Top

Published in:

01-02-2016 | Experimental

Improved stability of lipiodol–drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin

Authors: Mathieu Boulin, Antonin Schmitt, Elisabeth Delhom, Jean-Pierre Cercueil, Maëva Wendremaire, Diane-Charlotte Imbs, Audrey Fohlen, Fabrizio Panaro, Astrid Herrero, Alban Denys, Boris Guiu

Published in: European Radiology | Issue 2/2016

Abstract

Objectives

To investigate the relationship between the improved stability of an anticancer drug–lipiodol emulsion and pharmacokinetic (PK) profile for transarterial chemoembolisation (TACE) of hepatocellular carcinoma (HCC).

Methods

The stability of four doxorubicin– or idarubicin–lipiodol emulsions was evaluated over 7 days. PK and clinical data were recorded after TACE with the most stable emulsion in eight unresectable HCC patients, after institutional review board approval.

Results

The most stable emulsion was the one that combined idarubicin and lipiodol (1:2 v:v). At 7 days, the percentages of aqueous, persisting emulsion and oily phases were 50-0-50, 33-0-67, 31-39-30, and 10-90-0 for the doxorubicin–lipiodol (1:1 v:v), doxorubicin–lipiodol (1:2 v:v), idarubicin–lipiodol (1:1 v:v), and the idarubicin–lipiodol (1:2 v:v) emulsion, respectively. After TACE, mean idarubicin C_max and AUC_0-24h were 12.5 ± 9.4 ng/mL and 52 ± 16 ng/mL*h. Within 24 h after injection, 40 % of the idarubicin was in the liver, either in vessels, tumours, or hepatocytes. During the 2 months after TACE, no clinical grade >3 adverse events occurred. One complete response, five partial responses, one stabilisation, and one progression were observed at 2 months.

Conclusion

This study showed a promising and favourable PK and safety profile for the idarubicin–lipiodol (1:2 v:v) emulsion for TACE.

Key Points

• Transarterial chemoembolisation (TACE) regimens that improve survival in hepatocellular carcinoma are needed.

• Improved emulsion stability for TACE resulted in a favourable pharmacokinetic profile.

• Preliminary safety and efficacy data for the idarubicin–lipiodol emulsion for TACE were encouraging.

Lo CM, Ngan H, Tso WK et al (2002) Randomised controlled trial of transarterial lipiodol chemoembolisation for unresectable hepatocellular carcinoma. Hepatology 35:1164–1171PubMedCrossRef

Llovet JM, Real MI, Montana X et al (2002) Arterial embolization or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739PubMedCrossRef

Camma C, Schepis F, Orlando A et al (2002) Transarterial chemoembolisation for unresectable hepatocellular carcinoma: meta-analysis of randomised controlled trials. Radiology 224:47–54PubMedCrossRef

Llovet JM, Bruix J (2003) Systematic review of randomised trials for unresectable hepatocellular carcinoma: chemoembolisation improves survival. Hepatology 37:429–442PubMedCrossRef

Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet 379:1245–1255PubMedCrossRef

Forner A, Gilabert M, Bruix J, Raoul JL (2014) Treatment of hepatocellular carcinoma. Nat Rev Clin Oncol 11:525–535PubMedCrossRef

Varela M, Real MI, Burrel M et al (2007) Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 46:474–481PubMedCrossRef

Malagari K, Pomoni M, Moschouris H et al (2014) Chemoembolization of hepatocellular carcinoma with HepaSphere 30-60 ìm. Safety and efficacy study. Cardiovasc Intervent Radiol 37:165–175PubMedPubMedCentralCrossRef

Han S, Zhang X, Zou L et al (2014) Does drug-eluting bead transcatheter arterial chemoembolization improve the management of patients with hepatocellular carcinoma? A meta-analysis. Plos One 9, e102686PubMedPubMedCentralCrossRef

10.

