Pegylated liposomal doxorubicin

Jiang W, Lionberger R, Yu LX (2011) In vitro and in vivo characterizations of PEGylated liposomal doxorubicin. Bioanalysis 3 333-344... 

Cordon, A.N. et al.. Recurrent epithelial ovarian carcinoma a randomized phase III study of pegylated liposomal doxorubicin versus topotecan, /. Clin. Oncol., 19, 3312-3322,2001. 

Gabizon A, Barenholz Y. Liposomal anthracyclines— from basics to clinical approval of PEGylated liposomal doxorubicin. In Janoff AS, ed. Liposomes Rational Design. New York Marcel Dekker, 1999 343-362. 

Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal Doxorubicin review of animal and human studies. Clin Pharmacokinetics 2003 42 419 36. 

Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL(R)/CAELYX(R)) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma, a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001 37 870. 

Northfelt DW, Dezube BJ, Thommes JA, et al. 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 1998 16 2445. 

Chanan-Khan A, Szebeni J, Savay S, et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil) possible role in hypersensitivity reactions. Ann Oncol 2003 14 1430. 

Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 2004 1663(1-2) 167. 

Bao A, Goins B, Klipper R, Negrete G, Phillips WT. Direct Tc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies. J Pharmacol Exp Ther 2004 308 419. 

Tsavaris N, Kosmas C, Vadiaka M, et al. Pegylated liposomal doxorubicin in the CHOP regimen for older patients with aggressive (stage III/V) non-Hodgkin s lymphoma. Anticancer Res 2002 22 1845. 

In September 2007, the EMEA approved the use of trabectidin against ovarian cancer (OC) and STS. In November 2009, Yondelis received its second marketing authorization from the European Commission for its administration in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer presently, trabectedin (36) is under Phase II trials for the treatment of paediatric sarcomas as well as breast and prostate cancers. The European Commission and the US Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and... 

Kaye SB, Lubinski J, Matulonis U et al (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCAI or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30 372-379... 

It has also been demonstrated that PEGylated liposomal doxorubicin, Caelyx, can cross the BBB with a consequent accumulation in primary and secondary brain lesions [389], In 10 patients with metastatic brain tumors treated with radiolabeled Caelyx concurrent with radiotherapy, the accumulation of the liposomal doxorubicin was 7-13 times higher in the metastatic lesions compared to the normal brain. 

Using PEGylated liposomal doxorubicin (Caelyx), Keller et al. [427] compared the efficacy of the liposomal formulation with that of a common regimen in patients with taxane-refractory advanced breast cancer. The regimen scheme was Caelyx (50 mg/m2 every 28 weeks) or vinorelbine (30 mg/m2) or mitomycin C (10 mg/m2 every 28 days) plus vinblastine (5mg/m2 at days 1,14, 28, 42). Finally, progression free survival and overall survival were similar for Caelyx and the comparative regimen. 

Caelyx is liposomal doxorubicin very well used as a treatment of choice for a number of cancers with good tolerability and antitumor activity, as has been demonstrated in many phase I or II clinical trials. One such example is the conduct of phase I study of Caelyx (PEGylated liposomal doxorubicin, 25 M) mg/m2) in combination with cyclophosphamide (750-1000 mg/m2) and vincristine (1.2 mg/m2) every 21 days in patients with relapsed or refractory small cell lung cancer [442], The suggested doses were CaelyxTM 35 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.2 mg/m2 intravenously every 21 days. This combination was well tolerated... 

Chemotherapy refers to drug administration with highly serious side effects, such as nausea, hand and foot rashes, mouth sores, and increased risk of infection, easy bruising, and so on. Therefore, liposomal carriers have been used in order to improve the drug s biodistribution and protect the patient from those side effects. The main anticancer drugs used to treat ovarian cancer are carboplatin and cisplatin, paclitaxel, topotecan, and lurtotecan. PEGylated liposomal doxorubicin has been approved as a regimen for patients with metastatic ovarian cancer refractory to both paclitaxel and platinum based-therapy [449],... 

While platinum compounds and paclitaxel comprise the first-line treatment in combination with PEGylated liposomal doxorubicin for patients with ovarian... 

Marina, N. M., Cochrane, D., Harney, E., Zomorodi, K., Blaney, S.,Winick, N., Bernstein, M., and Link, M. P. (2002), Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors A pediatric oncology group study, Clin. Cancer Res., 8, 413-418. 

Caraglia, M., Addeo, R., Costanzo, R., Montella, L., Faiola, V., Marra, M., Abruzzesse, A., Palmieri, G., Budillon, A., Grillone, F., Venuta, S., Tagliaferri, P., and Del Prete, S. (2006), Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumors, Cancer Chemother. Pharmacol., 57, 34-39. 

