Polyethylene Glycol-Liposomal Doxorubicin

Abstract

Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours. In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study. In patients with advanced AIDS-related Kaposi’s sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin’s lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. Conclusions: Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent’s tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi’s sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin’s lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings. Polyethylene glycol (PEG)-liposomal doxorubicin consists of doxorubicin entrapped in PEG-coated liposomes. The antitumour activity of doxorubicin may arise mainly from interference with the topoisomerase II-DNA complex, resulting in fragmented DNA; other intracellular damage is caused by free radicals formed when the drug is metabolised. The latter mechanism is thought to be responsible not only for the antitumour activity of doxorubicin but also for adverse effects such as cardiotoxicity. PEG-liposomal doxorubicin was more effective than standard doxorubicin against human ovarian carcinoma xenografts in mice. The liposomal formulation has also demonstrated activity in vitro against a range of different human tumour cell cultures including breast, ovarian and lymphoma tumour cell types. Higher concentrations of PEG-liposomal doxorubicin than standard doxorubicin were required to inhibit tumour cell proliferation for all cell lines. PEG-liposomal doxorubicin also strongly inhibits the in vitro growth of human Kaposi’s sarcoma spindle cells and Kaposi’s sarcoma lesions. PEG-liposomal doxorubicin has a different pharmacokinetic profile from that of standard doxorubicin, including a longer circulation time, slower clearance, smaller volume of distribution and a larger area under the plasma concentrationtime curve (AUC). In addition, PEG-liposomal doxorubicin delivers 5.2 to 11.4 times more doxorubicin to Kaposi’s sarcoma lesions than does the same dose of standard doxorubicin. The plasma concentration profile of PEG-liposomal doxorubicin over a dose range of 10 to 20 mg/m² was reported to be linear, while an increase in dose to 50 mg/m² was associated with a nonlinear profile. After administration of PEG-liposomal doxorubicin 20 and 50 mg/m2, the AUC for doxorubicin was 564 and 902 mg · h/L, respectively, and the peak plasma doxorubicin concentration was 8.6 or 10.1 and 21.2 mg/L, respectively. Limited data suggest that PEG-liposomal doxorubicin preferentially accumulates in tumour tissue because it has a prolonged circulation time. Once trapped in the tumour tissue interstitial fluid, the liposomes are thought to slowly release doxorubicin which can then enter and damage tumour cells. After PEG-liposomal doxorubicin administration, doxorubicin concentrations were about 10 to 20 times higher in Kaposi’s sarcoma lesions or bone metastases than in normal skin or tumour-free muscle, respectively. Doxorubicin metabolites (e.g. doxorubicinol) were detected at low concentrations in urine, but were not detected or were detected in low concentrations in plasma after administration of PEG-liposomal doxorubicin. Clearance of single-dose PEG-liposomal doxorubicin 25 to 50 mg/m² administered intravenously was independent of dose. Bile is likely to be the major route of doxorubicin excretion after administration of PEG-liposomal doxorubicin, based on results from animal studies. The effect of hepatic dysfunction on PEG-liposomal doxorubicin pharmaco-kinetics has not yet been established. However, one study found no significant...