Bargellini I, Florio F, Golfieri R, Grosso M, Lauretti DL, Cioni R (2014) Trends in utilization of transarterial treatments for hepatocellular carcinoma: results of a survey by the Italian Society of Interventional Radiology. Cardiovasc Intervent Radiol 37:438–444PubMedCrossRef

11.

Heresbach D, Raoul JL, Bentue-Ferrer D, Bretagne JF, Van Den Driessche J, Gastard J (1989) Chimiothérapie couplée au Lipiodol®. Etude in vitro de la cinétique de liberation de l’adriamycine. Gastroenterol Clin Biol 13:775–778PubMed

12.

Favoulet P, Cercueil JP, Faure P et al (2001) Increased cytotoxicity and stability of Lipiodol-pirarubicin emulsion compared to classical doxorubicin-Lipiodol: potential advantage for chemoembolisation of unresectable hepatocellular carcinoma. Anticancer Drugs 12:801–806PubMedCrossRef

13.

Struk D, Rankin RN, Karlik SJ (1993) Stability studies on chemoembolization mixtures. Dialysis studies of doxorubicin and lipiodol with Avitene, Gelfoam, and Angiostat. Investig Radiol 28:1024–1027CrossRef

14.

Johnson PJ, Kalayci C, Dobbs N et al (1991) Pharmacokinetics and toxicity of intraarterial adriamycin for hepatocellular carcinoma : effect of coadministration of lipiodol. J Hepatol 13:120–127PubMedCrossRef

15.

Kalayci C, Johnson PJ, Roby N, Metivier EM, Williams R (1990) Intra-arterial doxorubicin and lipiodol for inoperable hepatocellular carcinoma: a comparison with intravenous doxorubicin. J Hepatol 11:349–353PubMedCrossRef

16.

Bern MA, McDermott W, Cady B et al (1978) Intraarterial hepatic infusion and intravenous adriamycin for treatment of hepatocellular carcinoma. Cancer 42:399–405PubMedCrossRef

17.

Gaba RC, Baumgarten S, Omene BO et al (2012) Lipiodol uptake does not predict doxorubicin drug delivery after chemoembolization in VX2 liver tumors. J Vasc Interv Radiol 23:265–273PubMedCrossRef

18.

Boulin M, Guiu S, Chauffert B et al (2011) Screening of anticancer drugs for chemoembolisation of hepatocellular carcinoma. Anticancer Drugs 22:741–748PubMedCrossRef

19.

Robert J (1993) Clinical pharmacokinetics of idarubicin. Clin Pharmacokinet 24:275–288PubMedCrossRef

20.

Yi SW, Kim YH, Kwon IC et al (1998) Stable lipiodolized emulsions for hepatoma targeting and treatment by transcatheter arterial embolization. J Control Release 50:135–143PubMedCrossRef

21.

Boulin M, Ciboulet A, Guiu B et al (2011) Randomised controlled trial of lipiodol transarterial chemoembolisation with or without amiodarone for unresectable hepatocellular carcinoma. Dig Liver Dis 43:905–911PubMedCrossRef

22.

Bruix J, Sherman M, American Association for the Study of Liver Diseases (2011) Management of hepatocellular carcinoma: an update. Hepatology 53:1020–1022PubMedPubMedCentralCrossRef

23.

Boulin M, Hillon P, Cercueil JP et al (2014) Idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma: results of the IDASPHERE phase I trial. Aliment Pharmacol Ther 39:1301–1313PubMedCrossRef

24.

Lencioni R, Llovet JM (2010) Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30:52–60PubMedCrossRef

25.

Spreafico C, Cascella T, Facciorusso A et al (2015) Transarterial chemoembolization for hepatocellular carcinoma with a new generation of beads: clinical-radiological outcomes and safety profile. Cardiovasc Intervent Radiol 38:129–134PubMedCrossRef

26.

Guiu B, Deschamps F, Aho S et al (2012) Liver/Biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol versus drug-eluting beads. J Hepatol 56:609–617PubMedCrossRef

27.

