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
Cancidas Pharmacology, Pharmacokinetics, Studies, Metabolism - Caspofungin acetate
Cancidas Pharmacology, Pharmacokinetics, Studies, Metabolism - Caspofungin acetate
CLINICAL PHARMACOLOGY
Pharmacokinetics Distribution
Plasma concentrations of caspofungin decline in a polyphasic
manner following single 1-hour IV infusions. A short a-phase
occurs immediately postinfusion, followed by a b-phase
(half-life of 9 to 11 hours) that characterizes much of the profile and exhibits
clear log-linear behavior from 6 to 48 hours postdose during which the plasma
concentration decreases 10-fold. An additional, longer half-life phase, g
-phase, (half-life of 40-50 hours), also occurs. Distribution, rather than excretion
or biotransformation, is the dominant mechanism influencing plasma clearance.
Caspofungin is extensively bound to albumin (~97%), and distribution into red
blood cells is minimal. Mass balance results showed that approximately 92% of
the administered radioactivity was distributed to tissues by 36 to 48 hours
after a single 70-mg dose of [3H] caspofungin acetate. There is little
excretion or biotransformation of caspofungin during the first 30 hours after
administration.
Metabolism
Caspofungin is slowly metabolized by hydrolysis and N-acetylation.
Caspofungin also undergoes spontaneous chemical degradation to an open-ring
peptide compound, L-747969. At later time points (5 to 20 days postdose), there
is a low level (3 to 7 picomoles/mg protein, or 0.6 to 1.3% of administered
dose) of covalent binding of radiolabel in plasma following single-dose administration
of [3H] caspofungin acetate, which may be due to two reactive intermediates
formed during the chemical degradation of caspofungin to L-747969. Additional
metabolism involves hydrolysis into constitutive amino acids and their degradates,
including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two
tyrosine derivatives are found only in urine, suggesting rapid clearance of
these derivatives by the kidneys.
Excretion
In a single-dose radiolabeled pharmacokinetic study, plasma,
urine, and feces were collected over 27 days. Plasma concentrations of radioactivity
and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter
drug levels fell more rapidly. Radiolabel remained quantifiable through Day
27, whereas caspofungin concentrations fell below the limit of quantitation
after 6 to 8 days postdose. After single intravenous administration of [3H]
caspofungin acetate, excretion of caspofungin and its metabolites in humans
were 35% of dose in feces and 41% of dose in urine. A small amount of caspofungin
is excreted unchanged in urine (~1.4% of dose). Renal clearance of parent drug
is low (~0.15 mL/min) and total clearance of caspofungin is 12 mL/min.
Special Populations Gender
Plasma concentrations of caspofungin in healthy men and women
were similar following a single 70-mg dose. After 13 daily 50-mg doses, caspofungin
plasma concentrations in women were elevated slightly (approximately 22% in
area under the curve [AUC]) relative to men. No dosage adjustment is necessary
based on gender.
Geriatric
Plasma concentrations of caspofungin in healthy older men and
women (³ 65 years of age) were increased slightly
(approximately 28% in area under the curve [AUC]) compared to young healthy
men after a single 70-mg dose of caspofungin. Age is not a significant determinant
of caspofungin pharmacokinetics in patients with fungal infections. No dosage
adjustment is necessary for the elderly (see PRECAUTIONS,
Geriatric Use).
Race
Regression analyses of patient pharmacokinetic data indicated
that no clinically significant differences in the pharmacokinetics of caspofungin
were seen among Caucasians, Blacks, and Hispanics. No dosage adjustment is necessary
on the basis of race.
Renal Insufficiency
In a clinical study of single 70-mg doses, caspofungin pharmacokinetics
were similar in volunteers with mild renal insufficiency (creatinine clearance
50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to
49 mL/min), advanced (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine
clearance <10 mL/min and dialysis dependent) renal insufficiency moderately
increased caspofungin plasma concentrations after single-dose administration
(range: 30 to 49% for AUC). However, in patients with invasive aspergillosis
who received multiple daily doses of CANCIDAS 50 mg, there was no significant
effect of mild to advanced renal impairment on caspofungin trough concentrations.
