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Pegylated liposomal adriamycin: a review of current and future applications
PSTT Vol. 2, No. 12 December 1999
research focus
reviews
Pegylated liposomal adriamycin: a review of current and future applications Conrad R. Lewanski and Simon Stewart Anthracyclines such as adriamycin have a broad spectrum of activity in human tumours, but are limited, to an extent, by their non-selective delivery to a host of normal tissues and hence, subsequent tox-
clinical use, including the cytotoxic drugs adriamycin and daunorubicin, and the anti-fungal agent amphotericin B. This review will focus on liposomal adriamycin.
icity. The development of liposomes has offered a drug delivery system with significant potential to target tumours whilst sparing normal tissues. A significant breakthrough has been achieved by coating the liposome with polyethylene glycol (pegylation), and thus altering the pharmacokinetics of the drug considerably. In this review, the authors discuss the promising data now emerging with pegylated liposomal adriamycin, and also describe possible future applications.
Conrad R. Lewanski* and Simon Stewart Department of Radiotherapy & Oncology Hammersmith Hospitals NHS Trust Charing Cross Hospital Fulham Palace Road London, UK W6 8RF *tel: 144 181 846 7659 fax: 144 181 846 1603 e-mail: [email protected]
▼ Liposomes were first described in 1965 (Ref. 1), and now form an important means of drug delivery. Liposomes are spheres composed of a phospholipid bilayer encompassing an aqueous core, which can be formulated in a variety of sizes, but on average they have diameters of 50–100 nm. Because the lipid bilayer is impermeable to larger molecules, hydrophilic drugs may be entrapped within the aqueous interior. Similarly, lipid-soluble drugs may be integrated within the lipid bilayer. When injected intravenously, liposomes will circulate (together with their enclosed drug) in the blood and localize preferentially in tumour tissue and also, to some extent, inflamed or infected tissue. Such targeting results from tumour tissue possessing capillaries with increased permeability, thereby permitting the liposome to leak directly into tumour tissue, resulting in slow, but steady free drug release. There is no evidence to support direct liposomal uptake by tumour cells. Several liposomal formulations now exist in
Rationale for pegylated formulations Conventional liposomal formulations suffered from extensive uptake by the reticulo-endothelial system (RES), which is comprised largely of Kupffer cells in the liver and, to a lesser extent, the bone marrow and lymphatic tissue.The addition of a hydrophilic polymer such as polyethylene glycol (PEG) onto the liposome surface attracts a water shell to surround the liposome (Fig. 1). This shell succeeds in reducing the adsorption of various plasma proteins (opsonins) to the liposome surface that would otherwise enhance recognition and uptake by the RES. Thus, up to 70% of a dose of conventional liposomal adriamycin may be found in RES tissues2, compared with only 10–20% of the pegylated variety3.This is manifested in a vastly reduced total body clearance rate, prolonged circulation half-life and significantly reduced volume of distribution (Table 1). Furthermore, the addition of polyethylene glycol alters the pharmacokinetics from dose-dependent to relatively dose-independent within the clinical dose range4. Clinical efficacy of pegylated liposomal adriamycin Kaposi’s sarcoma Although there is data to suggest that pegylated liposomal adriamycin (PLA) has activity in several malignancies5, it has been most extensively studied in AIDS-related Kaposi’s sarcoma, this being the only currently licensed indication for its use. Kaposi’s sarcoma provides an excellent target lesion for liposomal drugs as a result of its
1461-5347/99/$ – see front matter ©1999 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00217-5
473
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PSTT Vol. 2, No. 12 December 1999
Figure 1. Structure of a liposome composed of a phospholipid bilayer containing entrapped drug within an aqueous interior.
