubMedGoogle Scholar
  30. 30.
    Committee for Human Medicinal Products (CHMP) (2013) Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product. London, UKGoogle Scholar
  31. 31.
    US Food and Drug Administration (2017) Draft guidance on doxorubicin hydrochloride. Accessed 25 June 2018
  32. 32.
    US Food and Drug Administration (2001) Guidance for industry. bioanalytical method validationGoogle Scholar
  33. 33.
    Committee for Medicinal Products for Human Use (CHMP) (2010) Guideline on the investigation of bioequivalence. London, UKGoogle Scholar
  34. 34.
    Bhowmik S, Bhowmick S, Maiti K, Chakra A, Shahi P, Rajamannar T (2017) Phase-I randomized trial of doxorubicin hydrochloride liposome injection versus Caelyx((R)) in multiple myeloma. Leuk Lymphoma. PubMedCrossRefGoogle Scholar
  35. 35.
    Burade V, Bhowmick S, Maiti K, Zalawadia R, Jain D, Rajamannar T (2017) Comparative plasma and tissue distribution of Sun Pharma’s generic doxorubicin HCl liposome injection versus Caelyx((R)) (doxorubicin HCl liposome injection) in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats. Cancer Chemother Pharmacol 79(5):899–913. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Burade V, Bhowmick S, Maiti K, Zalawadia R, Ruan H, Thennati R (2017) Lipodox(R) (generic doxorubicin hydrochloride liposome injection): in vivo efficacy and bioequivalence versus Caelyx(R) (doxorubicin hydrochloride liposome injection) in human mammary carcinoma (MX-1) xenograft and syngeneic fibrosarcoma (WEHI 164) mouse models. BMC cancer 17(1):405. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Smith JA, Costales AB, Jaffari M, Urbauer DL, Frumovitz M, Kutac CK, Tran H, Coleman RL (2016) Is it equivalent? Evaluation of the clinical activity of single agent Lipodox(R) compared to single agent Doxil(R) in ovarian cancer treatment. J Oncol Pharm Pract 22(4):599–604. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shravanti Bhowmik
    • 1
    Email author
  • Subhas Bhowmick
    • 1
  • Kuntal Maiti
    • 1
  • Amaresh Chakra
    • 1
  • Pradeep Shahi
    • 1
  • Deepak Jain
    • 1
  • Thennati Rajamannar
    • 1
  1. 1.Sun Pharmaceutical Industries Limited (SPIL)MumbaiIndia

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