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Antimicrobial Agents and Chemotherapy, February 2001, p. 596-600, Vol. 45, No. 2
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.2.596-600.2001
Compartmental Pharmacokinetics of the Antifungal
Echinocandin Caspofungin (MK-0991) in Rabbits
Andreas H.
Groll,1
Bryan M.
Gullick,1
Ruta
Petraitiene,1
Vidmantas
Petraitis,1
Myrna
Candelario,1
Stephen C.
Piscitelli,2 and
Thomas J.
Walsh1,*
Immunocompromised Host Section, Pediatric
Oncology Branch, National Cancer Institute,1
and Pharmacokinetics Research Laboratory, Pharmacy
Department, Warren Grant Magnuson Clinical
Center,2 National Institutes of Health,
Bethesda, Maryland 20892
Received 17 April 2000/Returned for modification 26 August
2000/Accepted 28 October 2000
 |
ABSTRACT |
The pharmacokinetics of the antifungal echinocandin-lipopeptide
caspofungin (MK-0991) in plasma were studied in groups of three healthy
rabbits after single and multiple daily intravenous administration of
doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured
by a validated high-performance liquid chromatography method and fitted
into a three-compartment open pharmacokinetic model. Across the
investigated dosage range, caspofungin displayed dose-independent
pharmacokinetics. Following administration over 7 days, the mean peak
concentration in plasma (Cmax) ± standard error of the mean increased from 16.01 ± 0.61 µg/ml at the
1-mg/kg dose to 105.52 ± 8.92 µg/ml at the 6-mg/kg dose; the
mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 µg · h/ml, respectively. The mean
apparent volume of distribution at steady state
(Vdss) was 0.299 ± 0.011 liter/kg at the
1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not
significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the
6-mg/kg dose (NS), and the mean terminal half-life was between 30 and
34 h (NS). Except for a trend towards an increased Vdss, there were no significant differences in
pharmacokinetic parameters in comparison to those after single-dose
administration. Caspofungin was well tolerated, displayed linear
pharmacokinetics that fit into a three-compartment pharmacokinetic
model, and achieved sustained concentrations in plasma that were
multiple times in excess of reported MICs for susceptible opportunistic fungi.
| |
TEXT |
Caspofungin (MK-0991) is a novel,
investigational parenteral antifungal agent that belongs to a new
generation of semisynthetic cyclic lipopeptides of the echinocandin
family. It acts by noncompetitive inhibition of the synthesis of 1, 3-
-D-glucan, an essential homopolysaccharide in the cell
wall of many pathogenic fungi (11, 13). Similar to other
current investigational echinocandin derivatives, caspofungin has
potent and fungicidal in vitro activity against most clinically relevant Candida species without cross-resistance to
currently approved antifungal agents, and it has cell-wall damaging
effects on several Aspergillus species (3, 6, 8, 9,
15, 16, 20). The drug has demonstrated very promising activity in infection models of oropharyngeal (A. M. Flattery, G. K. Abruzzo, J. G. Smith, C. J. Gill, H. Rosen, H. Kropp, and K. Bartizal, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. F-40, 1996) and disseminated (1, 10; K. Bartizal, J. G. Smith, C. J. Gill, A. M. Flattery, L. Kong, C. Leighton, J. Stone, D. Cylc, A. Yuan, and G. K. Abruzzo, Abstr. 36th
Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-80, 1997)
candidiasis and significantly prolonged the survival in mouse models of
disseminated (1; K. Bartizal et al., Abstr. 36th Intersci. Conf.
Antimicrob. Agents Chemother.) and pulmonary (E. M. Bernard, T. Ishimaru, and D. Armstrong, Abstr. 36th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. F-39, 1996) aspergillosis, both in healthy and immunocompromised animals, respectively. In addition to its antifungal activity, caspofungin was also effective as a preventive and
therapeutic modality against Pneumocystis carinii pneumonia in dexamethasone-immunocompromised rodents (19). Little is
known, however, about the pharmacokinetics of caspofungin. The purpose of this study was to characterize the pharmacokinetics of caspofungin in plasma in the rabbit, to compare them with those of other
echinocandins, and to provide the basis for the investigation of the
concentration-response relationships of caspofungin in experimental
rabbit models of invasive fungal infections.
Study drug.
