A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Abelcet Pharmacology, Pharmacokinetics, Studies, Metabolism - Amphotericin B
Abelcet Pharmacology, Pharmacokinetics, Studies, Metabolism - Amphotericin B
CLINICAL PHARMACOLOGY
Pharmacokinetics
The assay used to measure
amphotericin B in the blood
after the administration of ABELCET® does not distinguish
amphotericin B that is complexed with the phospholipids of ABELCET®
from amphotericin B that is uncomplexed.
The pharmacokinetics
of amphotericin B after the administration
of ABELCET® are non linear. Volume of distribution
and clearance from blood
increase with increasing dose
of ABELCET®, resulting in less than proportional increases
in blood concentrations of amphotericin
B over a dose range of 0.6-5
mg/kg/day. The pharmacokinetics
of amphotericin B in whole blood
after the administration
of ABELCET® and amphotericin B desoxycholate are:
Pharmacokinetic Parameters
of Amphotericin B in Whole Blood
in Patients Administered Multiple Doses of ABELCET®
or Amphotericin B Desoxycholate |
|
Pharmacokinetic Parameter
|
ABELCET ® |
Amphotericin B |
| 5 mg/kg/day for 5-7 days |
0.6 mg/kg/day for 42 daysa |
| Mean ± SD |
Mean ± SD |
| Peak Concentration (mg/mL) |
1.7 ± 0.8 ( n= 10)b |
1.1 ± 0.2 (n= 5) |
Concentration at End of Dosing Interval
(mg/mL) |
0.6 ± 0.3 ( n= 10)b |
0.4 ± 0.2 ( n= 5) |
| Area Under Blood Concentration-Time Curve |
|
|
| (AUC 0-24h)(µg*h/mL) |
14 ± 7 ( n= 14)b, c |
17.1 ± 5 (n= 5) |
| Clearance (mL/ h* kg) |
436 ± 188.5 ( n= 14)b,
c |
38 ± 15 (n= 5) |
Apparent Volume of Distribution (Vdarea)
(L/kg) |
131 ± 57.7 (n= 8) |
5 ± 2.8 (n= 5) |
| Terminal Elimination Half-Life (h) |
173.4 ± 78 ( n= 8)c |
91.1 ± 40.9 (n= 5) |
| Amount Excreted in Urine Over 24 h |
|
|
| After Last Dose (% of dose)d |
0.9 ± 0.4 ( n= 8)c |
9.6 ± 2.5 (n= 8) |
- a Data from patients with mucocutaneous
leishmaniasis. Infusion rate was 0.25 mg/kg/h.
- b Data from studies in patients with cytologically proven
cancer being treated with chemotherapy or neutropenic patients with
presumed or proven fungal infection. Infusion rate
was 2.5mg/kg/h.
- c Data from patients with mucocutaneous
leishmaniasis. Infusion rate was 4 mg/kg/h.
- d Percentage of dose
excreted in 24 hours after last dose.
The large volume of distribution
and high clearance from
blood of amphotericin B after
the administration
of ABELCET® probably reflect uptake by tissues. The long
terminal elimination
half-life probably reflects
a redistribution
from tissues. Although amphotericin B is excreted slowly, there is little
accumulation in the blood after
repeated dosing. AUC of amphotericin B increased approximately 34% from
day 1 after the administration of ABELCET® 5 mg/kg/day
for 7 days. The effect of gender
or ethnicity on the pharmacokinetics
of ABELCET® has not been studied.
Tissue concentrations of amphotericin B have been obtained at autopsy
from one heart transplant
patient who received three
doses of ABELCET® at 5.3 mg/kg/day:
| Concentration in Human Tissues |
| Organ |
Amphotericin B |
| Tissue Concentration (mg/g) |
|
|
290
|
|
|
222 |
|
|
196 |
|
|
7.6 |
|
|
6.9 |
|
|
5 |
|
|
1.6 |
This pattern of distribution
is consistent with that observed in preclinical studies in dogs in which
greatest concentrations of amphotericin B after ABELCET®
administration were
observed in the liver, spleen, and lung; however, the relationship of
tissue concentrations of amphotericin
B to its biological activity
when administered as ABELCET® is unknown.
Special Populations
Hepatic Impairment: The effect
of hepatic impairment
on the disposition of
ABELCET® is not known.
Renal Impairment: The effect
of renal impairment
on the disposition of ABELCET® is not known. The effect
of dialysis on the elimination
of ABELCET® has not been studied; however, amphotericin
B is not removed by hemodialysis
when administered as amphotericin B desoxycholate.
Pediatric and Elderly Patients: The pharmacokinetics
and pharmacodynamics of pediatric
patients (£16 years of age) and elderly
patients (£65 years of age) have not
been studied.