Table 1. Pharmacokinetics of free, pegylated liposomal and conventional liposomal adriamycin Dose (mg/m2)
Terminal Total body half-life (h) clearance (ml/min)
Volume of distribution
Free adriamycin 25 50
8.7 10.4
755 422
254 365
Pegylated liposomal adriamycin
25 50
45.2 45.9
1.33 1.5
4.1 5.9
Conventional liposomal adriamycin
25
6.7
388
18.8
highly vascular nature. Liposomes permeate the ‘leaky’ capillaries from a relatively higher concentration within the plasma to the tumour tissue itself. Drug concentrations within skin biopsies at 48 and 96 hours after intravenous injection of pegylated liposomal adriamycin have been reported at 20- and 13-fold higher than surrounding normal tissue, respectively6. Furthermore, comparative data with conventional free adriamycin at 20 mg/m2 shows that a fivefold improvement in drug delivery can be achieved with the pegylated liposomal form. Conventional therapies for AIDS-related Kaposi’s sarcoma have utilized either bleomycin and vincristine (BV) or adriamycin, bleomycin and vincristine (ABV) combinations. Several randomized studies have compared the efficacy of these regimens with the pegylated liposomal form of adriamycin (Table 2). The two larger studies show a clear benefit to PLA in terms of overall response rates as compared with either BV or ABV, 474
although significant differences in the duration of response have not been observed. It has been suggested that the lower overall response rates seen in the two larger studies, as compared with the smaller studies, might reflect a more rigorous application of response criteria or more extensive disease in these patients11. Trials have tended to employ four to six cycles of chemotherapy at two- to three-weekly intervals using 20 mg/m2 of PLA. Breast cancer Anthracyclines such as adriamycin are considered to be some of the most active single agents in advanced breast cancer. However, their use is often limited by acute toxicity.The first reported Phase II study evaluating the efficacy of PLA in advanced breast cancer observed a 31% response rate (including four complete responders) amongst 71 patients at doses of 45–60 mg/m2 every three to four weeks, some of whom had received prior non-anthracycline-based chemotherapy12. This is comparable to response rates seen with the non-liposomal agent, but offered a distinctly different toxicity profile. PLA rarely produced any nausea or vomiting and could be delivered without prophylactic antiemetic therapy in the majority of cases. Significant alopecia was also rare, with only mild myelosuppression evident in most cases. It thus appears that PLA offers a new therapeutic option for patients with advanced breast cancer, especially for those seeking treatment associated with low acute toxicity. Further studies assessing dose escalation and the role of prior exposure to adriamycin are currently in progress. Ovarian cancer Although paclitaxel and cisplatin are the current accepted firstline treatment for stage three or four ovarian cancer, PLA has been investigated in women with either platinum or paclitaxel
research focus
PSTT Vol. 2, No. 12 December 1999
reviews
Table 2. Randomized clinical studies comparing the efficacy of pegylated liposomal adriamycin (PLA) with either BV a or ABV b chemotherapies Author
Number of patients
Regime
Response rate (%) Overall Complete
Median duration of response (wks)
D.W. Northfelt et al.7
133 125
PLA ABV
46** 25**
1 0
13 13
J.S.W. Stewart et al.8
116 102
PLA BV
59** 23**
6 1
20 18
M. Harrison et al.9
56 51
PLA BV
72 65
7 7
8 8
G. Rizzardini et al.10
11 15
PLA BV
100 87
9 0
NR NR
**5 p < 0.001 between treatments. a
Bleomycin and vincristine (BV).
b
Adriamycin, bleomycin and vincristine (ABV) combinations.
refractory disease. A Phase II study in such a scenario has reported an overall response rate of 26% to PLA administered at 50 mg/m2 every three weeks in 35 women13.The response duration ranged from eight to 21 months, thus comparing favourably with other salvage regimens. No patient discontinued the drug because of toxicity, thus offering hope that this drug may one day be used in combination with other agents. Toxicity of pegylated liposomal adriamycin Adriamycin, similar to most anti-neoplastic drugs, has a low therapeutic index. The non-liposomal drug causes myelosuppression (principally neutropenia) in 60–80% of patients receiving conventional doses. A moderate-to-strong emetogenic potential, stomatitis, reversible alopecia, severe vesicant reactions upon extravasation, reactivation of skin damage in sites of previous radiation therapy and the feared cardiotoxicity are additional toxicities seen with the non-liposomal agent. The side effect profile of PLA differs in several respects as a result of its altered pharmacokinetics. Some toxicities, such as myelosuppression, remain the most frequent dose-limiting adverse event and, as such, in this respect PLA does not appear to offer any advantage over the non-liposomal drug. Indeed, at commonly used doses14, leucopenia is encountered in approximately 60% of treated patients. New toxicities may also develop. One such adverse effect is palmar-plantar erythrodyaesthesia (or hand–foot syndrome), characterized by inflammation and pain in the skin of the palms and soles. This is rarely seen with the non-liposomal version, but is observed in approximately 17.5% of patients receiving PLA, although it rarely
