Download CNS pharmacokinetics of antifungal agents

Review
CNS pharmacokinetics
of antifungal agents
Shravan Kethireddy & David Andes†
University of Wisconsin School of Medicine and Public Health, Madison 600 Highland Ave, H4/572,
Madison, WI 53792, USA
1.
Fungal infections and CNS
involvement
2.
Factors impacting CNS drug
penetration and accumulation
3.
Antifungal CNS
pharmacokinetic and treatment
investigations
4.
Amphotericin B formulations
5.
Flucytosine
6.
Triazoles
7.
Echinocandins
8.
Expert opinion
Expert Opin. Drug Metab. Toxicol. (2007) 3(4):573-581
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The goal in treatment of infections is to achieve a beneficial effect whilei
ib
minimizing toxicity. It is widely recognized that the principles of pharmah
cokinetics and pharmacodynamics are critical to determining an adequate
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dose–response relationship. There has been an increased involvement
p of the
y
CNS to infection from opportunistic and endemic fungi over lthe
last several
t
decades due to establishment of solid-organ and bone marrow
transplantaric it has become
tion as well as immunosuppression from HIV. In this tregard
critical to define optimal dosing regimens by ansunderstanding of the
nagent to the targeted CNS
processes which govern delivery of an antifungal
o
i
t is to: i) summarize published
site of involvement. The objective of this review
u
experimental and clinical antifungal pharmacokinetics;
and ii) examine the
b
i
r
relationship between CNS antifungal
pharmacokinetics
and efficacy.
t
s
Examination of these studies reveal
marked
variability
among
antifungal
i
d
drugs with regard to cerebrospinal fluid and brain parenchymal penetration.
drelationship between CNS antifungal pharmaFormal examination of the
n
cokinetics and efficacy a
The few experimental studies available
g are limited.
suggest that brainn
parenchymal
kinetics is a superior predictor of antifungal
ti
efficacy than cerebrospinal
fluid concentrations.
n
i
Keywords: antifungal
Pr , central nervous system, cerebrospinal fluid, pharmacokinetics
d. 1. Fungal infections and CNS involvement
t
L
Outcome following invasive fungal infections is generally poor. When these
pathogens breach the CNS, treatment success becomes even more dismal. The
ability of antifungal drugs to achieve adequate concentrations in the tissues of the
CNS is one of numerous factors that impact treatment outcome of these infections.
All systemic fungal pathogens have been associated with CNS involvement. Those
which most commonly disseminate to the CNS include Cryptococcus neoformans,
Candida spp. and Aspergillus spp. (Table 1). One common factor to consider when
designing an optimal antimicrobial therapy is where within an end organ does the
pathogen reside? For example, common bacterial pathogens, such as Streptococcus
pneumoniae, primarily produce disease of the meninges. Similar considerations for
fungi are difficult since these pathogens do not respect the tissue compartments
within the CNS. Histopathologic studies have demonstrated organism invasion of
the meninges and parenchymal tissues with all fungal pathogens [1].
2.
Factors impacting CNS drug penetration and accumulation
The pharmacologic goal of antimicrobial administration is to achieve adequate
concentrations at the site of infection. For most tissue sites, serum drug concentrations provide an excellent surrogate of the interstitial tissue concentration where
pathogens reside for most end organs. The tissues of the CNS and eye, however, are
relatively protected tissue sites due to blood tissue barriers that limit diffusion of
many molecules. Furthermore, there are tissue efflux pumps that can impact CNS
10.1517/17425225.3.4.573 © 2007 Informa UK Ltd ISSN 1742-5225
573
CNS pharmacokinetics of antifungal agents
Table 1. Incidence of CNS involvement associated with
invasive fungal infection.
Organism
CNS involvement Mortality
Invasive candidiasis
3 – 64%
11 – 67%
Invasive aspergillosis
4 – 6%
80 – 90%
Cryptococosis
67 – 84%
< 1%
Histoplasmosis*
5 – 20%
20 – 40%
Coccidioidomycosis*
25%
26%
Blastomycosis‡
40%
4.3 – 22%
Zygomycosis
12%
79 – 98%
Dematiacious (cladophialophora) 100%
71 – 74%
Data taken from [37,49,63-66].
