Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 3 - May, 1994
Theo Smart

One potentially more effective and safer alternative to standard amphotericin may be liposomal amphotericins. In these "high-tech" versions of the drug, amphotericin is encapsulated in tiny fat globules known as "liposomes." Liposomal amphotericin needs to be administered through intravenous infusion like the standard drug, but it is hoped that the liposomes will be preferentially absorbed at the sites of infection and avoid most of amphotericin's side effects. Three liposomal amphotericins have finally entered clinical testing, but it is unclear how much of an advance they actually represent.

Background

It was first hypothesized by researchers in the 1960s that liposomes might be a new way to deliver drugs. These researchers believed that liposomes, which contain water, could carry water-soluble medications inside of them, while fat soluble drugs could be tucked into the lipid layer (or layers).

By altering a liposome's composition, electrical charge and size, scientists hoped to make their drugs preferentially taken up by specific diseased organs. There, the liposome globules would be broken down and the drug released by macrophages, whose role it is to break down foreign particles in the body. Meanwhile, other tissues such as the kidneys would be protected from unnecessary and toxic accumulations of substances like amphotericin B.

Liposomal versions of amphotericin B have been developed by three biotech companies. The three versions include AmBisome (developed by Vestar and Fujisawa), Amphocil (Liposome Technology), and ABLC (Liposome Company). At this point, no version has been approved in the United States.

Part of the delay may be because the companies behind the products are small and relatively inexperienced. Then there are other problems that are peculiar to liposomes. In the first place, although liposomal encapsulation does in fact markedly reduce the incidence of adverse effects, improving efficacy is not a foregone conclusion. The amphotericin must be released from the liposome to be active, and depending on the packaging, this may not occur so readily.[1]

Laboratory comparisons show that to be effective, doses of liposomal amphotericin B need to be significantly higher than doses of the standard amphotericin. The dose of AmBisome required to suppress cryptococcus neoformans in cell culture studies was four times higher than the effective dose of standard amphotericin B.[2] Unless the liposomal drug's bioavailability and its uptake by infected cells is significantly higher, using liposomal amphotericin may just be a very elaborate (and expensive) way to lower the dosage of amphotericin B a patient is receiving.

Pharmacokinetics

All three liposomal agents also behave differently. Since these compounds have different chemical structures, weights and sizes, they have different absorption and stability patterns in the body (pharmacokinetics). Their efficacy (or lack of it) may not be the same across the board. Each formulation's effectiveness may vary in an individual manner according to the type of fungus and the site of infection.[3]

The complexity of the issues surrounding the pharmacokinetic data makes these data still harder to interpret. Is it better for the liposomes to be quickly taken up from the blood, or should they circulate longer and in higher concentrations? Clinical trials could provide the answers, but the competing liposomal drugs have never been directly compared in people. AmBisome achieves the highest blood levels, from eight to 50 times higher than standard amphotericin B. The blood levels of Amphocil and ABLC are respectively two- and five-fold lower than AmBisome's. On the other hand, ABLC is more rapidly taken up by organs which can ingest liposomes such as the liver, spleen, lungs, lymph nodes and bone marrow. Treatment for cryptococcal meningitis is compounded by the difficulty of getting drugs to the cerebral-spinal fluid (CSF), which is the site of infection. Even with standard amphotericin B, the level of medication in the CSF are only two to four percent of levels circulating in the blood.[4]

Liposomes have even more difficulty permeating the CSF. Some researchers have suggested that the smallest molecules (in this case AmBisome) may be able to penetrate into the meninges (the membrane surrounding the brain and spinal cord) because of the inflammation that occurs with the disease. Or perhaps macrophages and other phagocytes that ingest liposomes may be able to deliver free amphotericin B into the CSF[5] (in which case ABLC might get more drug to the site of infection).