Caspofungin (MK-0991; Merck & Co., Rahway, N.J.)
was provided as a lyophilized powder and dissolved according to the
recommendations of the manufacturer in sterile water to produce a
50-mg/ml stock solution that was maintained at 
70° C. Prior to use,
the drug was freshly diluted with sterile water to 10-, 5-, and 2-mg/ml solutions for the 6-, 3-, and 1 mg/kg dosage group, respectively. The
reconstituted drug was administered at ambient temperature as a slow
intravenous bolus over 1 min through the indwelling catheter.
Animals.
Healthy female New Zealand White rabbits
(Hazleton, Denver, Pa.) weighing 2.5 to 3.5 kg were used in all
experiments. They were individually housed and maintained with water
and standard rabbit feed ad libitum according to National Institutes of
Health Guidelines for Laboratory Animal Care (4). Vascular
access was established in each rabbit 
72 h prior to experimentation by the surgical placement of a subcutaneous silastic central venous catheter as previously described (21).
Single-dose studies.
Three groups of three rabbits were
studied by single-dose studies. Animals received caspofungin at either
1, 3, or 6 mg/kg of body weight as a single steady intravenous bolus
over 1 min. Plasma samples were drawn immediately before
administration, immediately after administration (maximum concentration
of drug in plasma [Cmax]), and then at 10 and
30 min and 1, 2, 4, 8, 12, 18, 24, 48, 72, and 96 h postdosing.
Multiple-dose studies.
A different set of three groups of
three rabbits were studied by multiple-dose studies. Animals received
caspofungin at either 1, 3, or 6 mg/kg of body weight daily as an
intravenous bolus over 1 min for a total of seven doses. Plasma samples
were drawn immediately before administration of the seventh dose,
immediately after administration (Cmax), and
then at 10 and 30 min and 1, 2, 4, 8, 12, 18, 24, 48, 72, and 96 h
postdosing. Hepatic and renal toxicities were monitored in plasma
24 h after the last drug dose and compared to normal values. All
animals were clinically evaluated each day and weighed before the first
dose and at the end of the study.
Processing of blood samples.
Blood samples were collected in
heparinized syringes. Plasma was immediately separated by
centrifugation and stored at 80°C until shipment in dry ice to the
laboratories of Merck, Sharp & Dohme-Chibret, Riom, France, for assay.
Analytical method.
Drug levels in plasma were determined after
solid-phase extraction and dilution in mobile phase by reversed-phase
high-performance liquid chromatography. The mobile phase consisted of
acetonitrile-0.01 M KH2PO4 (60:40, vol/vol),
pH 3. Separation was achieved using a Brownlee Cyano column (220 by 4.6 mm [inner diameter]; particle size, 5 µm; Perkin-Elmer, Norwalk,
Conn.). Caspofungin was detected by fluorometric detection (excitation
at 224 nm; emission at, 302 nm).
Quantitation was based on an internal standard method using the
semisynthetic echinocandin L-733,560 as the internal standard. Eight-point standard curves (range of concentrations: 0.15 to 10 µg/ml) were linear with r2 values
greater then 0.998. The lower limit of quantification (LLQ) was 0.15 µg/ml. Accuracies were within ±15% and intra- and interday
variability (precision) was <5%.
Pharmacokinetic data analysis.
Pharmacokinetic parameters for
caspofungin were determined using compartmental analysis. Experimental
plasma concentration-time data were fitted to a three-compartment open
model with intravenous bolus input and linear first-order elimination
from the central compartment using iterative weighted nonlinear
least-squares regression in the Adapt II (5) computer
program. Model selection was guided by Akaike's information criterion
(23). The model fit the data well, with
r2 values for the individual fits
ranging from 0.974 to 0.999 (mean, 0.991). The regression lines through
the plot of observed versus estimated concentrations did not
differ from the line of identity, and no bias was observed.
Cmax values were determined as model-estimated concentrations immediately after bolus administration, and
AUC0-
values were calculated from estimated plasma
concentration profiles using the trapezoidal rule and extrapolation to
infinity by standard techniques. Dose linearity after single and after
multiple dosing was determined by comparison of the
dose-normalized area under the curve from 0 h to
infinity (AUC0-) across dosage levels by
analysis of variance (ANOVA) and linear regression analysis. Accumulation was assessed for each dosage level by comparing the mean
AUC between doses after multiple dosing as an approximation of AUC
between doses at steady state with the mean AUC0- after
single dosing.