*Disseminated disease.
‡Patients with HIV/AIDS.
accumulation for many drugs. In order for drugs to enter the
cerebrospinal fluid (CSF) and parenchyma of the brain, the
compounds need to traverse either the epithelial layer of
the choroid plexus or the cerebral endothelium. This tissue
barrier is structurally different from other blood tissue barriers
due to the size of the intercellular connections through which
drugs pass. All other tissue sites possess fenestrated cell connections for which the space between cells is 100 Å, allowing
ready diffusion of most pharmacologic molecules. However, to
gain access to the CNS, drugs must traverse tight junctions
which are much smaller (20 Å) and preclude diffusion of large
molecular weight (MW) drugs. The blood–brain barrier is one
of these tissue barriers and is composed of the layer of
endothelium from the vessels surrounding the brain and spinal
cord. The endothelial cells are linked by tight junctions with
only 0.02% of the capillaries possessing fenestrations [2]. The
choroid plexus makes up a second drug barrier termed the
blood–CSF barrier [9]. Although the capillary membrane at
the choroid plexus is mostly fenestrated, the ependymal cell
layer of the plexus which contacts the CSF is constituted by
tight junctions that similarly limit large molecule transport [3].
Once a compound traverses the CNS tissue barriers, there
are efflux pumps (P-glycoprotein [P-gp]) in the choroid
plexus that can impact the ability of drugs to accumulate in
the CNS.
There are several physiochemical properties that impact the
ability of drugs to traverse the CNS tissue barrier. These
factors include: compound i) molecular size; ii) lipophilicity;
iii) plasma protein binding; iv) efflux pump affinity;
v) molecular charge; and vi) cerebral blood flow. The impact of
molecular size is intuitive, the larger the molecule the less it
would be expected to be able to traverse the tight junctions of
the CNS tissue barrier. The diffusion coefficient is an estimate
of the ability of a compound to penetrate the CNS serum
barrier and is approximately proportional to the reciprocal of
the square root of the molecular mass. Doubling the size of a
574
drug from a MW of 250 – 400 Da can decrease permeation by
100-fold [4,5]. The upper limit of MW to allow for efficient
diffusion is 300 – 400 Da [4]. Among the available antifungal
agents, one would expect that a small molecule such as flucytosine (120 g/mol) would diffuse easily due to its
small MW (Table 2). Conversely, the large MW of the cyclic
hexapeptide echinocandin molecules would be anticipated to
limit penetration of drugs such as caspofungin, anidulafungin
and micafungin. The MW of each of the echinocandins
exceeds 1000 g/mol. Polyene and triazole molecules are of
intermediate-to-large size. Although the MW of the parent
amphotericin B molecule is identical among the four preparations (amphotericin B deoxycholate, liposomal amphotericin
B, amphotericin B lipid complex and amphotericin B colloidal
dispersion), the particle size of the complex varies markedly.
Among the lipid preparations, the liposomal product is
two orders of magnitude smaller than other lipid associated
preparations. Among the triazoles, fluconazole and voriconazole would appear to have an advantage over either
itraconazole or posaconazole for CNS diffusion due to their
lower MW (Table 2).
A second drug property that impacts penetration into the
CNS is binding to plasma protein. The large size of serum
proteins, such as albumin, precludes penetration of protein
bound molecules. In the absence of inflammation, there is
very little albumin in the CSF (CSF:serum albumin ratio of
1:200). Plasma protein binding varies widely among the
antifungal agents. The amphotericin B preparations and each of
the echinocandins exhibit binding to albumin in excess of 95%.
Conversely, protein binding to flucytosine is negligible. Among
the triazole compounds, fluconazole is least impacted by
protein binding (10%), voriconazole is intermediate (58%),
and both itraconazole and posaconazole exhibit a very high
degree of binding (> 98%). The lower protein bound drugs
would be expected to penetrate more readily than those bound
to a higher degree.