necessitates a delay in treatment15. It is thought to be the result of the rupture of small blood capillaries in the palms and soles subsequent to pressure effects, causing the local release of liposomal drug. Prevention is centred upon avoiding trauma to the hands and feet. Acute hypersensitivity reactions can also occur with the first infusion of PLA in approximately 7–9% of cases, often within the first few minutes14. Such reactions, characterized by flushing, back pain, fevers and dyspnoea, often resolve within 24 hours once the infusion has stopped and rarely recur with subsequent infusions. These reactions are not observed with the non-liposomal drug, and thus it must be assumed that this represents a reaction to the liposome itself. Some toxicities are, however, either eliminated or significantly attenuated. Hair loss following PLA is mild, and is seen in only 5–10% of patients14, unlike after the non-liposomal form where it is often the rule. Similarly, whereas free adriamycin causes severe local inflammation at sites of extravasation, PLA appears to only initiate mild irritation16. Perhaps more importantly, nausea and vomiting appear to be significantly ameliorated with PLA in comparison with the non-liposomal form. It is, however, the cardiotoxicity that is the most feared complication of free adriamycin and this is where PLA may offer significant advantages. The irreversible cardiomyopathy that is seen in 1.7–6.8% of patients receiving the free drug appears to have a close relationship with cumulative dose17; with a threshold of 450–550 mg/m2, beyond which the incidence escalates rapidly, with almost 50% affected at 1000 mg/m2 (Ref. 18). The risk appears to be even higher amongst the elderly, 475
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research focus
children, those with pre-existing cardiac conditions and those receiving prior mediastinal irradiation19. A strong correlation with higher peak-plasma concentrations has been observed20.Thus, liposomal preparations should offer a theoretical advantage by virtue of a slow release of their contents producing significantly lower peak-plasma concentrations compared with the free drug. This is confirmed in animal data in rabbits and dogs, suggesting that up to 50% larger doses of PLA may be delivered compared with free drug, without an attendant increase in cardiotoxicity21. Data on PLA cardiotoxicity in humans is sparse, given the fact that few have received cumulative doses in excess of 500 mg/m2. However, endomyocardial biopsies of ten patients with Kaposi’s sarcoma who received cumulative PLA doses of 440–840 mg/m2 were obtained and compared with those of historical controls who had received cumulative doses of standard adriamycin of 174–671 mg/m2 (Ref. 22). Despite higher cumulative doses of anthracycline, the PLA group had biopsy evidence suggesting significantly lower cardiotoxicity relative to the control group. Indeed, two patients that received 780 and 860 mg/m2 of PLA, had no evidence of cardiotoxicity on endomyocardial biopsy. To date, no or minimal cardiotoxicity has been observed in patients with Kaposi’s sarcoma receiving PLA in clinical trials. The future PLA is now regarded as an established and highly efficacious treatment for Kaposi’s sarcoma, and one that compares very favourably with pre-existing combination chemotherapies. Its role in the treatment of solid tumours remains experimental, although it is likely to strengthen in due course as increasing focus is placed upon quality-of-life issues, particularly in palliative settings such as platinum-refractory ovarian cancer and advanced metastatic breast cancer. Recently, attempts have been made to further improve the targeting of liposomes to tumour cells by conjugating adriamycin-containing liposomes with monoclonal antibodies directed to tumour-specific antigens, creating so-called ‘immunoliposomes’. Monoclonal antibodies may be coupled at the polyethylene glycol terminus of the liposome. One such approach has targeted the Her2 (or erbB2) oncoprotein, which is over-expressed in several malignancies. In Her2 over-expressing human-breast tumour xenograft models in nude mice, treatment with adriamycin-loaded anti-Her2 immunoliposomes produced significantly increased tumour cytotoxicity compared with either free adriamycin or standard PLA (Ref. 23). Quantitative analysis of Her2 over-expressing breast cancer cells incubated with fluorescently labelled anti-Her2 immunoliposomes showed binding of 8000–23,000 liposomes per cell, compared with ,0.2% of this figure to cells with low-Her2 expression, demonstrating the selectivity of such an approach24. 476
