Pegylated Liposomal Doxorubicin
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- Plosker, G.L. Drugs (2008) 68: 2535. doi:10.2165/0003495-200868170-00008
Pegylated liposomal doxorubicin (Doxil®, Caelyx™) is associated with less frequent neutropenia, alopecia and cardiotoxicity than conventional doxorubicin and has an improved pharmacokinetic profile, allowing for intravenous administration over 1 hour. In the US and EU (as well as a number of other countries), pegylated liposomal doxorubicin is approved for use in combination with the proteasome inhibitor bortezomib for the treatment of patients with relapsed or refractory multiple myeloma. Results of the primary efficacy analysis of a large phase III trial in bortezomib-naive patients with relapsed or refractory multiple myeloma demonstrated that the combination of pegylated liposomal doxorubicin plus bortezomib significantly prolonged the time to progression (TTP) compared with bortezomib alone. In addition, pegylated liposomal doxorubicin plus bortezomib significantly increased TTP in most subgroup analyses, including in patients with or without previous anthracycline exposure. A number of secondary outcomes, including progression-free survival and overall survival at 15 months, were also improved with the combination compared with bortezomib alone in the overall study population. Pegylated liposomal doxorubicin plus bortezomib was associated with a higher incidence of grade 3 or 4 adverse events than bortezomib alone, which was mainly attributed to an increase in myelosuppression and gastrointestinal events with the combination. These events were predictable and often managed by dosage modifications and supportive therapy. The addition of pegylated liposomal doxorubicin to bortezomib treatment did not increase the incidence of cardiotoxicity or peripheral neuropathy, but did induce hand-foot syndrome in a proportion of patients. Pegylated liposomal doxorubicin plus bortezomib is now established as an additional standard of care in the treatment of patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
In several animal models of colon, breast, ovarian, lung and other types of cancer, pegylated liposomal doxorubicin markedly inhibited tumour growth rates and, in many cases, improved survival compared with conventional doxorubicin. A synergistic effect of enhanced apoptotic activity and suppressed anti-apoptotic pathways has been shown with the combination of doxorubicin and the proteasome inhibitor bortezomib in various tumour model systems.
The pharmacokinetics of doxorubicin were evaluated following single-dose intravenous administration of pegylated liposomal doxorubicin 30 mg/m2 plus bortezomib in patients with advanced haematological malignancies. The mean volume of distribution was similar to that of plasma volume (≈3 L). The mean value for elimination half-life was 79.9 hours and that for plasma clearance was 33.6 mL/h. In contrast, conventional doxorubicin has a much higher volume of distribution (700–1100 L/m2) and rate of clearance (24–73 L/h/m2). Following administration of pegylated liposomal doxorubicin, almost all of the circulating drug is in the encapsulated form. Distribution of drug to tissues also appears to be in the encapsulated form; degradation and clearance from tissues occurs slowly.
The combination of pegylated liposomal doxorubicin and bortezomib significantly prolonged the TTP (primary endpoint) compared with bortezomib alone in a phase III trial in 646 bortezomib-naive patients with relapsed or refractory multiple myeloma. Patients were randomized to received pegylated liposomal doxorubicin 30 mg/m2 administered as an intravenous infusion over ≥1 hour on day 4 of each 21-day cycle plus bortezomib 1.3 mg/m2 administered as an intravenous bolus on days 1, 4, 8 and 11 (n = 324) or bortezomib alone (n = 322) for up to eight cycles. Combination therapy was associated with a 45% reduction in the risk of disease progression. Median TTP was 6.5 months with bortezomib alone compared with 9.3 months when used in combination with pegylated liposomal doxorubicin (p = 0.000004; hazard ratio 1.82). Pegylated liposomal doxorubicin plus bortezomib was also associated with significant advantages over bortezomib alone for several secondary outcomes, including progression-free survival and overall survival after 15 months.
A number of subgroup analyses of the phase III trial have been conducted (most have been reported as abstracts and/or posters). For the primary outcome of TTP, results consistently favoured combination therapy over bortezomib alone regardless of patient and disease characteristics (e.g. older or younger age, higher or lower baseline serum β2-microglobulin level, refractory or non-refractory disease) or treatment history (e.g. prior exposure or no prior exposure to anthracyclines or to thalidomide/lenalidomide).
In the large phase III trial comparing pegylated liposomal doxorubicin plus bortezomib with bortezomib alone in patients with relapsed or refractory multiple myeloma, the most frequently reported nonhaematological treatment-emergent adverse events reported in ≥15% of patients in either group were gastrointestinal disturbances (e.g. nausea, diarrhoea, constipation, vomiting, anorexia), fatigue, pyrexia and asthenia. Compared with bortezomib alone, combination therapy with pegylated liposomal doxorubicin plus bortezomib was associated with significantly higher incidences of treatment-emergent nausea, diarrhoea, vomiting, pyrexia, anorexia, stomatitis and hand-foot syndrome. Congestive heart failure was reported in 3% of patients in both groups. The incidence of peripheral neuropathy, a dose-limiting adverse event with bortezomib, was not increased by pegylated liposomal doxorubicin. Neutropenia, thrombocytopenia and anaemia were the most frequently reported haematological disturbances in both treatment groups. Neutropenia of any grade occurred significantly more frequently with combination therapy than with bortezomib alone. Overall, grade 3 or 4 adverse events occurred significantly more frequently with combination therapy than with bortezomib alone, which reflected an increase in myelosuppression and gastrointestinal disturbances among patients treated with the combination. These events were consistent with the known toxicities of pegylated liposomal doxorubicin and bortezomib, and could often be managed by dosage modifications and supportive therapy.