A third drug property that governs permeation across the
CNS tissue barrier is molecule lipophilicity. Capillaries of the
brain are devoid of aqueous pores to facilitate aqueous
diffusion, thus lipid diffusion becomes a critical determinant
of drug penetration. The permeability coefficient for lipid
diffusion is known as the lipid:aqueous partition or the
octanol:water partition (Log P) [6,7]. Drugs which readily
enter the CNS compartments often possess an octanol:water
partition coefficient of ∼ 1. However, highly lipophilic
compounds also frequently demonstrate a high level of binding to serum proteins. Thus, drug properties of lipophilicity
and protein binding can be conflicting characteristics in regard
to CNS penetration. Among the antifungal drugs, the two
triazole compounds, itraconazole and posaconazole, possess
high lipophilicity. However, as discussed, this physiochemical
characteristic is associated with high affinity for serum
albumin. The characteristics of protein binding and
lipophilicity conflict in regard to CNS penetration, making
pharmacokinetic predictions difficult.
Expert Opin. Drug Metab. Toxicol. (2007) 3(4)
Kethireddy & Andes
Table 2. Physiochemical properties of antifungal agents.
Molecular weight
Log P
% Protein binding to albumin
P-glycoprotein substrate
Fluconazole
309
2.17
10
+
Itraconazole
705
6.99
98
++
Voriconazole
349
2.56
58
+
Posaconazole
700
6.1
99
+
5-FC
120
-0.89
5
-
(*<
AmB
924
0.95
> 95
-
ABLC*
1.6 – 11 um
0.4 µm)
0.95
> 95
-
L-AmB*
0.08 um
0.95
> 95
-
ABCD
0.12 – 0.14 µm
Caspofungin
1093
-2.8
98
-
Anidulafungin
1140
0.21
98
-
Micafungin
1291
-3.8
98
-
Data taken from [6,67,68].
*Particle size.
5-FC: 5-Flurocytosine; ABCD: AmB colloidal dispersion; ABLC: AmB lipid complex; AmB: Amphotericin B; L-AmB: Liposomal AmB.
Once within the CNS space, the drug must accumulate to
achieve therapeutic concentrations. Efflux pumps at the CNS
tissue barrier are capable of removing molecules from the CSF.
Substrates of P-gp, a membrane bound P-ATPase efflux pump,
has a high affinity for lipophilic molecules. These transporters
protect the brain from toxic xenobiotics and also decrease
entry of some therapeutic drugs into the CNS. The only antifungal compounds that serve as substrates for P-gp are drugs
from the azole class. Among the triazole drugs, itraconazole
exhibits the most significant affinity for this protein [8].
The understanding of these basic principles of CNS
pharmacokinetics should allow prediction of antifungal
penetration and accumulation. However, the complex and
often conflicting nature of several of these physiochemical
properties can make these predictions difficult. The studies
examining the reliability of these predictions for CNS
pharmacokinetics and treatment efficacy of antifungal drugs
are considered herein.
Antifungal CNS pharmacokinetic and
treatment investigations
3.
Interpretation of pharmacokinetic studies in the CNS requires
consideration of several important experimental variables.
First among these is the realization that the CNS is not
a homogenous pharmacologic compartment. More simply
put, CSF concentrations do not necessarily predict brain
parenchymal or meningeal concentrations. In fact, there is
even a lack of rapid equilibration within different CSF
locations such as the lumbar cistern and ventricles. As a
general rule, brain tissue concentrations are most often greater
than those detected in the CSF. A second study variable that
markedly impacts kinetic measurements is the presence of
CNS inflammation, often associated with an infectious process.
Inflammation can disrupt the CNS blood barrier tight junctions
and enhance the ability of pharmaceutical agents to penetrate
the CNS. Yet, the degree of inflammation is difficult to measure and accurately reproduce from study to study. Finally, it is
critical to consider the manner in which CNS kinetic data are
presented. Most studies report CSF concentrations relative to
serum and include an estimate of penetration. It is not uncommon to find reports based on a single and simultaneous measurement of serum and the CSF, especially in human studies.