None of the companies have gathered information on this topic, although one study of AmBisome (using a dose of five milligrams per kilogram of body weight) in mice found low but measurable levels of amphotericin B in the rodents' brain tissue. Still, the clinical data seem to be encouraging. AmBisome

Clinical Studies: Vestar's AmBisome, licensed to Fujisawa in the U.S., is probably the most extensively studied of the liposomal amphotericins. AmBisome is approved for use in several European countries, including Britain, and in Latin America. Vestar claims that in two years, the drug has been used by more than 10,000 patients worldwide, including 300 people with AIDS. In the U.S., though, AmBisome has only just recently gone into clinical trials. Fujisawa delayed its development in order to devote company resources to getting approval for FK-506, an immune-suppressant like cyclosporine.[6]

Clinical studies in Europe have used doses of from one to five milligrams per kilogram of a patient's body weight. This range of doses appears to be well tolerated. AmBisome has been given to immune-compromised patients in order to treat suspected or diagnosed systemic fungal infections as well as candidiasis, aspergillus, cryptococcal meningitis and visceral leishmaniasis. While high rates of efficacy are usually reported, none of these studies were controlled, i.e. they did not include a comparison arm using another treatment or placebo.

One study did use a "retrospective" control and announced that AmBisome worked in eight out of nine patients compared to three out of ten patients on standard amphotericin B. Most investigators observe an efficacy rate for standard amphotericin B therapy that is higher than 30 percent, however.[7]

A number of other studies of AmBisome have reported anywhere from a 35 to 78 percent response rate in patients who have failed on amphotericin B therapy, either due to intolerance or progression on standard therapy.[8] Response rates to AmBisome appear to be lower for pulmonary aspergillus. Autopsies show much lower tissue concentrations of drug in the lungs than in other organs.[9]

A few case studies have been performed in patients with cryptococcal meningitis. One study in 23 patients who failed on amphotericin were treated with AmBisome (1mg/kg of body weight the first day, 2mg/kg the second day and 3mg/kg the third day and thereafter for at least 42 days). Eighteen out of 23 patients responded to treatment. Fourteen were considered complete responders: in twelve of these patients, the infection was cleared from the brain in seven to 36 days (a median of eleven days).[10] Smaller studies have reported similar results.[11,12]

Still, data from uncontrolled studies such as these will not convince the U.S. Food and Drug Administration to approve the drug. To provide more data, Vestar now is conducting three AmBisome controlled trials in Europe. Two studies (200 patients each) will compare two doses of AmBisome to standard amphotericin B in bone marrow transplant patients with suspected fungal infections. The third study will be in AIDS patients with cryptococcal meningitis.[13]

In the U.S., Fujisawa has opened a dose-ranging study of AmBisome in low neutrophil (neutropenic) patients at Loyola University near Chicago and at the National Institutes of Health in Bethesda. (Neutrophils are a type of white blood cell that helps defend against fungus infections.) If the FDA consents, the company plans to perform an open-label pilot study through the NIH's AIDS Clinical Trials Group (ACTG) that will test AmBisome as a treatment of histoplasmosis. This study is supposed to start in late spring or early summer. Fujisawa also plans to perform a controlled study starting this fall comparing AmBisome to standard amphotericin B in neutropenic patients with suspected fungal infections.

Access to AmBisome: After meetings with New York activists, Fujisawa has consented to offer AmBisome on an emergency, individual basis to patients with cryptococcal meningitis who relapse or fail on standard amphotericin B. Depending upon the FDA's response, this "expanded access" program may commence as soon as late April.[14] (More information on this program can be obtained by calling Fujisawa Pharmaceuticals at 708/317-0600.)

ABLC

Clinical Studies: The Liposome Company has filed in several European countries for approval of its Amphotericin B Lipid Complex (ABLC). ABLC is currently in phase II/III clinical studies for cryptococcal meningitis in the U.S.[15] Rather than the fat bubble of a true liposome, this drug is more like a tiny ribbon of fat.[16] In one phase II study comparing the drug to amphotericin B, eleven out of twenty patients on ABLC responded to therapy, compared to seven out of seven who responded to standard therapy.[17] Apparently, as has been said elsewhere, ribbons are not enough. Another study reported similar results with a higher percentage of responders on the highest dose (5mg/kg per day).[18]

With the FDA's go-ahead, the company plans to expand the current cryptococcal meningitis study into a phase III trial.[19] Obtaining further information from this company is very difficult. Its representatives will not discuss any plans for their compound. They will not even list trial sites for the current study or give a telephone number for queries from interested clinicians.