Statistical analysis.
Differences between the means of
pharmacokinetic parameters across dosage levels were evaluated by ANOVA
with Bonferroni's correction for multiple comparisons. Student's or
Welch's t test was used in addition for comparison of
pharmacokinetic parameters after single dosing with those after
multiple dosing. A two-tailed P value of <0.05 was
considered statistically significant.
Pharmacokinetics in plasma.
The estimated plasma
concentration-versus-time profiles of caspofungin are shown in Fig.
1, and the corresponding mean
compartmental pharmacokinetic parameters are listed in Table
1. Administration of caspofungin at
single doses of 1, 3, and 6 mg/kg resulted in escalating peak levels in
plasma that ranged from 20.02 ± 1.18 to 123.4 ± 5.17 µg/ml (means ± standard errors of the means). The drug
exhibited a rapid initial distribution phase, followed by a second,
somewhat slower distribution-elimination phase, and a prolonged
elimination phase with a mean terminal half-life ranging from 26 to
31 h. Mean plasma levels fell below LLQ in a dose-dependent manner
after 8, 12, and 18 h postdosing. Caspofungin demonstrated linear
pharmacokinetics in plasma with no changes in dose-normalized AUC0- or total clearance (CL) across the investigated dosage range. The apparent volume of distribution at steady state (Vss) was comparatively small and independent of
the dosage.
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FIG. 1.
Concentration-versus-time plots after single
dosing (A) and after multiple daily dosing over seven days (B) with 1, 3, and 6 mg of caspofungin per kg, respectively.
Each point plots the mean concentration ± standard error of the
mean (error bars) for three rabbits each at that time.
|
|
After multiple dosing over 7 days, peak concentrations in plasma were
not significantly different from those observed after
administration of
a single dose. Mean levels in plasma fell below
the LLQ in a
dose-dependent manner after 8, 24, and 48 h. Levels
in plasma at
the end of the dosing interval were below the LLQ
in all rabbits
receiving the 1-mg/kg dose and in two of three
rabbits receiving the
3-mg/kg dose, respectively. There were no
significant differences in
AUC, CL, and half-life compared to
those after single dosing. The
Vss, however, showed a trend towards
larger
values after multiple dosing (
P < 0.05,
P = 0.16, and
P < 0.05 for the 1-, 3-, and 6-mg/kg
dosages, respectively, by
t test only). No differences in
dose-normalized AUC
0- across the investigated dosage
range were noted by ANOVA and linear
regression, indicating
dose-independent, linear pharmacokinetics
of the compound also after
multiple
dosing.
Blood urea nitrogen, serum creatinine, bilirubin, and alanine
aminotransferase levels determined after 7 days of treatment
with
caspofungin were within the range of normal values determined
in 24 healthy, drug-naive animals. Infusion-related toxicity or
other
clinical abnormalities, including abnormal weight changes,
were not
observed.
The results of this study demonstrate linear pharmacokinetics of
caspofungin over the investigated dosage range of 1 to 6
mg/kg/day,
with dose-proportional increases in the AUC
0- with
increasing dosage. Plasma concentration data fitted well
into a
three-compartment open pharmacokinetic model that revealed
a prolonged
terminal elimination half-life in the range of 30
to 35 h. There
were no significant differences in pharmacokinetic
parameters between
single-dose and multiple-dose administration
except for a trend towards
an increased
V after multiple dosing.
The investigated
dosages achieved sustained concentrations in
plasma that were multiple
times in excess of MICs reported for
susceptible opportunistic fungi
(
8,
15). Caspofungin was
well tolerated without evidence
of renal or hepatic
toxicities.
The favorable pharmacokinetic profile of caspofungin stands in marked
contrast to that of cilofungin, the first echinocandin
derivative that
had entered clinical development. The pharmacokinetics
of this drug in
the rabbit were characterized by a very rapid
elimination from the
bloodstream via first-order kinetics, and
its antifungal efficacy in
vivo was limited. Increased antifungal
efficacy, particularly in the
brain, could only be achieved through
intermittent and continuous
infusion of daily dosages of as much
as 180 mg/kg that elicited
nonlinear saturation kinetics (
14,
22).
The pharmacokinetics of caspofungin in plasma in the rabbit appear
somewhat different from those of the investigational echinocandin
VER-002 (v-echinocandin; formerly LY303366) in the same species.