It is important to recognize the amount of time necessary for
equilibration of drug in the CSF. The time to peak serum
concentrations is much earlier than the time to peak CSF
concentration. With these caveats in mind, the most valid
parameters of drug entry into the CSF include: i) CSF:serum
concentration ratio at steady-state; and ii) CSF: serum ratio of
the area under the concentration–time curve.
There are several study types that allow one to understand
and predict the likelihood of adequate antifungal CNS
pharmacokinetics for treatment of CNS fungal infections.
These investigations include both animal models and human
trials (Tables 3 and 4). The study designs include: i) measurement of antifungal drug concentrations in CSF or brain parenchyma, with or without CNS inflammation; ii) measurement
of CNS concentration and correlation with antifungal treatment effect; and iii) examination of antifungal treatment effect
without CNS drug concentration measurements. Several assay
methodologies have been used measure of CNS antifungal concentrations including microdialysis, postmortem tissue samples,
positron emission tomography (PET) imaging and, most
commonly, CSF sampling. Unfortunately, there is significant
heterogeneity in study design for antifungal CNS kinetics
which makes comparison across studies and drugs somewhat
Expert Opin. Drug Metab. Toxicol. (2007) 3(4)
575
CNS pharmacokinetics of antifungal agents
Table 3. CNS pharmacokinetics of antifungal agents in animal models.
CSF concentration
Brain concentration
Ref.
Fluconazole
42 – 84% (75%)
50 – 100%
[24,26,30,34,35,69]
Itraconazole
< 1% (< 1%)
Hydroxy itraconazole found in one study
[30,34,35]
[39]
Voriconazole
68 – 100%
Detectable in guinea-pig brain
Posaconazole
NA
NA
5-FC
NA
NA
AmB
< 1%
3% (18%)
[9,10,17]
ABLC
< 1%
(27%)
[10]
ABCD
< 1%
(22%)
[10]
L-AmB
< 1%
(3%)
[10]
Caspofungin
0
10 – 20%
[50]
Anidulafungin
0
9 – 15%
[51]
Micafungin
0
8 – 18%
[58,70]
Value in parentheses represents study in presence of CNS infection.
5-FC: 5-Flurocytosine; ABCD: AmB colloidal dispersion; ABLC: AmB lipid complex; AmB: Amphotericin B; CSF: Cerebrospinal fluid; L-AmB: Liposomal AmB;
NA: Not applicable.
difficult. The available literature for each of the antifungal
drugs from animal models is listed in Table 3.
4.
Amphotericin B formulations
The CNS pharmacokinetics of amphotericin B (AmB) deoxycholate and the lipid-associated preparations have been examined
in experimental studies using rabbit models both with and
without CNS infection [9,10]. Systemic administration of each
of the formulations did not produce measurable concentrations in the CSF regardless of CNS inflammation due to
candida or cryptococcal meningitis. However, detectable brain
parenchymal concentrations were observed even in the absence
of CNS infection. Brain concentrations in non-infected
animals ranged 3 – 27% of those observed in rabbit serum.
The penetration of these compounds was enhanced in presence of infection two- to fourfold. The tissue concentrations
observed with common dosing regimens would be expected to
effectively inhibit the growth of or kill invading fungi. The
degree of penetration in a Candida meningitis model was
similar among AmB, AmB lipid complex (ABLC) and
AmB colloidal dispersion (ABCD). The penetration of LAmB
relative to serum concentrations was lower than the other preparations. However, the kinetics of liposomal AmB (L-AmB)
are characterized by very high serum concentrations which are
more than 30-fold greater than each of the other amphotericin
B formulations. Thus, the absolute concentrations of L-AmB
in the brains of rabbits in this model were significantly higher
than the other preparation (L-AmB brain tissue concentrations
3.6- to 5.2-fold greater than AmB, ABLC, ABCD). Interestingly
these differences in brain parenchymal concentrations favoring
the L-AmB formulation were associated with enhanced
therapeutic efficacy in this model. The investigators observed
576
a strong correlation between the maximal (peak concentration)
and total (AUC) AmB concentration in the brain tissue and
Candida burden in brain tissue at the end of therapy. This
concentration-dependent pharmacodynamic relationship is
similar to that observed for these antifungals in other infection
sites. Human CNS pharmacokinetic evaluation of AmB and
ABLC are limited to a report of CSF concentrations in a small
series of patients with CNS infections. Similar to animal model
studies, concentrations in CSF were either undetectable or
very low relative to serum AmB levels. Limited CSF accumulation of amphotericin B led to the development of intrathecal
therapy for several CNS fungal infections [11,12]. However,
despite the lack of measurable CSF amphotericin B concentrations, there is a large clinical experience of successful use of
these products for treatment of CNS fungal infections [13-15].