Keller, A. M., Mennel, R. G., Georgoulias, V. A., Nabholtz, J. M., Erazo, A., Lluch, A., Vogel, C. L., Kaufmann, M., Minckwitz, G., Henderson, G., Mellars, L., Alland, L., and Tendler, G. (2004), Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer./. Clin. Oncol., 22, 3893-3901. 

Vorobiof, D. A., Rapoport, B. L., Chasen, M. R., Slabber, C., McMichael, G., Eek, R., and Mohammed, C. (2004), First in line therapy with paclitaxel (Taxol ) and pegylated liposomal doxorubicin (Caelyx ) in patients with metstatic breast cancer A multicentre phase II study, Breast, 13,219-226. 

Overmoyer, B., Silvermann, P. Holder, L. W.,Tripathy, D., and Henderson, I. C. (2005), Pegylated liposomal doxorubicin and cyclophosphamide as first-line therapy for patients with metastatic or recurrent breast cancer, Clin. Breast Cancer, 6,150-157. 

Coleman, R. E., Biganzoli, L., Canney, P., Dirix, L., Mauriac, L., Chollet, P, Batter, V., Ngalula-Kabanga, E., Dittrich, C., and Piccart, M. (2006), A randomized phase II study of two different schedules of pegylated liposomal doxorubicin in metastatic breast cancer (EORTC-10993), Eur. J. Cancer, 42, 882-887. 

Leighl, N., Burkes, R. L., Dancey, J. E., Lopez, P. G., Higgins, B. P., Walde, P L. D., Rudinskas, L. C., Rahim, Y. H., Rodgers, A., Pond, G. R., and Shepherd, F. A. (2003), A phase I study of pegylated liposomal doxorubicin (Caelyx ) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small-cell lung cancer, Clin. Lung Cancer, 5,107-112. 

Rose, P (2005), Pegylated liposomal doxorubicin Optimizing the dosing schedule in ovarian cancer, Oncologist, 10,205-214. 

Katsaros, D., Oletti, M. V., Rigault de la Longrais, I. A., Ferrero, A., Celano, A., Fracchioli, S., Donadio, M., Passera, R., Cattel, L., and Bumma, C. (2005), Clinical and pharmacokinetic phase II study of pegylated liposomal doxorubicin and vinorelbine in heavily pretreated recurrent ovarian carcinoma, Ann Oncol, 16,300-306. 

Verhaar-Langereis, M., Karakus, A., van Eijkeren, M., Voest, E., and Witteveen, E. (2006), Phase II study of the combination of pegylated liposomal doxorubicin and topo-tecan in platinum-resistant ovarian cancer, Int. J. Gynecol. Cancer, 16, 65-70. 

Sterically stabilized liposomal doxorubicin (pegylated liposomal doxorubicin Caelyx/Doxil) is coated with polyethylene glycol (3), which results in so-called stealth liposomes. In liposomal daunorubicin the liposome consists of a lipid bilayer of distearoylphosphati-dylcholine and cholesterol in a 2 1 molar ratio (4). Both formulations have a hydrophilic outer layer, which attracts a coating of water around the liposomal shell. This increases the circulation time by making the formulation virtually invisible to the reticuloendothelial system. 

Pegylated liposomal doxorubicin (Caelyx/Doxil) and liposomal daunorubicin (DaunoXome) produce lower peak plasma concentrations and longer circulation times than free drug (7). 

Caelyx has linear pharmacokinetics and its disposition occurs in two phases, the first relatively short (5 hours) and the second prolonged (55 hours). Unlike free doxorubicin, most of the pegylated liposomal doxorubicin is... 

Cardiac adverse events that have been considered probably or possibly related to pegylated liposomal doxorubicin have been reported in 3-9% of patients (14-16). These include hypotension, pericardial effusion, thrombophlebitis, heart failure, and tachycardia (14,15). 

Left ventricular failure has been reported in a few patients, particularly those who received high cumulative lifetime doses of pegylated liposomal doxorubicin (over 550 mg/m ) (14,15). However, cumulative doses of 450 mg/m or more and 550 mg/m have been administered without significant reduction in ejection fraction or the development of cardiac failure (17,18). To date, no or minimal cardiotoxicity has been observed in patients with AIDS-related Kaposi s sarcoma who received pegylated liposomal doxorubicin in high cumulative doses (19). 

Pooled data from 12 phase I or II studies, in 308 patients with solid tumors who received pegylated liposomal doxorubicin in doses of 10-80 mg/m, showed that there was neutropenia (neutrophil count below 1 x 10 /1) in 50%, anemia in 19%, and thrombocytopenia in 9.2% (27). 

Of 71 patients with metastatic breast cancer treated with pegylated liposomal doxorubicin in doses of 45-60 mg/m given 3- or 4-weekly, grade 3/4 neutropenia occurred in 10% and thrombocytopenia in 1% (27). 

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