Amphotericin lipid-based formulations

Amphotericin B-induced ARF occurs in as many as 40% to 65% of patients treated with the conventional desoxycholate formulation.30 Nephrotoxicity is due to renal arterial vasoconstriction and distal renal tubule cell damage. Risk factors include high doses, treatment for at least 7 days, preexisting kidney dysfunction, and concomitant use of other nephrotoxic drugs.31 Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease the incidence of ARF amphotericin B lipid complex, amphotericin colloidal dispersion, and liposomal amphotericin B. The range of... 

In patients who cannot tolerate voriconazole, amphotericin B can be used. Full doses (1 to 1.5 mg/kg/day) are generally recommended, with response measured by defervescence and radiographic clearing. The lipid-based formulations may be preferred as initial therapy in patients with marginal renal function or in patients receiving other nephrotoxic drugs. The optimal duration of treatment is unknown. 

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug s functional properties relative to those of the unencapsulated or nonlipid-associated drug. Lipid-based formulations increase the circulation time and alter the biodistribution of associated amphotericin. Increasing drug levels at site of action and reducing levels in normal tissues offers 2 distinct clinical advantages An increased therapeutic index and altered toxicity profile relative to free drug. 

The following table presents pharmacokinetic parameters at steady-state for lipid-based formulations of amphotericin B the assay used to measure serum levels did not distinguish between free and complex amphotericin B. 

A commercial product based on conventional liposomes has been introduced for the parenteral delivery of the anti-fungal drug, amphotericin B, which is poorly tolerated in conventional formulations. AmBisome, a liposomal formulation of amphotericin B, comprises SUV of diameter 50-100 ran. Two other lipid-based formulations of amphotericin B have also recently been commercially introduced ... 

Amphotericin can cause both glomerular and tubular damage. Lipid-based formulations (colloidal dispersion, lipid complex, and liposomal amphotericin) are less nephrotoxic than conventional amphotericin deoxy-cholate (97). However, several caveats have to be kept in mind in making such comparisons. For example, there are no defined equivalent doses for amphotericin deoxycholate and its lipid-based counterparts. 

Veerareddy PR,Vobalaboina V. Lipid-based formulations of amphotericin B. Drugs Today (Bare) 2004 40 133-45. 

Lipid-based formuiations - For use in patients refractory to conventional amphotericin B deoxycholate therapy or where renal impairment or unacceptable toxicity precludes the use of the deoxycholate formulation for the treatment of invasive fungal infections (lipid complex) for the treatment of invasive aspergillosis (cholesteryl) for the treatment of infections caused by... 

Cannon JP, Garey KW, Danziger LEI. A prospective and retrospective analysis of the nephrotoxicity and efficacy of lipid-based amphotericin B formulations. Pharmacotherapy 2001 21 1107-14. 

Liposomes are lipid-based vesicles useful in delivering conventional as well as macromolecular therapeutic agents (35). The commercially available liposomal formulations include Doxil (doxorubicin) and Ambisome (amphotericin B), which are available for the treatment of tumors and fungal infections, respectively. Egg yolk and soy lecithins that are mainly composed of phospholipids (< 95%) are commonly used as raw materials for liposome preparation. Of the two, soy lecithins are generally preferred for reasons of... 

Comparative smdies of the lipid-based amphotericin B formulations with Ftmgizotre would appear to indicate that they are less potent on a weight-for-weight basis compared with amphotericin B. However, with the reduced toxicity profile of the lipid formrdations, higher doses of amphotericin B can be tolerated by the patient, thereby oflsetting any loss in dmg potency experienced due to its formulation in a Upid delivety system. 

Despite early enthusiasm, more recent studies have yielded more equivocal information. In a randomized, double blind study, Wingard et al [146] have compared the safety of two Upid formulations of amphotericin B in febrile neutropenic patients. Subjects were randomized to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n=78), liposomal amphotericin B (L-Amph) at a dose of 3 mg/kg/ d (n=85), or L-Amph at a dose of 5 mg/kg/d (n=81). They found that the incidence of nephrotoxicity (doubhng of the base-... 

There are relatively few examples of human exposure to intravenous administration of solid fine-particle active agents. Several particle-based products for intravenous injection are currently available in the United States these include Ambisome (Astellas Pharma US, Inc.), which is a liposomal formulation of amphotericin B Abelcet (Enzon Pharma, Inc.), an amphotericin B lipid complex Doxil (Tibotec), a liposomal formulation of doxorubicin hydrochloride and Abraxane (American Bioscience, Inc.), a paclitaxel product in which the active agent molecnles are protein bound. The particles in liposome and lipid complexes are generally not rigid solid particles, and the protein-bound paclitaxel particles are also expected to be deformable. 

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