In fact, amphotericin B remains the standard of treatment for
certain CNS infections, such as cryptococcal meningitis [16].
Similarly, there are numerous animal model treatment studies
demonstrating efficacy with these polyene drugs [9,10,17-22].
Taken together, these data suggest a poor correlation between
AmB CSF concentration and efficacy in treatment of CNS
fungal infections. The experimental data from Groll et al.
suggest that the ability of these drugs to achieve adequate brain
parenchymal concentrations may better correlate with
treatment efficacy than CSF measurements.
5.
Flucytosine
Both animal and human studies have examined the CNS
pharmacokinetics of flucytosine. Bennett and associates accessed
serum and CSF concentrations in animals and humans with
CNS mycoses. Using a bioassay to measure drug concentrations
they found that CSF concentrations in humans ranged
Expert Opin. Drug Metab. Toxicol. (2007) 3(4)
Kethireddy & Andes
17 – 62 µg/ml and were ∼ 74% of simultaneously determined
serum concentrations [23]. These concentrations far exceed those
associated with growth inhibition in vitro and would be anticipated to be adequate for efficacy. However, studies examining
the relationship between CSF concentrations and therapeutic
effect are unavailable.
6.
Triazoles
The available triazole antifungal agents (fluconazole,
voriconazole, itraconazole and posaconazole) exhibit variable
physiochemical characteristics and, not surprisingly, differ in
CNS pharmacokinetics. The pharmacokinetics of each of
these compounds in the CSF and brain parenchyma has been
extensively examined in animal models both with and without
CNS infection. Among the triazoles, fluconazole achieves the
highest concentrations in the CSF. Even in models with an intact
CNS blood barrier, concentrations were in the range of 42 – 84%
of those observed in serum. For example, Madu et al.
found that CSF concentrations of fluconazole were 84.3% of
those observed in serum following intravenous administration
of drug to healthy rabbits [24]. Achievable concentrations are
even greater in the presence of CNS infection. Several human
CSF kinetics studies with fluconazole report similar findings.
For example, Foulds et al. examined the fluconazole concentration in serum and CSF in patients without meningeal
inflammation [25]. CSF concentrations were in the range of
52 – 62% of those in serum at steady-state. Study of brain tissue fluconazole kinetics demonstrated a concentration profile
that closely approximates that observed in the CSF. Using
intracerebral microdialysis in rats, Yang et al. found that
fluconazole rapidly reaches equilibrium between the plasma
and brain extracellular fluid with an average brain distribution
coefficient of 0.60 [26]. Thaler and colleagues examined
fluconazole penetration by HPLC analysis in non-inflammed
human cerebral tissue and found an average brain/plasma ratio
of 1.33, indicating nearly complete equilibration with
serum [27]. PET scan imaging of 18F-labeled fluconazole in
healthy human volunteers revealed relatively homogenous distribution of the drug throughout the brain with calculated
values in the range of 4.15 – 5.48 µg/ml [28]. In a murine histoplasmosis meningitis model, Haynes et al. reported brain
parenchymal fluconazole concentrations as high as 13.85 µg/ml
following dose levels relevant to those used in patients [18].
These concentrations are several-fold higher than that needed to
inhibit growth (minimum inhibitory concentration [MIC90])
of Histoplasma spp. [29]. The ability of fluconazole to achieve
concentrations in the various CNS compartments greater than
the MIC90 of common fungal pathogens would suggest it
would be effective in therapy of these infections. Indeed, multiple experimental and clinical trial studies with fluconazole
for treatment of susceptible Candida, Cryptococcal and endemic
fungi demonstrate the successful use of this triazole [22,30-33].