In
comparison to caspofungin, at similar dosages, VER-002 exhibited
an
approximately twofold faster clearance and twofold lower
Cmax and AUC values but a three- to fourfold
larger
V (18; A. H. Groll,
D. Mickiene, V. Petraitis,
R. Petraitiene, A. Field-Ridley, M.
Candelario, J. Bacher, C. McMillian, S. C. Piscitelli, and T.
J. Walsh, Abstr. 38th
Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. J-59, 1998.). It
is yet unknown whether these subtle differences
in the pharmacokinetics
of both compounds also result in different
pharmacodynamics.
Similar to cilofungin (
22), VER-002 (
17), and
the original diamino analog L-733,560 (
2), the in vitro
fungicidal activity
of caspofungin against
Candida spp.
appears to be concentration
dependent (
7). The
implications of these observations remain
to be investigated in
vivo.
The low apparent
Vss in the rabbit is reflective
of the extensive protein binding of caspofungin across all species (12;
J.
A. Stone, S. D. Holland, W. D. Ju, Z. Zhang, M. Schwartz, V. L.
Hoagland, K. E. Mazina, T. L. Hunt, and
S. Waldman, Abstr. 38th
Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. C-51, 1998).
Tissue distribution studies with radiolabeled drug
in mice following
intraperitoneal administration revealed preferential
distribution
to liver, kidney, and small intestine and a slower CL from
all
tissues than from plasma (
12). The slow equilibration
rates
of most tissues is consistent with the existence of a terminal
elimination phase beyond the dosing interval of 24 h and the
increasing
Vss after multiple dosing in our
study and may be important for
the dynamics of the drug against
infections located in tissues.
Indeed, infection models investigating
cilofungin and VER-002
have demonstrated a correlation of antifungal
efficacy with concentrations
in tissue, and time of exposure was
important for achieving effective
concentrations in tissue and
antifungal efficacy (22; A. H. Groll,
D. Mickiene, V. Petraitis,
R. Petraitiene, C. McMillian, S. Piscitelli,
and T. J. Walsh,
Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 2001, 1999].
While caspofungin does not interact in a significant manner with the
cytochrome P450 enzyme system, it undergoes substantial
hepatic
metabolism and biliary excretion (
11). The experimental
work with cilofungin indicates saturable elimination pathways
for the
class of echinocandins, either by saturable biliary excretion
of the
parent or by metabolite inhibition (
14,
22). These
circumstances may also be relevant to caspofungin at higher dosages
or
in more narrow dosing regimens and should specifically be considered
when the drug is projected to be given concurrently with other
drugs
that may compete with its biliary elimination mechanisms.
Thus, the
potential of drug-drug interactions with drugs such
as cyclosporine,
amphotericin B, certain antineoplastic agents
(anthracyclines, vinca
alkaloids,
cis-platinum, etoposide) and
antibacterial agents
(macrolides, metronidazole) needs to be carefully
studied during
preclinical
development.
In conclusion, caspofungin displayed linear pharmacokinetics in plasma
that fit into a three-compartment open pharmacokinetic
model. No
accumulation in plasma was observed after multiple dosing,
and the
compound was well tolerated without hepatic or renal laboratory
toxicity. The characterization of the pharmacokinetics in the
rabbit
will aid in selecting appropriate dosing regimens in infection
models
and may be useful for the translation of the findings of
these models
into clinical
studies.
| |
ACKNOWLEDGMENTS |
We thank Jeffrey Grove at Merck, Sharp & Dohme-Chibret for expert
assistance with the analytical assay.
| |
FOOTNOTES |
*
Corresponding author. Mailing address:
Immunocompromised Host Section, Pediatric Oncology Branch, National
Cancer Institute, National Institutes of Health, Building 10, Rm.
13N240, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 402-0023. Fax:
(301) 402-0575. E-mail: walsht{at}mail.nih.gov.
| |
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Antimicrobial Agents and Chemotherapy, February 2001, p. 596-600, Vol. 45, No. 2
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.2.596-600.2001
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Pfaller, M. A., Diekema, D. J., Messer, S. A., Hollis, R. J., Jones, R. N.
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Kirkpatrick, W. R., Perea, S., Coco, B. J., Patterson, T. F.
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Groll, A. H., Mickiene, D., Petraitis, V., Petraitiene, R., Ibrahim, K. H., Piscitelli, S. C., Bekersky, I., Walsh, T. J.
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