a comparative analysis of lipid-complexed and liposomal

7/28/2019 A Comparative Analysis of Lipid-complexed and Liposomal

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A comparative analysis of lipid-complexed and liposomal

amphotericin B preparations in haematological oncology

A. D. CL A RK, S. MCKE N DRI C K , P. J. TA N S E Y, I . M. F RA N KL I N A N D R. CH O P RA*

Glasgow Royal Infirmary, Glasgow, and *Christie Hospital, Manchester

Received 9 March 1998; accepted for publication 30 June 1998

Summary. No comparative clinical information on theproperties of lipid-associated amphotericin preparations is

presently available. In this single-centre retrospective analy-

sis over a 5-year period the indications, efficacy and toxicity

of true liposomal amphotericin (AmBisome

) were com-

pared with a lipid complexed preparation (Abelcet

). In a

novel approach APACHE III scores were used in addition to

neutrophil counts, disease status and additional immuno-

suppression to accurately assess the severity of illness in both

groups and enable valid comparison. Overall, AmBisome at a

median dose of 19mg/kg/d was found to have similarclinical outcome to Abelcet at a median dose of 48 mg/kg/d.

Nephrotoxicity and electrolyte abnormalities were similar in

both groups. Rigors and febrile episodes were more common

with Abelcet. Prospective randomized comparative trials are

required to clarify the optimum dosages and therapeutic and

economic issues associated with these agents.

Keywords: Abelcet, AmBisome, liposomes, lipid complex,

fungal infection.

The incidence of systemic fungal infections in neutropenicpatients is high and a substantial number are not diagnosed

antemortem (Beck Sague & Jarvis, 1993; Bodey et al, 1992;

Jantunen et al, 1997). This realization has meant that more

patients are now being treated empirically with parenteral

antifungal agents.

Amphotericin has for many years been the gold standard

in treating systemic fungal infection. However, its usage is

limited by toxicity, primarily nephrotoxicity (Pizz o, 1993).

Over the last decade lipid-associated preparations have

become available, which complex amphotericin with lipids,

to which this drug has an affinity intermediate between

fungal ergosterol, highest affinity, and human cholesterol,

lowest affinity (de Marie et al, 1994; Janoff et al, 1993;

Ringden et al, 1991; Leenders & de Marie, 1996; Hillery,

1997). This plays a part in reducing the toxicity of the drug

and enables higher dosages of amphotericin to be adminis-

tered. Theoretically this may increase the therapeutic index.

The pharmacokinetic and pharmacodynamic properties of

these preparations differ and this has led to speculation

about the putative efficacy of the different agents (Janknegt

et al, 1992; Adler Moore, 1994; Mehta, 1997; Richardson,

1997). Information exists from comparative trials of lipid

formulations and conventional amphotericin (Prentice et al,1997) but there is a paucity of data concerning comparison

between lipid complexed and true liposomal amphotericin. It

is possible that one preparation may be clearly superior to

another or that they may exhibit a different spectrum of

activity related to host- or pathogen-specific factors such as

macrophage or fungal phospholipase production (Hiemenz &

Walsh, 1996). Alternatively, there may be no difference in

efficacy and the choice of drug would then be based on

economic considerations and side-effect profiles.

We have analysed the usage of two such preparations in a

single centre over a 5-year period (199297). Initially

AmBisome was used as the lipid preparation of ampho-

tericin. As a result of perceived cost considerations, Abelcet

replaced AmBisome as the first-line lipid formulation of

amphotericin for the second half of the study period.

PATIENTS AND METHODS

Patient selection and details. Between October 1992 and

January 1997, 59 adult patients received 68 treatment

courses of either liposomal amphotericin (AmBisome),

n32, or lipid complex amphotericin (Abelcet), n36.

AmBisome was the lipid preparation of choice from the start

of the study period until February 1995; Abelcet was then

used for the remainder of the period. The underlying

British Journal of Haematology, 1998, 103, 198204

198 1998 Blackwell Science Ltd

Correspondence: Dr Andrew D. Clark, Academic Transfusion

Medicine Unit, Department of Medicine, University of Glasgow,

Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER.


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199Analysis of Lipid-associated Amphotericin B Preparations

1998 Blackwell Science Ltd, British Journal of Haematology 103: 198204

haematological conditions were similar in each group

(Table I). There were a larger number of myeloma patients

in the Abelcet arm (n10) compared to the AmBisome arm

(n3). A greater number of allogeneic sibling bone marrow

transplantation/peripheral blood stem cell transplantation

(BMT/PBSCT) procedures had been performed in the

AmBisome patients. In total, 57 episodes occurred in

transplanted patients and 11 in the setting of high-dose

chemotherapy.