PSTT Vol. 2, No. 12 December 1999
Targeting of human B-cell lymphoma cell lines has also been achieved with adriamycin-containing immunoliposomes using antibodies to the CD 19 surface antigen25. The immunoliposomes demonstrated a threefold higher association with the CD 19 positive B-cell lymphoma line in comparison with standard liposomes, which also translated into a higher cell cytotoxicity. Therapeutic experiments in nude mice implanted with CD 19 positive B lymphoma cells have confirmed a greater efficacy with immunoliposomes compared with standard adriamycinloaded liposomes. Alternative methods of drug delivery have also been recently investigated. PLA has been injected into the submucosal layer of the bladder wall by using a flexible cystoscope in canine subjects, with assessment of the regional pelvic lymph nodes for subsequent uptake of chemotherapeutic agent26. In comparison with intravenous doses, such delivery achieved an approximate 15–100-fold higher concentration of adriamycin in the draining nodes, which remained at this concentration for at least one week after injection, thereby offering future therapeutic potential. A different approach has been attempted with liver metastases, where PLA was administered to three patients via a reservoir into the hepatic artery27. A partial response was observed in one patient and stable disease in another, with no serious adverse effects. Recent interest has also focussed on combining PLA with other agents, such as immunomodulators. One group has assessed the therapeutic effect of PLA followed by liposomal interleukin-2 (IL-2) in mice bearing transplanted lung adenocarcinomas28. The combined treatment produced a doubling of long-term survivors (100% versus 50%) compared with PLA alone with no additive toxicity. IL-2 treatment alone was completely ineffective. One area that has generated considerable interest has been the potential value of liposomal drugs in crossing the blood–brain barrier (BBB). Malignancies within the central nervous system pose unique management problems, because the BBB limits the penetration of many conventional chemotherapeutic agents. Intravenous PLA administration to rats inoculated with a cerebral malignant sarcoma demonstrated 14-fold higher tumour levels than free adriamycin, indicating that brain tumours need not necessarily be considered to be an inaccessible compartment29. This result also has important implications with regard to using liposomes as a carrier for several other agents with known activity in the treatment of brain tumours, such as radiosensitizers, growth factor inhibitors and other cytotoxic agents. Liposomal daunorubicin (an anthracycline drug with a similar spectrum of activity to adriamycin) has recently been used in 14 children with recurrent or progressive brain tumours at doses of 60 mg/m2 every four weeks30. Six children demonstrated a response, thereby offering hope for this unfortunate
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PSTT Vol. 2, No. 12 December 1999
group of patients. However, not all malignancies have proved responsive to PLA. A Phase II study of PLA in 16 patients with poor prognosis soft-tissue sarcomas treated with 50 mg/m2 every four weeks showed no responses31,32. Nevertheless, the area of liposomal drug delivery is expanding rapidly and will undoubtedly form a major therapeutic asset in both solid and haematological malignancies within the next few years. References
reviews
13
Muggia, F.M. et al. (1997) J. Clin. Oncol. 15, 987–993
14
Dezube, B.J. (1996) Doxil Clinical Series, Sequus Pharmaceuticals Inc. 1
15
Alberts, D.S. and Garcia, D.J. (1997) Drugs 54, 30–35
16
Madhavan, S. and Northfelt, D.W. (1995) J. Natl. Cancer Inst. 87, 1556–1557
17
Shan, K., Lincoff, A.M. and Young, J.B. (1996) Ann. Intern. Med. 125, 47–58
18
Launchbury, A.P. and Habboubi, N. (1993) Cancer Treat. Rev. 19, 197–228
19
Von Hoff, D.D et al. (1979) Ann. Intern. Med. 91, 710–717
20
Legha, S.S. et al. (1982) Ann. Intern. Med. 96, 133–139
21
Working, P.K. et al. (1999) J. Pharmacol. Exp.Ther. 289, 1128–1133
22
Berry, G. et al. (1998) Ann. Oncol. 9, 711–716
1
Bangham, A.D., Standish, M.M. and Watkins, J.C. (1965) J. Mol. Biol. 13, 238–252
23
Park, J.W. et al. (1997) Cancer Lett. 118, 153–160
2
Gabizon, A. et al. (1997) Adv. Drug Deliv. Rev. 24, 337–344
24
Kirpotin, D. et al. (1997) Biochemistry 36, 66–75
3
Stewart, J.S.W. (1996) The Discriminating Liposome 2, 1–8
25
4
Allen,T.M. and Hansen, C. (1991) Biochim. Biophys.Acta 1068, 133–141
Lopes de Menezes, D.E., Pilarski, L.M. and Allen,T.M. (1998) Cancer Res. 58, 3320–3330
5
Hortobagyi, G.N. (1997) Drugs 54 (Suppl. 4), 1–7
26
Kiyokawa, H. et al. (1999) J. Urol. 161, 665–667
6
Northfelt, D.W. (1994) Proc.Am. Soc. Clin. Oncol. 13, 51
27
Konno, H. et al. (1995) Eur. Surg. Res. 27, 301–306
7
Northfelt, D.W. et al. (1998) J. Clin. Oncol. 16, 2445–2451
28
Cabanes, A. et al. (1999) Clin. Cancer Res. 5, 687–693
8
Stewart, J.S.W. et al. (1998) J. Clin. Oncol. 16, 683–691
29
Siegal,T., Horowitz, A. and Gabizon, A. (1995) J. Neurosurg. 83,