Idée JM, Guiu B (2013) Use of lipiodol as a drug-delivery system for transcatheter arterial chemoembolization of hepatocellular carcinoma: a review. Crit Rev Oncol Hematol 88:530–549PubMedCrossRef

28.

Shi M, Lu LG, Fang WQ et al (2012) Roles played by chemolipiodolization and embolization in chemoembolization for hepatocellular carcinoma: single-blind, randomized trial. J Natl Cancer Inst 105:59–68PubMedCrossRef

29.

Favelier S, Boulin M, Hamza S et al (2013) Lipiodol trans-arterial chemoembolisation of hepatocellular carcinoma with idarubicin: first experience. Cardiovasc Intervent Radiol 36:1039–1046PubMedCrossRef

30.

Dubbelboer IR, Lilienberg E, Hedeland M et al (2014) The effects of lipiodol and cyclosporin A on the hepatobiliary disposition of doxorubicin in pigs. Mol Pharm 11:1301–1313PubMedCrossRef

31.

Raoul JL, Bourguet P, Bretagne JF et al (1988) Hepatic artery injection of I131 labeled Lipiodol. I Biodistribution study results in patients with hepatocellular carcinoma and liver metastases. Radiology 168:541–545PubMedCrossRef

32.

Okayasu I, Hatakeyama T, Yoshida S et al (1988) Selective and persistent deposition and gradual drainage of iodized oil, lipiodol, in hepatocellular carcinoma after injection into the feeding hepatic artery. Am J Clin Pathol 90:534–544

33.

Fukushima T, Yamashita T, Goto N et al (2001) A pharmacokinetic study of idarubicin in Japanese patients with malignant lymphoma: relationship with leukocytopenia and neutropaenia. Int J Hematol 74:297–302PubMedCrossRef

34.

Guiu B, Schmitt A, Reinhardt S et al (2015) Idarubicin-loaded oncozene® drug eluting embolics for chemoembolization of hepatocellular carcinoma: in vitro loading and release, and in vivo pharmacokinetics. J Vasc Interv Radiol 26:262–270PubMedCrossRef

35.

Looby M, Linke R, Weiss M (1997) Pharmacokinetics and tissue distribution of idarubicin and its active metabolite idarubicinol in the rabbit. Cancer Chemother Pharmacol 69:554–556CrossRef

36.

Namur J, Citron SJ, Sellers MT et al (2011) Embolization of hepatocellular carcinoma with drug-eluting beads: doxorubicin tissue concentration and distribution in patient liver explants. J Hepatol 55:1332–1338PubMedCrossRef

Title: Improved stability of lipiodol–drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin
Authors: Mathieu Boulin
Antonin Schmitt
Elisabeth Delhom
Jean-Pierre Cercueil
Maëva Wendremaire
Diane-Charlotte Imbs
Audrey Fohlen
Fabrizio Panaro
Astrid Herrero
Alban Denys
Boris Guiu
Publication date: 01-02-2016
Publisher: Springer Berlin Heidelberg
Published in: European Radiology / Issue 2/2016
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI: https://doi.org/10.1007/s00330-015-3855-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Improved stability of lipiodol–drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin

Abstract

Objectives

Methods

Results

Conclusion

Key Points

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusion

Key Points

Please log in to get access to this content

Other articles of this Issue 2/2016

Comparison of post contrast CT urography phases in bladder cancer detection

Normalizing computed tomography data reconstructed with different filter kernels: effect on emphysema quantification

Intrahepatic mass-forming cholangiocarcinoma: prognostic value of preoperative gadoxetic acid-enhanced MRI

Change in volume parameters induced by neoadjuvant chemotherapy provide accurate prediction of overall survival after resection in patients with oesophageal cancer

The prevalence of tenosynovitis of the interosseous tendons of the hand in patients with rheumatoid arthritis

Optimizing radiation dose by using advanced modelled iterative reconstruction in high-pitch coronary CT angiography