No dosage adjustment is necessary for patients with renal insufficiency. Caspofungin
is not dialyzable, thus supplementary dosing is not required following hemodialysis.
MICROBIOLOGY
Mechanism of Action
Caspofungin acetate, the active ingredient of CANCIDAS, inhibits
the synthesis of b (1,3)-D-glucan, an essential component
of the cell wall of Aspergillus species and Candida
species. b
(1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity against Candida species and
in regions of active cell growth of the hyphae of
Aspergillus fumigatus.
Activity in vitro
Activity in vitro
Caspofungin was active when parenterally administered to immunocompetent and immunosuppressed mice as long as 24 hours after disseminated infections with C. albicans, in which the endpoints were prolonged survival of infected mice and reduction of C. albicans from target organs. Caspofungin exhibits in vitro activity against Aspergillus species (Aspergillus fumigatus, Aspergillus
flavus, and Aspergillus terreus) and Candida species (Candida albicans, Candida glabrata, and Candida
guilliermondii). Susceptibility testing was performed according to the National Committee for Clinical
Laboratory Standards (NCCLS) (for Aspergillus species) and
M27-A (for Candida species). Standardized susceptibility testing methods for ß (1,3)-D-glucan synthesis
inhibitors have not been established for yeasts and filamentous fungi, and results of susceptibility studies
do not correlate with clinical outcome.
Drug Resistance
A study in mice infected with C. albicans and treated with orally administered doses of caspofungin suggests that there is a potential for resistance development to occur. In vitro resistance development to caspofungin by Aspergillus
species has not been studied. In limited clinical experience, drug resistance
in patients with invasive aspergillosis has not been observed. The incidence
of drug resistance by various clinical isolates of Candida and Aspergillus species is unknown.
CLINICAL STUDIES
Esophageal Candidiasis (and information on oropharyngeal candidiasis)
The safety and efficacy of CANCIDAS in the treatment of esophageal candidiasis was evaluated in one large, controlled, noninferiority, clinical trial and two smaller dose-response studies.
In all 3 studies, patients were required to have symptoms and microbiological documentation of
esophageal candidiasis; most patients had advanced AIDS (with CD4 counts < 50/mm3).
Of the 166 patients in the large study who had culture-confirmed esophageal candidiasis at baseline, 120 had Candida albicans and 2 had Candida tropicalis as the sole baseline pathogen whereas 44 had mixed baseline cultures containing C. albicans and one or more additional Candida species.
In the large, randomized, double-blind study comparing CANCIDAS 50 mg/day versus
intravenous fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for an average of 9 days (range 7-21 days). The primary endpoint was favorable overall response at 5 to 7 days following discontinuation of study therapy, which required both complete resolution of symptoms and significant endoscopic improvement. The definition of endoscopic response was based on severity of disease at baseline using a 4-grade scale and required at least a two-grade reduction from baseline endoscopic score or reduction to grade 0 for patients with a baseline score of 2 or less.
The proportion of patients with a favorable overall response for the primary endpoint was comparable for CANCIDAS and fluconazole as shown in the following table.
The proportion of patients with a favorable symptom response was also comparable (90.1% and
89.4% for CANCIDAS and fluconazole, respectively). In addition, the proportion of patients with a
favorable endoscopic response was comparable (85.2% and 86.2% for CANCIDAS and fluconazole,
respectively).
As shown in the following table, the esophageal candidiasis relapse rates at the Day 14 post-treatment visit were similar for the two groups. At the Day 28 post-treatment visit, the group treated with CANCIDAS had a numerically higher incidence of relapse, however, the difference was not statistically significant.