9
Harrison, M. et al. (1995) Br. J. Cancer 72 (Suppl. 25), 12
1029–1037
10
Rizzardini, G. et al. (1995) Can. J. Infect. Dis. 6 (Suppl. C), 371
30
Lippens, R.J. (1999) Pediatr. Hematol. Oncol. 16, 131–139
11
Coukell, A.J. and Spencer, C.M. (1997) Drugs 53, 520–538
31
Garcia, A.A. et al. (1998) Ann. Oncol. 9, 1131–1133
12
Ranson, M.R. et al. (1997) J. Clin. Oncol. 15, 3185–3191
32
Iwanga, K. et al. (1999) J. Pharm. Sci. 88, 248–252
In the January issue of Pharmaceutical Science & Technology Today… Update – latest news and views Quantitative structure–property relationships in pharmaceutical research – part I S. Singh, M. Grover, B. Singh and M. Bakshi Percutaneous penetration enhancers: local versus transdermal delivery B. Michniak and C.S. Asbill How good are human airway epithelial cell lines for in vitro drug transport and metabolism studies? B. Forbes Pharmaceutical applications of microcalorimetry in drug development M.A. Phipps and L. Mackin
Monitor – analytical technology and drug delivery Products
477
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Pegylated liposomal adriamycin: a review of current and future applications Conrad R. Lewanski and Simon Stewart Anthracyclines such as adriamycin have a broad spectrum of activity in human tumours, but are limited, to an extent, by their non-selective delivery to a host of normal tissues and hence, subsequent tox-
clinical use, including the cytotoxic drugs adriamycin and daunorubicin, and the anti-fungal agent amphotericin B. This review will focus on liposomal adriamycin.
icity. The development of liposomes has offered a drug delivery system with significant potential to target tumours whilst sparing normal tissues. A significant breakthrough has been achieved by coating the liposome with polyethylene glycol (pegylation), and thus altering the pharmacokinetics of the drug considerably. In this review, the authors discuss the promising data now emerging with pegylated liposomal adriamycin, and also describe possible future applications.
Conrad R. Lewanski* and Simon Stewart Department of Radiotherapy & Oncology Hammersmith Hospitals NHS Trust Charing Cross Hospital Fulham Palace Road London, UK W6 8RF *tel: 144 181 846 7659 fax: 144 181 846 1603 e-mail: [email protected]
▼ Liposomes were first described in 1965 (Ref. 1), and now form an important means of drug delivery. Liposomes are spheres composed of a phospholipid bilayer encompassing an aqueous core, which can be formulated in a variety of sizes, but on average they have diameters of 50–100 nm. Because the lipid bilayer is impermeable to larger molecules, hydrophilic drugs may be entrapped within the aqueous interior. Similarly, lipid-soluble drugs may be integrated within the lipid bilayer. When injected intravenously, liposomes will circulate (together with their enclosed drug) in the blood and localize preferentially in tumour tissue and also, to some extent, inflamed or infected tissue. Such targeting results from tumour tissue possessing capillaries with increased permeability, thereby permitting the liposome to leak directly into tumour tissue, resulting in slow, but steady free drug release. There is no evidence to support direct liposomal uptake by tumour cells. Several liposomal formulations now exist in
Rationale for pegylated formulations Conventional liposomal formulations suffered from extensive uptake by the reticulo-endothelial system (RES), which is comprised largely of Kupffer cells in the liver and, to a lesser extent, the bone marrow and lymphatic tissue.The addition of a hydrophilic polymer such as polyethylene glycol (PEG) onto the liposome surface attracts a water shell to surround the liposome (Fig. 1). This shell succeeds in reducing the adsorption of various plasma proteins (opsonins) to the liposome surface that would otherwise enhance recognition and uptake by the RES. Thus, up to 70% of a dose of conventional liposomal adriamycin may be found in RES tissues2, compared with only 10–20% of the pegylated variety3.This is manifested in a vastly reduced total body clearance rate, prolonged circulation half-life and significantly reduced volume of distribution (Table 1). Furthermore, the addition of polyethylene glycol alters the pharmacokinetics from dose-dependent to relatively dose-independent within the clinical dose range4. Clinical efficacy of pegylated liposomal adriamycin Kaposi’s sarcoma Although there is data to suggest that pegylated liposomal adriamycin (PLA) has activity in several malignancies5, it has been most extensively studied in AIDS-related Kaposi’s sarcoma, this being the only currently licensed indication for its use. Kaposi’s sarcoma provides an excellent target lesion for liposomal drugs as a result of its
1461-5347/99/$ – see front matter ©1999 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00217-5
473
reviews
research focus
PSTT Vol. 2, No. 12 December 1999
Figure 1. Structure of a liposome composed of a phospholipid bilayer containing entrapped drug within an aqueous interior.
