DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 57-2
Pharmocokinetic Parameters for Amphotericin B Formulations after Multiple Administrations in Humans
PRODUCT DOSE (MG/KG) C MAX
(μg/mL) AUC (1-24hr)
(μg.hr/mL) V (L/kg) Cl (mL/hr/kg)
AmBisome (L-AMB) 5 83±35.2 555±311 0.11±0.08 11±6
Amphotec (ABCD) 5 3.1 43 4.3 117
Ablecet (ABLC) 5 1.7±0.8 14±7 131±7.7 426±188.5
Fungizone (C-AMB) 0.6 1.1±0.2 17.1±5 5±2.8 38±15
For details, see Boswell et al. (1998). From Boswell GW, Buell D, Bekersky I. AmBisome (liposomal amphotericin B): A comparative review.
J Clin Pharmacol, 1998, 38:583–592. ©1998 The American College of Clinical Pharmacology. Reprinted by permission of SAGE Publications.
(Table 57–2). C-AMB is released from its complex with deoxycholate
in the bloodstream, and the amphotericin B that remains in
plasma is more than 90% bound to proteins, largely β-lipoprotein.
Excretion into the urine is negligible with all the formulations.
Azotemia, liver failure, or hemodialysis does not have a measurable
impact on plasma concentrations. Concentrations of amphotericin B
(via C-AMB) in fluids from inflamed pleura, peritoneum, synovium,
and aqueous humor are approximately two-thirds of trough concentrations
in plasma. Little amphotericin B from any formulation penetrates
into cerebrospinal fluid (CSF), vitreous humor, or normal
amniotic fluid.
Antifungal Activity. Amphotericin B has useful clinical activity against
Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis,
Histoplasma capsulatum, Sporothrix schenckii, Coccidioides spp.,
Paracoccidioides braziliensis, Aspergillus spp., Penicillium marneffei,
and the agents of mucormycosis. Amphotericin B has limited activity
against the protozoa Leishmania spp. and Naegleria fowleri. The drug
has no antibacterial activity.
Fungal Resistance. Some isolates of Candida lusitaniae have
been relatively resistant to amphotericin B. Aspergillus terreus
and perhaps Aspergillus nidulans may be more resistant to amphotericin
B than other Aspergillus species (Steinbach et al., 2004).
Mutants selected in vitro for resistance to nystatin (a polyene antifungal
discussed later) or amphotericin B replace ergosterol with
certain precursor sterols. The rarity of significant amphotericin B
resistance arising during therapy has left it unclear whether ergosterol-deficient
mutants retain sufficient pathogenicity to survive
in deep tissue.
Therapeutic Uses. The recommended doses were given earlier for
each formulation. Candida esophagitis responds to much lower doses
than deeply invasive mycoses. Intrathecal infusion of C-AMB is useful
in patients with meningitis caused by Coccidioides. Too little is
known about intrathecal administration of lipid formulations to recommend
them. C-AMB can be injected into the CSF of the lumbar
spine, cisterna magna, or lateral cerebral ventricle. Fever and
headache are common reactions that may be decreased by intrathecal
administration of 10-15 mg of hydrocortisone. Local injections
of amphotericin B into a joint or peritoneal dialysate fluid commonly
produce irritation and pain. Intraocular injection following pars plana
vitrectomy has been used successfully for fungal endophthalmitis.
Intravenous administration of amphotericin B is the treatment
of choice for mucormycosis and is used for initial treatment of
cryptococcal meningitis, severe or rapidly progressing histoplasmosis,
blastomycosis, coccidioidomycosis, and penicilliosis marneffei,
as well as in patients not responding to azole therapy of invasive
aspergillosis, extracutaneous sporotrichosis, fusariosis, alternariosis,
and trichosporonosis. Amphotericin B (C-AMB or L-AMB) is
often given to selected patients with profound neutropenia who have
fever that does not respond to broad-spectrum antibacterial agents
over 5-7 days.
Untoward Effects. The major acute reactions to intravenous amphotericin
B formulations are fever and chills. Infusion-related reactions
are worst with ABCD, slightly less with C-C-AMB, even less with
ABLC, and least with L-AMB. Tachypnea and respiratory stridor or
modest hypotension also may occur, but true bronchospasm or anaphylaxis
is rare. Patients with pre-existing cardiac or pulmonary disease
may tolerate the metabolic demands of the reaction poorly and
develop hypoxia or hypotension. The reaction ends spontaneously in
30-45 minutes; meperidine may shorten it. Pretreatment with oral
acetaminophen or use of intravenous hydrocortisone hemisuccinate,
0.7 mg/kg, at the start of the infusion decreases reactions. Febrile
reactions abate with subsequent infusions. Infants, children, and
patients receiving therapeutic doses of glucocorticoids are less prone
to reactions.
Azotemia occurs in 80% of patients who receive C-AMB
for deep mycoses (Carlson and Condon, 1994). Lipid formulations
are less nephrotoxic, being much less with ABLC, even less with
L-AMB, and minimal with ABCD. Toxicity is dose-dependent and
usually transient and increased by concurrent therapy with other
nephrotoxic agents, such as aminoglycosides or cyclosporine.
Although permanent histological changes in renal tubules occur
even during short courses of C-AMB, permanent functional impairment
is uncommon in adults with normal renal function prior to
treatment unless the cumulative dose exceeds 3-4 g. Renal tubular
acidosis and renal wasting of K + and Mg 2+ also may be seen during
and for several weeks after therapy. Supplemental K + is required in
one-third of patients on prolonged therapy. Saline loading has
decreased nephrotoxicity, even in the absence of water or salt deprivation.
Administration of 1 L of normal saline intravenously on
the day that C-AMB is to be given has been recommended for adults
who are able to tolerate the Na + load and who are not already receiving
that amount in intravenous fluids.
Hypochromic, normocytic anemia commonly occurs during
treatment with C-AMB. Anemia is less with lipid formulations and
usually not seen over the first 2 weeks. The anemia is most likely