The kinetics of itraconazole has been similarly investigated.
Both animal models and human studies of CSF pharmacokinetics
report nearly undetectable concentrations [30,34-36]. These
findings would not be terribly surprising given the larger MW
and high protein binding. However, study of brain parenchymal
concentrations demonstrate that itraconazole does accumulate
in this tissue space. Haynes et al. found brain parenchymal
concentrations of the microbiologically active itraconazole
metabolite (hydroxyl-itraconazole) approaching those measured
in the serum of mice with Histoplasma meningitis [18].
Several CNS fungal infection models have undertaken
comparative CSF kinetic and efficacy studies with fluconazole
and itraconazole [30,34-36]. The kinetic results from these investigations confirm those discussed above for which fluconazole
would appear to have an advantage based on CSF concentrations.
However, despite the lack of appreciable CSF concentrations
of itraconazole, therapeutic efficacy is similar to that observed
for fluconazole in cryptococcal, Coccidioides and Histoplasma
meningitis models. For example, Sorensen and colleagues
measured serum and CSF concentrations of fluconazole and
itraconazole in a rabbit Coccidioides meningitis model [30].
Itraconazole CSF concentrations were undetectable; however,
fluconazole concentrations exceeded the Coccidiodes spp.
MIC90. Despite this marked difference in CSF concentrations,
there was no difference in the ability of either treatment to
reduce the burden of organisms in the spinal cord and brain of
these mice. It is hypothesized that the activity of itraconazole
in this model is due to a combination of higher concentrations
in the target tissues of the brain parenchyma and the lower
MIC values for this drug organism combination [37]. An animal model study of Histoplasma CNS infection also supports
this theory [18]. Haynes et al. compared the CNS kinetics and
efficacy of several antifungals in a murine model. They similarly found undetectable itraconazole concentrations in the
CSF but parenchymal concentrations that are higher than the
MIC of the infecting organisms. Similar to other groups comparing the efficacy of fluconazole and itraconazole in these
CNS infection models, they reported no difference in efficacy
in this CNS endemic fungal infection model. More importantly, most comparable clinical trials have also not demonstrated differences in treatment efficacy for CNS fungal
infections. Two cryptococcal meningitis trials comparing the
efficacy of fluconazole and itraconazole for consolidation
therapy have observed therapeutic equivalence [16,38]. However,
these patient trials have not included CNS pharmacokinetic
evaluation. Taken together, these animal models and clinical
trials point to discordance between triazole CSF concentrations
and treatment efficacy similar to that observed for AmB.
Although brain parenchymal concentrations were not examined
in the animal model treatment studies, one certainly wonders
if the ability of itraconazole to accumulate in this tissue
accounts for efficacy in these models.
The newer triazole voriconazole is structurally related to
fluconazole, whereas posaconazole is similar in structure to
itraconazole. Lutsar and colleagues studied voriconazole concentrations in the CSF and brain in uninfected guinea-pigs
and in the CSF of humans with a wide range of CNS
Expert Opin. Drug Metab. Toxicol. (2007) 3(4)
577
CNS pharmacokinetics of antifungal agents
Table 4. CNS pharmacokinetics of antifungal agents in
humans.
CSF
concentration
Brain
concentration
Ref.
Fluconazole
52 – 82%
(70 – 89%)
116%
[18,25,31,71]
Itraconazole
(< 10%)
NA
[42]
Voriconazole
(38 – 68%)
1.2 – 1.9 µg/g
[39, 40,
42-44]
Posaconazole
NA
NA
5-FC
74%
NA
[23]
AmB
(0 – 4%)
NA
[72]
ABLC
(< 1%)
NA
[13]
ABCD
NA
NA
L-AmB
NA
NA
Caspofungin
NA
NA
Anidulafungin
NA
NA
Micafungin
NA
NA
7.
Value in parentheses represents study in presence of CNS infection.