MICROBIOLOGY
Mechanism of Action
The active component of
ABELCET®, amphotericin B, acts by binding to sterols in
the cell membrane
of susceptible fungi,
with a resultant change in the permeability of the membrane. Mammalian
cell membranes also contain sterols,
and damage to human cells is
believed to occur through the same mechanism
of action.
Activity in vitro and in vivo
ABELCET® shows in vitro activity against Aspergillus sp.(n=3)
and Candida sp.(n=10), with
MICs generally < 1 µg/mL. Depending upon the species
and strain of Aspergillus
and Candida tested, significant
in vitro differences in susceptibility to amphotericin B have been
reported (MICs ranging from 0.1 to > 10 µg/mL). However, standardized
techniques for susceptibility testing for antifungal
agents have not been established, and results of susceptibility studies
do not necessarily correlate with clinical
outcome.
ABELCET® is active in animal
models against Aspergillus fumigatus, Candida
albicans, C. guillermondii, C. stellatoideae, and C. tropicalis, Cryptococcus
sp., Coccidioidomyces sp., Histoplasma sp., and Blastomyces
sp. in which end-points were clearance
of microorganisms from target
organ (s) and/or prolonged survival
of infected animals.
Drug Resistance
Fungal species with decreased
susceptibility to amphotericin B have been isolated after serial
passage in culture
media containing the drug, and
from some patients receiving prolonged therapy. Although the relevance
of drug resistance
to clinical outcome
has not been established, fungal species which are resistant to amphotericin
B may also be resistant to ABELCET®.
CLINICAL STUDIES
Fungal Infections
Data from 473 patients were pooled from three open-label studies in which
ABELCET® was provided for the treatment
of patients with invasive
fungal infections who were judged by their physicians to be refractory
to or intolerant of conventional amphotericin B, or who had preexisting
nephrotoxicity. Results of these studies demonstrated effectiveness of
ABELCET® in the treatment
of invasive fungal infections
as a second line therapy.
Patients were defined by their individual physician
as being refractory to or failing conventional amphotericin B therapy
based on overall clinical judgement after receiving a minimum
total dose of 500 mg
of amphotericin B. Nephrotoxicity was defined as a serum
creatinine that had increased
to > 2.5 mg/dL in adults and >1.5 mg/dL in pediatric
patients, or a creatinine
clearance of < 25 mL/min
while receiving conventional amphotericin B therapy.
Of the 473 patients, four were enrolled more than once; each enrollment
contributed separately to the denominator. The median
age was 39 years (range of <
1 to 93 years); 307 patients were male
and 166 female. Patients were Caucasian
(381, 81%), African-American (41, 9%), Hispanic (27, 6%), Asian (10, 2%),
and various other races (14,3%). The median
baseline neutrophil count
was 4,000 PMN/mm3; of these, 101 (21%) had a baseline neutrophil
count < 500/mm3.
Two-hundred eighty-two patients of the 473 patients were considered evaluable
for response to therapy;
the other 191 patients were excluded on the basis
of unconfirmed diagnosis, confounding factors, concomitant systemic antifungal
therapy, or receiving 4 doses or less of ABELCET®. For
evaluable patients, the following fungal infections were treated (n=282):
aspergillosis (n=111), candidiasis
(n=87), zygomycosis (n=25),
cryptococcosis (n=16), and fusariosis (n=11). There were fewer than 10
evaluable patients for each of several other fungal species
treated.
For each type of fungal infection
listed above there were some patients successfully treated. However, in
the absence of controlled
studies it is unknown how response
would have compared to either continuing conventional amphotericin B therapy
or the use of alternative antifungal
agents.
Renal Function: Patients with aspergillosis
who initiated treatment with ABELCET® when serum
creatinine was above 2.5
mg/dL experienced a decline
in serum creatinine
during treatment. Serum creatinine levels were also lower during treatment
with ABELCET® when compared to the serum
creatinine levels of patients
treated with conventional amphotericin B in a retrospective historical
control study. Meaningful
statistical testing of the differences between these two groups is precluded
since these data were obtained from two separate studies.
In a randomized study of ABELCET® for the treatment
of invasive candidiasis
in patients with normal baseline
renal function, the incidence
of nephrotoxicity was significantly less for ABELCET® at
a dose of 5 mg/kg/day than for
conventional amphotericin B at a dose of 0.7 mg/kg/day.
Despite generally less nephrotoxicity of ABELCET® observed
at a dose of 5 mg/kg/day compared
with conventional amphotericin B therapy at a dose
range of 0.6-1 mg/kg/day, dose-limiting
renal toxicity may still be
observed with ABELCET®. Renal toxicity of doses greater
than 5 mg/kg/day of ABELCET® has not been formally studied.
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