Access to ABLC: At least ABLC is available free, through a compassionate use emergency protocol. This program covers patients who have failed or are intolerant to traditional therapies. Doctors can enroll their patients by calling 800/4-ABLC-RX. However, several calls to this number were answered only by a recording device.

Amphocil

Amphocil, or Amphotericin B Colloidal Dispersion is approved in Britain, but is only in early efficacy trials in the United States. This compound is not a true liposome, either. It is a suspension of amphotericin B in a solution of lipids. Amphocil has been studied in a number of fungal infections in Europe. In the U.S., there has been a study in 30 patients with cryptococcal meningitis who were failing on amphotericin B. The company claims the study was closed because it was producing "little data." There is another open label study in 240 patients with systemic fungal infections who cannot tolerate amphotericin due to its kidney toxicity. A dose ranging study (currently up to 7.5mg/kg) is underway, and a study of Amphocil (6mg/kg) in comparison to amphotericin B for treating invasive aspergillus should start sometime this year.[20]

Liposomal Amphotericin as an anti-HIV agent?

A number of preliminary laboratory studies have noted that amphotericin has potent anti-HIV activity at the same doses used to treat fungal infections.[21] Amphotericin's toxicity made it an unlikely drug to use for long-term therapy, but the liposomal versions may not suffer from such grave problems.

One laboratory study already has found that AmBisome has anti-HIV activity.[22] It is also worth noting that liposomal drugs accumulate in macrophages, lymph nodes and the gut whereas existing antivirals do not. During the early stage of infection, HIV appears to preferentially seek out macrophages, and most of its activity is in the lymph nodes. Since this stage may be when the future course of disease is determined, it makes sense to evaluate agents that inhibit HIV at that point in the disease. But no one is doing this right now even though waiting just a few years may harm hundreds of thousands of people.

Conclusion

Liposomal amphotericins have arrived, but like so many other AIDS drugs, it is unclear how to use them. While they may extend the period amphotericin therapy can be tolerated, there is no data showing their efficacy as first-line therapy for life-threatening fungal infections. In fact, the data gathered so far on these drugs has been so inadequate that the FDA is holding meetings in April covering trial design for liposomal products.

The agency is stressing that the companies need to produce much more data on absorption by different organs to establish liposomal agents' lack of toxicity.[23] Furthermore, companies have to perform controlled clinical trials to determine whether the drugs will only be rarely used as a last resort or whether they represent a significant advance in the treatment of systemic fungal infections.

1 Janknegt R., et al. Clinical Pharmacokinetics, 1992; 23(4):279-91.

2 Gulminetti R, et al. IX International Conference on AIDS, June 1993; abstract PO-B09-1386.

3 Janknegt R, et al. op cit.

4 Ibid.

5 Adler-Moore J, et al. Journal of Antimicrobial Chemotherapy, 1991; 28 Suppl. B:63-71.

6 Personal communication. Richard Hiles.

7 Tollemar J, et al. Mycoses, 1992; 35(9-10) 215-20.

8 Chopra R, et al. Leukemia and Lymphoma, 1992; 7 Suppl.:73-7.

9 Ringden O et al. Journal of Amtimicrobial Chemotherapy, 1991; 28 Suppl B:73-82.

10 Coker RJ,et al. AIDS, 1993; 7(6):829-35.

11 Lazar JT, et al. VII International Conference. on AIDS, June 1991, abstract W.B.2177.

12 Coker R, et al. Journal of Antimicrobial Chemotherapy, 1991; 28 Suppl. B:105-9.

13 Personal communication. Michael Ross.

14 Personal communication. Don Buell.

15 Personal communication. Sherry Duffy.

16 Bangham A. op cit.

17 Graybill JR et al. XXXI Interscience Conference on Antimicrobial Agents and Chemotherapy, 1991; abstract 289.

18 al-Haddadin D et al. VIII International Conference AIDS. July 1992, abstract PoB-3132.

19 Personal communication. Sherry Duffy.

20 Personal communication. Gwen Donovan.

21 Nielsen C, et al. Journal of Virology Methods, 1991;35(1);15-25.

22 Pontani DR, et al. Antiviral Research, 1989; 11(3):119-25.

23 Personal Communication. David Feigel and Theresa Wu.

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