Table 1. Pharmacokinetics of free, pegylated liposomal and conventional liposomal adriamycin Dose (mg/m2)
Terminal Total body half-life (h) clearance (ml/min)
Volume of distribution
Free adriamycin 25 50
8.7 10.4
755 422
254 365
Pegylated liposomal adriamycin
25 50
45.2 45.9
1.33 1.5
4.1 5.9
Conventional liposomal adriamycin
25
6.7
388
18.8
highly vascular nature. Liposomes permeate the ‘leaky’ capillaries from a relatively higher concentration within the plasma to the tumour tissue itself. Drug concentrations within skin biopsies at 48 and 96 hours after intravenous injection of pegylated liposomal adriamycin have been reported at 20- and 13-fold higher than surrounding normal tissue, respectively6. Furthermore, comparative data with conventional free adriamycin at 20 mg/m2 shows that a fivefold improvement in drug delivery can be achieved with the pegylated liposomal form. Conventional therapies for AIDS-related Kaposi’s sarcoma have utilized either bleomycin and vincristine (BV) or adriamycin, bleomycin and vincristine (ABV) combinations. Several randomized studies have compared the efficacy of these regimens with the pegylated liposomal form of adriamycin (Table 2). The two larger studies show a clear benefit to PLA in terms of overall response rates as compared with either BV or ABV, 474
although significant differences in the duration of response have not been observed. It has been suggested that the lower overall response rates seen in the two larger studies, as compared with the smaller studies, might reflect a more rigorous application of response criteria or more extensive disease in these patients11. Trials have tended to employ four to six cycles of chemotherapy at two- to three-weekly intervals using 20 mg/m2 of PLA. Breast cancer Anthracyclines such as adriamycin are considered to be some of the most active single agents in advanced breast cancer. However, their use is often limited by acute toxicity.The first reported Phase II study evaluating the efficacy of PLA in advanced breast cancer observed a 31% response rate (including four complete responders) amongst 71 patients at doses of 45–60 mg/m2 every three to four weeks, some of whom had received prior non-anthracycline-based chemotherapy12. This is comparable to response rates seen with the non-liposomal agent, but offered a distinctly different toxicity profile. PLA rarely produced any nausea or vomiting and could be delivered without prophylactic antiemetic therapy in the majority of cases. Significant alopecia was also rare, with only mild myelosuppression evident in most cases. It thus appears that PLA offers a new therapeutic option for patients with advanced breast cancer, especially for those seeking treatment associated with low acute toxicity. Further studies assessing dose escalation and the role of prior exposure to adriamycin are currently in progress. Ovarian cancer Although paclitaxel and cisplatin are the current accepted firstline treatment for stage three or four ovarian cancer, PLA has been investigated in women with either platinum or paclitaxel
research focus
PSTT Vol. 2, No. 12 December 1999
reviews
Table 2. Randomized clinical studies comparing the efficacy of pegylated liposomal adriamycin (PLA) with either BV a or ABV b chemotherapies Author
Number of patients
Regime
Response rate (%) Overall Complete
Median duration of response (wks)
D.W. Northfelt et al.7
133 125
PLA ABV
46** 25**
1 0
13 13
J.S.W. Stewart et al.8
116 102
PLA BV
59** 23**
6 1
20 18
M. Harrison et al.9
56 51
PLA BV
72 65
7 7
8 8
G. Rizzardini et al.10
11 15
PLA BV
100 87
9 0
NR NR
**5 p < 0.001 between treatments. a
Bleomycin and vincristine (BV).
b
Adriamycin, bleomycin and vincristine (ABV) combinations.