Relapse Rates at 14 and 28 Days Post-therapy in Patients with Esophageal Candidiasis at Baseline
In this trial, which was designed to establish noninferiority of CANCIDAS to fluconazole for the treatment of esophageal candidiasis, 122 (70%) patients also had oropharyngeal candidiasis. A favorable response was defined as complete resolution of all symptoms of oropharyngeal disease and all visible oropharyngeal lesions. The proportion of patients with a favorable oropharyngeal response at the 5- to 7-day post-treatment visit was numerically lower for CANCIDAS, however, the difference was not statistically significant. The results are shown in the following table.
As shown in the following table, the oropharyngeal candidiasis relapse rates at the Day 14 and the Day 28 post-treatment visits were statistically significantly higher for CANCIDAS than for fluconazole.
The results from the two smaller dose-ranging studies corroborate the efficacy of CANCIDAS for esophageal candidiasis that was demonstrated in the larger study.
Invasive Aspergillosis
Sixty-nine patients between the ages of 18 and 80 with invasive
aspergillosis were enrolled in an open-label, noncomparative study to evaluate
the safety, tolerability, and efficacy of CANCIDAS. Enrolled patients had previously
been refractory to or intolerant of other antifungal therapy(ies). Refractory
patients were classified as those who had disease progression or failed to improve
despite therapy for at least 7 days with amphotericin B, lipid formulations
of amphotericin B, itraconazole, or an investigational azole with reported activity
against Aspergillus. Intolerance to previous therapy was defined as a doubling
of creatinine (or creatinine ³ 2.5 mg/dL while
on therapy), other acute reactions, or infusion-related toxicity. To be included
in the study, patients with pulmonary disease must have had definite (positive
tissue histopathology or positive culture from tissue obtained by an invasive
procedure) or probable (positive radiographic or computed tomography evidence
with supporting culture from bronchoalveolar lavage or sputum, galactomannan
enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive
aspergillosis. Patients with extrapulmonary disease had to have definite invasive
aspergillosis. The definitions were modeled after the Mycoses Study Group Criteria.1
Patients were administered a single 70-mg loading dose of CANCIDAS and subsequently
dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range
of 1 to 162 days.
An independent expert panel evaluated patient data, including
diagnosis of invasive aspergillosis, response and tolerability to previous antifungal
therapy, treatment course on CANCIDAS, and clinical outcome.
A favorable response was defined as either complete resolution
(complete response) or clinically meaningful improvement (partial response)
of all signs and symptoms and attributable radiographic findings. Stable, nonprogressive
disease was considered to be an unfavorable response.
Among the 69 patients enrolled in the study, 63 met entry diagnostic
criteria and had outcome data; and of these, 52 patients received treatment
for >7 days. Fifty-three (84%) were refractory to previous antifungal therapy
and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and
18 had extrapulmonary disease. Underlying conditions were hematologic malignancy
(N=24), allogeneic bone marrow transplant or stem cell transplant (N=18), organ
transplant (N=8), solid tumor (N=3), or other conditions (N=10). All patients
in the study received concomitant therapies for their other underlying conditions.
Eighteen patients received tacrolimus and CANCIDAS concomitantly, of whom 8
also received mycophenolate mofetil.
Overall, the expert panel determined that 41% (26/63) of patients
receiving at least one dose of CANCIDAS had a favorable response. For those
patients who received >7 days of therapy with CANCIDAS, 50% (26/52) had a
favorable response. The favorable response rates for patients who were either
refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10),
respectively. The response rates among patients with pulmonary disease and extrapulmonary
disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary
disease, 2 of 8 patients who also had definite, probable, or possible CNS involvement
had a favorable response. Two of these 8 patients had progression of disease
and manifested CNS involvement while on therapy.
There is substantial evidence that CANCIDAS is well tolerated
and effective for the treatment of invasive aspergillosis in patients who are
refractory to or intolerant of itraconazole, amphotericin B, and/or lipid
formulations of amphotericin B. However, the efficacy of CANCIDAS has not been
evaluated in concurrently controlled clinical studies, with other antifungal
therapies.
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