Abstract
Purpose
To examine the removal of pegylated liposomal doxorubicin (PLD) during plasmafiltration (PF) and determine whether the drug could be withheld prior to its organ distribution responsible for mucocutaneous toxicity.
Methods
Six patients suffering from platinum-resistant ovarian cancer were treated with a 1-h IV infusion 50 mg/m2 of PLD/cycle—for three cycles q4w. Over 44 (46)–47(49) h postinfusion, five patients (14 cycles in total) underwent PF using a cascade PF method consisted of plasma separation by centrifugation and plasma treatment using filtration based one volume of plasma treatment, i.e., 3.18 L (±0.6 L) and plasma flow 1.0 L/h (0.91–1.48 L/h). Doxorubicin concentration in blood was monitored by a high-performance liquid chromatography method for 116 h postinfusion. Pharmacokinetic parameters determined from plasma concentration included volume of distribution, total body clearance, half-life of elimination, and area under the plasma concentration versus time. The amount of doxorubicin in the body eliminated by the patient and via extracorporeal treatment was evaluated. Toxicity was tested using CTCAE v4.0.
Results
The efficacy of PF and early responses to PLD/PF combination strategy were as follows: over 44(46) h postinfusion considered necessary for target distribution of PLD to tumor, patients eliminated 46 % (35–56 %) of the dose administered. Over 44(46)–47(49) h postinfusion, a single one-volume plasma filtration removed 40 % (22–45 %) (Mi5) of the remaining doxorubicin amount in the body. Total fraction eliminated attained 81 % (75–86 %). The most common treatment-related adverse events (grade 1–2) such as nausea (4/14 cycles—28 %) and vomiting (3/14 cycles—21 %) appeared during 44 h postinfusion. Hematological toxicity—anemia (5/14 cycles—35 %) was reported after cycle II termination. Symptoms of PPE-like syndrome (grade 1–2) appeared in one patient concomitantly with thrombophlebitis and malignant effusion. In this study, only one adverse reaction (1/14—7 %) as short-term malaise and nausea was reported by the investigator as probably related to PF.
Conclusion
A single one-volume PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach. There were no serious signs of drug toxicity and/or PF-related adverse events. Kinetically guided therapy with pegylated liposomal doxorubicin combined with PF may be a useful tool to the higher efficacy and tolerability of therapy with PLD.
References
Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Pt 1):6387–6392
Lammers T, Kiessling F, Hennink WE, Storm G (2012) Drug targeting to tumors: principles, pitfalls and (pre-)clinical progress. J Control Release 161(2):175–187
Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, Kaplan LD, Du Mond C, Mamelok RD, Henry DH (1998) Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. J Clin Oncol 16(7):2445–2451
Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19(14):3312–3322
O’Brien ME, Wigler N, Indar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomaczak 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):440–449
Gibson JM, Alzghari S, Ahn C, Trantham H, La-Beck NM (2013) The role of pegylated liposomal doxorubicin in ovarian cancer: a meta-analysis of randomized clinical trials. Oncologist 18(9):1022–1031
Charrois GJ, Allen TM (2003) Multiple injections of pegylated liposomal Doxorubicin: pharmacokinetics and therapeutic activity. J Pharmacol Exp Ther 306(3):1058–1067
Sabnani MK, Rajan R, Rowland B, Mavinkurve V, Wood LM, Gabizon AA, La-Beck NM (2015) Liposome promotion of tumor growth is associated with angiogenesis and inhibition of antitumor immune responses. Nanomedicine 11(2):259–262
Pütz G, Schmah O, Eckes J, Hug MJ, Winkler K (2010) Controlled application and removal of liposomal therapeutics: effective elimination of pegylated liposomal doxorubicin by double-filtration plasmapheresis in vitro. J Clin Apher 25(2):54–62
Eckes J, Schmah O, Siebers JW, Groh U, Zschiedrich S, Rautenberg B, Hasenburg A, Jansen M, Hug MJ, Winkler K, Pütz G (2011) Kinetic targeting of pegylated liposomal doxorubicin: a new approach to reduce toxicity during chemotherapy (CARL-trial). BMC Cancer 11(337):1–11
McClellan SD, Whitaker CH, Friedberg RC (1997) Removal of vancomycin during plasmapheresis. Ann Pharmacother 31(10):1132–1136
Blaha M, Andrys C, Langrova H, Studnicka J, Drsata J, Lanska M, Blaha V, Zak P (2015) Changes of the complement system and rheological indicators after therapy with rheohemapheresis. Atheroscler Suppl 18:140–145
Bellott R, Pouna P, Robert J (2001) Separation and determination of liposomal and non-liposomal daunorubicin from the plasma of patients treated with Daunoxome. J Chromatogr B Biomed Sci Appl 757(2):257–267
Hedaya MA (2012) Basic pharmacokinetics, second edition in pharmacy education series. CRC Press: Hoboken, p 1. Online resource: 581 p
Boers-Sonderen MJ, van Herpen CM, van der Graaf WT, Desar IM, van der Logt MG, de Beer YM, Ottedvanger PB, van Erp NP (2014) Correlation of toxicity and efficacy with pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD) Caelyx(R). Cancer Chemother Pharmacol 74(3):457–463
Lorusso D, Di Stewfano A, Carone V, Fagotti A, Pisconti S, Scambia G (2007) Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia (‘hand-foot’ syndrome). Ann Oncol 18(7):1159–1164
Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89(5):1037–1047
Tsai CC, Chang CH, Chen LC, Chang YJ, Lan KL, Wu YH, Hsu CW, Liu IH, Ho CL, Lee WC, Ni HC, Chang TJ, Ting G, Lee TW (2011) Biodistrubution and pharmacokinetics of 188Re-liposomes and their comparative therapeutic efficacy with 5-fluorouracil in C26 colonic peritoneal carcinomatosis mice. Int J Nanomedicine 6:2607–2619
Kintzel PE, Eastlund T, Calis KA (2003) Extracorporeal removal of antimicrobials during plasmapheresis. J Clin Apher 18(4):194–205
Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54(4):987–992
Tejada-Berges T, Granai CO, Gordinier M, Gajewski W (2002) Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer. Expert Rev Anticancer Ther 2(2):143–150
Acknowledgments
This short study was supported by the Grant IGA MZ NT 14035-3/2013.
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Martínková, J., Bláha, M., Kubeček, O. et al. Plasmafiltration as a possible contributor to kinetic targeting of pegylated liposomal doxorubicin (PLD) in order to prevent organ toxicity and immunosuppression. Cancer Chemother Pharmacol 77, 429–437 (2016). https://doi.org/10.1007/s00280-015-2936-z
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DOI: https://doi.org/10.1007/s00280-015-2936-z