Page 868 - Basic _ Clinical Pharmacology ( PDFDrive )

854 SECTION VIII Chemotherapeutic Drugs

TABLE 48–1 Properties of conventional amphotericin B and some lipid formulations. 1

Drug Physical Form Dosing (mg/kg/d) C max Clearance Nephrotoxicity Infusional Toxicity Daily Cost ($)
Conventional formulation
Fungizone Micelles 1 — — — — 24
Lipid formulations
AmBisome Spheres 3–5 ↑ ↓ ↓ ↓ 1300
Amphotec Disks 5 ↓ ↑ ↓ ↑(?) 660
Abelcet Ribbons 5 ↓ ↑ ↓ ↓(?) 570
1
Changes in C max (peak plasma concentration), clearance, nephrotoxicity, and infusional toxicity are relative to conventional amphotericin B.

packaged in a lipid-associated delivery system (Table 48–1 and in the urine over a period of several days. The serum half-life is
Box: Lipid Formulation of Amphotericin B). approximately 15 days. Hepatic impairment, renal impairment,
and dialysis have little impact on drug concentrations, and there-
OH fore no dose adjustment is required. The drug is widely distributed
O OH
CH 3 1 in most tissues, but only 2–3% of the blood level is reached in
37 OH
HO O OH OH OH OH O cerebrospinal fluid, thus occasionally necessitating intrathecal
CH 3 COOH therapy for certain types of fungal meningitis.
OH
CH 3 NH 2
O
O OH Mechanisms of Action & Resistance
CH 3
Amphotericin B is selective in its fungicidal effect because it
Amphotericin B exploits the difference in lipid composition of fungal and mam-
malian cell membranes. Ergosterol, a cell membrane sterol, is
Amphotericin B is poorly absorbed from the gastrointesti- found in the cell membrane of fungi, whereas the predominant
nal tract. Oral amphotericin B is thus effective only on fungi sterol of bacteria and human cells is cholesterol. Amphotericin
within the lumen of the tract and cannot be used for treatment B binds to ergosterol and alters the permeability of the cell by
of systemic disease. The intravenous injection of 0.6 mg/kg/d of forming amphotericin B–associated pores in the cell membrane
amphotericin B results in average blood levels of 0.3–1 mcg/mL; (Figure 48–1). As suggested by its chemistry, amphotericin B
the drug is more than 90% bound by serum proteins. Although combines avidly with lipids (ergosterol) along the double bond–
it is mostly metabolized, some amphotericin B is excreted slowly rich side of its structure and associates with water molecules

Lipid Formulation of Amphotericin B

Therapy with amphotericin B is often limited by toxicity, espe- Three such formulations are now available and have
cially drug-induced renal impairment. This has led to the devel- differing pharmacologic properties as summarized in
opment of lipid drug formulations on the assumption that Table 48–1. Although clinical trials have demonstrated
lipid-packaged drug binds to the mammalian membrane less different renal and infusion-related toxicities for these
readily, permitting the use of effective doses of the drug with
lower toxicity. Liposomal amphotericin preparations package the preparations compared with regular amphotericin B,
active drug in lipid delivery vehicles, in contrast to the colloidal there are no trials comparing the different formula-
suspensions, which were previously the only available forms. tions with each other. Limited studies have suggested
Amphotericin binds to the lipids in these vehicles with an affinity at best a moderate improvement in the clinical efficacy
between that for fungal ergosterol and that for human choles- of the lipid formulations compared with conventional
terol. The lipid vehicle then serves as an amphotericin reservoir, amphotericin B. Because the lipid preparations are much
reducing nonspecific binding to human cell membranes. This
preferential binding allows for a reduction of toxicity without more expensive, their use is usually restricted to patients
sacrificing efficacy and permits use of larger doses. Furthermore, intolerant to, or not responding to, conventional ampho-
some fungi contain lipases that may liberate free amphotericin B tericin treatment.
directly at the site of infection.