refractory disease. A Phase II study in such a scenario has reported an overall response rate of 26% to PLA administered at 50 mg/m2 every three weeks in 35 women13.The response duration ranged from eight to 21 months, thus comparing favourably with other salvage regimens. No patient discontinued the drug because of toxicity, thus offering hope that this drug may one day be used in combination with other agents. Toxicity of pegylated liposomal adriamycin Adriamycin, similar to most anti-neoplastic drugs, has a low therapeutic index. The non-liposomal drug causes myelosuppression (principally neutropenia) in 60–80% of patients receiving conventional doses. A moderate-to-strong emetogenic potential, stomatitis, reversible alopecia, severe vesicant reactions upon extravasation, reactivation of skin damage in sites of previous radiation therapy and the feared cardiotoxicity are additional toxicities seen with the non-liposomal agent. The side effect profile of PLA differs in several respects as a result of its altered pharmacokinetics. Some toxicities, such as myelosuppression, remain the most frequent dose-limiting adverse event and, as such, in this respect PLA does not appear to offer any advantage over the non-liposomal drug. Indeed, at commonly used doses14, leucopenia is encountered in approximately 60% of treated patients. New toxicities may also develop. One such adverse effect is palmar-plantar erythrodyaesthesia (or hand–foot syndrome), characterized by inflammation and pain in the skin of the palms and soles. This is rarely seen with the non-liposomal version, but is observed in approximately 17.5% of patients receiving PLA, although it rarely
necessitates a delay in treatment15. It is thought to be the result of the rupture of small blood capillaries in the palms and soles subsequent to pressure effects, causing the local release of liposomal drug. Prevention is centred upon avoiding trauma to the hands and feet. Acute hypersensitivity reactions can also occur with the first infusion of PLA in approximately 7–9% of cases, often within the first few minutes14. Such reactions, characterized by flushing, back pain, fevers and dyspnoea, often resolve within 24 hours once the infusion has stopped and rarely recur with subsequent infusions. These reactions are not observed with the non-liposomal drug, and thus it must be assumed that this represents a reaction to the liposome itself. Some toxicities are, however, either eliminated or significantly attenuated. Hair loss following PLA is mild, and is seen in only 5–10% of patients14, unlike after the non-liposomal form where it is often the rule. Similarly, whereas free adriamycin causes severe local inflammation at sites of extravasation, PLA appears to only initiate mild irritation16. Perhaps more importantly, nausea and vomiting appear to be significantly ameliorated with PLA in comparison with the non-liposomal form. It is, however, the cardiotoxicity that is the most feared complication of free adriamycin and this is where PLA may offer significant advantages. The irreversible cardiomyopathy that is seen in 1.7–6.8% of patients receiving the free drug appears to have a close relationship with cumulative dose17; with a threshold of 450–550 mg/m2, beyond which the incidence escalates rapidly, with almost 50% affected at 1000 mg/m2 (Ref. 18). The risk appears to be even higher amongst the elderly, 475
reviews
research focus
children, those with pre-existing cardiac conditions and those receiving prior mediastinal irradiation19. A strong correlation with higher peak-plasma concentrations has been observed20.Thus, liposomal preparations should offer a theoretical advantage by virtue of a slow release of their contents producing significantly lower peak-plasma concentrations compared with the free drug. This is confirmed in animal data in rabbits and dogs, suggesting that up to 50% larger doses of PLA may be delivered compared with free drug, without an attendant increase in cardiotoxicity21. Data on PLA cardiotoxicity in humans is sparse, given the fact that few have received cumulative doses in excess of 500 mg/m2. However, endomyocardial biopsies of ten patients with Kaposi’s sarcoma who received cumulative PLA doses of 440–840 mg/m2 were obtained and compared with those of historical controls who had received cumulative doses of standard adriamycin of 174–671 mg/m2 (Ref. 22). Despite higher cumulative doses of anthracycline, the PLA group had biopsy evidence suggesting significantly lower cardiotoxicity relative to the control group. Indeed, two patients that received 780 and 860 mg/m2 of PLA, had no evidence of cardiotoxicity on endomyocardial biopsy. To date, no or minimal cardiotoxicity has been observed in patients with Kaposi’s sarcoma receiving PLA in clinical trials. The future PLA is now regarded as an established and highly efficacious treatment for Kaposi’s sarcoma, and one that compares very favourably with pre-existing combination chemotherapies. Its role in the treatment of solid tumours remains experimental, although it is likely to strengthen in due course as increasing focus is placed upon quality-of-life issues, particularly in palliative settings