Indication for antifungal therapy. All patients received

antifungal prophylaxis with Fluconazole 100 mg daily p.o.and oral polyenes. Patients were commenced on parenteral

antifungal therapy for one of two reasons (Table II). First,

microbiological culture confirmation of fungal infection, i.e.

proven infection. Second, strongly suspected fungal infection

on the basis of either (i) severe mucositis, fever and positive

cultures from stools suggesting colonization with Candida

species, or (ii) suggestive CXR/CT scan appearances, or (iii)

pyrexia of unknown origin (PUO) resistant to broad-

spectrum antibiotics for 96 h.

Indications for liposomal or lipid complex amphotericin.

Patients were treated with lipid formulations (Table III) if

(i) there was progression of underlying proven or suspected

fungal infection as judged on clinical or radiological grounds

on conventional amphotericin treatment, or (ii) if there wasrenal or hepatic impairment. This could be pre-existing at

the start of antifungal therapy or have deteriorated as a

result of therapy with conventional amphotericin B. (iii) In

occasional patients there was difficulty in obtaining central

venous access and in one patient there was an unacceptable

reaction to conventional amphotericin B with chills and

rigors unresponsive to pethidine and piriton.

Abnormal renal function was defined as either doubling of

baseline creatinine on amphotericin or a creatinine value

>200mmol/l at time of institution of antifungal agent.

Abnormal hepatic function was defined as bilirubin or

transaminases>5 times the upper limit of the normal range.

Table I. Patient characteristics.

Abelcet AmBisome

Male 27 17Female 9 15

Median age 42 35

Aetiology

CML 11 14

AML 7 8

ALL 1 1

CLL 1 0

NHL 3 2

Myeloma 10 3

Hairy cell leukaemia 1 1

Aplastic anaemia 1 1

Breast 0 2

Biphenoleukaemia 1 0

TreatmentMatched unrelated 7 6

Allogeneic 7 14

Autologous 14 9

Chemotherapy 8 3

Table II. Indications for antifungal therapy.

Abelcet AmBisome

Proven 8 7

Broncho-alveolar lavage 4 2

Mucor spp. Aspergillus flavus

Aspergillus fumigatus Aspergillus fumigatus

Aspergillus fumigatus


Blood 1 3

Candida tropicalis Candida albicans

Candida albicans

Candida tropicalis

Cerebrospinal fluid 1 1

Candida parapsilosis Candida parapsilosis

Sputum 0 1


Peripheral blood stem cell 1 0

Candida albicans

Oesophageal biopsy 1 0

Candida albicans*

Suspected 15 11

Pyrexia of unknown origin 13 14

* Deep-seated invasive infection.


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Lipid formulation amphotericin B was commenced in line

with licensed dosages. AmBisome most usually was pre-

scribed at 2 3 mg/kg and Abelcet at 5 mg/kg.

Assessment of disease severity and facilitation of valid intra-

and inter-group comparisons. We assessed neutrophil counts at

commencement and cessation of therapy, disease status in

terms of stable or progressive disease, and additionalimmunosuppressive agents used, i.e. any combination of

cyclosporin with or without corticosteroids, CAMPATH,

antilymphocyte globulin or donor lymphocytes.

The acute physiology, age and chronic health evalua-

tion (APACHE III) scores (Knaus et al, 1991) and predicted

likelihood of hospital mortality (APACHE Investigators,

personal communication) were calculated. These para-

meters were then used as an additional indicator that the

groups were equivalent, further validating the

comparison.

Administration. AmBisome (NeXstar Pharmaceuticals,

Boulder, Colorado, U.S.A.) and Abelcet (The Liposomal

Company, Princeton, New Jersey, U.S.A.) were prepared and

infused according to standard protocols.

Statistics. Parametric data were analysed using anunpaired t-test and non-parametric data by the Chi-squared

method.

RESULTS

Dosages

The duration of therapy, daily and cumulative dosages of

lipid formulations of amphotericin are shown in Table IV.

Overall, AmBisome patients received a median dose of

19mg/kg/d. Abelcet patients received a median dose of

48 mg/kg/d. In both groups patients with proven infections

were treated with higher doses and for longer periods.

Lipid preparations enabled amphotericin B therapy to be

salvaged when toxicity prevented continuation of therapeu-tic dosages of conventional amphotericin. There was no

significant difference between preparations. In Abelcet

patients 19/32 (59%) and in AmBisome patients 17/31

(55%) had received previous conventional amphotericin

therapy. Median number of days on conventional therapy

were 5 d (range 224) for Abelcet and 4 d (range 118) for

AmBisome patients. The median cumulative dosages of

conventional amphotericin were 240 mg (range 501340)

for Abelcet patients and 190 mg (range 201100 mg) for

AmBisome patients (PNS).

1998 Blackwell Science Ltd, British Journal of Haematology 103: 198204

200 A. D. Clark et al

Table III. Indication for lipid preparations.

Abelcet AmBisome

Renal 27 18Hepatic 1 0

Renal and hepatic 1 4

No central access 3 5

Disease progression 4 4

Reaction 0 1

Table IV. Dosages, duration of therapy and outcome in liposomal and lipid complex treated

patients. Non-evaluable patients had received

a comparative analysis of lipid-complexed and liposomal

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