such as platinum-refractory ovarian cancer and advanced metastatic breast cancer. Recently, attempts have been made to further improve the targeting of liposomes to tumour cells by conjugating adriamycin-containing liposomes with monoclonal antibodies directed to tumour-specific antigens, creating so-called ‘immunoliposomes’. Monoclonal antibodies may be coupled at the polyethylene glycol terminus of the liposome. One such approach has targeted the Her2 (or erbB2) oncoprotein, which is over-expressed in several malignancies. In Her2 over-expressing human-breast tumour xenograft models in nude mice, treatment with adriamycin-loaded anti-Her2 immunoliposomes produced significantly increased tumour cytotoxicity compared with either free adriamycin or standard PLA (Ref. 23). Quantitative analysis of Her2 over-expressing breast cancer cells incubated with fluorescently labelled anti-Her2 immunoliposomes showed binding of 8000–23,000 liposomes per cell, compared with ,0.2% of this figure to cells with low-Her2 expression, demonstrating the selectivity of such an approach24. 476
PSTT Vol. 2, No. 12 December 1999
Targeting of human B-cell lymphoma cell lines has also been achieved with adriamycin-containing immunoliposomes using antibodies to the CD 19 surface antigen25. The immunoliposomes demonstrated a threefold higher association with the CD 19 positive B-cell lymphoma line in comparison with standard liposomes, which also translated into a higher cell cytotoxicity. Therapeutic experiments in nude mice implanted with CD 19 positive B lymphoma cells have confirmed a greater efficacy with immunoliposomes compared with standard adriamycinloaded liposomes. Alternative methods of drug delivery have also been recently investigated. PLA has been injected into the submucosal layer of the bladder wall by using a flexible cystoscope in canine subjects, with assessment of the regional pelvic lymph nodes for subsequent uptake of chemotherapeutic agent26. In comparison with intravenous doses, such delivery achieved an approximate 15–100-fold higher concentration of adriamycin in the draining nodes, which remained at this concentration for at least one week after injection, thereby offering future therapeutic potential. A different approach has been attempted with liver metastases, where PLA was administered to three patients via a reservoir into the hepatic artery27. A partial response was observed in one patient and stable disease in another, with no serious adverse effects. Recent interest has also focussed on combining PLA with other agents, such as immunomodulators. One group has assessed the therapeutic effect of PLA followed by liposomal interleukin-2 (IL-2) in mice bearing transplanted lung adenocarcinomas28. The combined treatment produced a doubling of long-term survivors (100% versus 50%) compared with PLA alone with no additive toxicity. IL-2 treatment alone was completely ineffective. One area that has generated considerable interest has been the potential value of liposomal drugs in crossing the blood–brain barrier (BBB). Malignancies within the central nervous system pose unique management problems, because the BBB limits the penetration of many conventional chemotherapeutic agents. Intravenous PLA administration to rats inoculated with a cerebral malignant sarcoma demonstrated 14-fold higher tumour levels than free adriamycin, indicating that brain tumours need not necessarily be considered to be an inaccessible compartment29. This result also has important implications with regard to using liposomes as a carrier for several other agents with known activity in the treatment of brain tumours, such as radiosensitizers, growth factor inhibitors and other cytotoxic agents. Liposomal daunorubicin (an anthracycline drug with a similar spectrum of activity to adriamycin) has recently been used in 14 children with recurrent or progressive brain tumours at doses of 60 mg/m2 every four weeks30. Six children demonstrated a response, thereby offering hope for this unfortunate
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group of patients. However, not all malignancies have proved responsive to PLA. A Phase II study of PLA in 16 patients with poor prognosis soft-tissue sarcomas treated with 50 mg/m2 every four weeks showed no responses31,32. Nevertheless, the area of liposomal drug delivery is expanding rapidly and will undoubtedly form a major therapeutic asset in both solid and haematological malignancies within the next few years. References
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In the January issue of Pharmaceutical Science & Technology Today… Update – latest news and views Quantitative structure–property relationships in pharmaceutical research – part I S. Singh, M. Grover, B. Singh and M. Bakshi Percutaneous penetration enhancers: local versus transdermal delivery B. Michniak and C.S. Asbill How good are human airway epithelial cell lines for in vitro drug transport and metabolism studies? B. Forbes Pharmaceutical applications of microcalorimetry in drug development M.A. Phipps and L. Mackin
Monitor – analytical technology and drug delivery Products
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