5-FC: 5-Flurocytosine; ABCD: AmB colloidal dispersion; ABLC: AmB lipid
complex; AmB: Amphotericin B; CSF: Cerebrospinal fluid; L-AmB: Liposomal
AmB; NA: Not applicable.
fungal disease. In animals without CNS infection, CSF concentrations were very similar to those observed in serum.
Among a group of 14 patients with invasive fungal infections,
CSF concentrations of voriconazole were nearly half (46%) of
those reported concomitantly in serum [39]. Brain tissue levels
of voriconazole have also been reported in a patient with an
intracerebral aspergillosis [40]. Drug concentrations in biopsies
ranged 1.2 – 1.9 µg/g, indicating that voriconazole also accumulates in the brain parenchyma. These concentrations are
above or near the MIC90 for most target fungal pathogens [41].
Other anecdotal publications also include measurement of
voriconazole concentration in CSF or brain tissue and report
similar findings. In humans treated for CNS aspergillosis, CSF
concentrations have been measured in 38 – 68% of those
observed in plasma [42-44]. Although clinical experience with
voriconazole in treatment of CNS fungal infections is small,
the limited reports suggest efficacy [41].
The most recently approved triazole, posaconazole, has not
been evaluated as extensively with regard to CNS efficacy and
no published or presented CNS kinetic studies are available at
this time. However, the in vivo activity of posaconazole has
been investigated in several animal models of CNS fungal
infections with Aspergillus, Cryptococcus and Phaeohyphomycosis.
In these studies, posaconazole was administered using clinically relevant dosing regimens and compared with either AmB
or another triazole. Without exception, outcome following
posaconazole therapy as measured by survival or fungal CNS
burden was equivalent or superior to the other therapies [45-48].
578
For example, Imai et al. found posaconazole therapy of CNS
aspergillosis in neutropenic mice to be equivalent to AmB at
reducing brain parenchymal organism burden [46]. It will be
important for future studies to include kinetic investigation in
the CNS. Given the structural similarities to itraconazole, one
would anticipate low CSF concentrations, but significant
accumulation in the brain parenchyma. Few anecdotal reports
detail successful use of posaconazole for CNS fungal infections
in humans [49].
Echinocandins
The CNS pharmacokinetics of each of the three available
echinocandin compounds, caspofungin, micafungin and
anidulafungin, has been studied in detail using a non-infected
rabbit model [50-52]. In each instance, the investigators have
reported undetectable CSF concentrations even using dose levels far exceeding those used in current clinical regimens. However,
these same investigations found brain parenchymal concentrations
in the range of 10 – 20% of those measured in serum. For
example, Groll et al. performed extensive tissue distribution
studies with anidulafungin in healthy rabbits [51]. Although a CSF
assay for anidulafungin did not identify a measurable amount
of drug, brain parenchymal concentrations ranged 0.24 – 3.9 µg/g
over a dose range of 0.5 – 10 mg/kg [51]. These tissue concentrations exceed the MIC90 of fungal pathogens in the echinocandin
spectrum and would be anticipated to be sufficient for treatment success. This same research group has undertaken similar
investigation of the CNS kinetics of caspofungin and
micafungin and report nearly identical findings [50,52].
Numerous animal model studies have examined the efficacy
of each of the echinocandin drugs in CNS fungal infection
models [53-57]. Comparative studies using these models have
examined echinocandin efficacy relative to other antifungal
drugs and have demonstrated therapeutic equivalence. For
example, Imai and colleagues compared the efficacy of conventional amphotericin, ABLC and caspofungin in a murine
model of CNS aspergillosis [53]. Caspofungin prolonged
survival in > 80% of infected animals when compared to
controls [53]. Similar observations were made by Ibrahim and
colleagues in a murine model of zygomycosis [54]. Singh et al.
and Hussain et al. both found clinical efficacy of caspofungin
in murine models of CNS aspergillosis and azole resistant
candida meningitis, respectively [55,56]. Each of these studies
did not include pharmacokinetic assays. However, in a
recent study by Hope et al., micafungin was evaluated in a
rabbit model of Candida meningoencephalitis. in which detailed
kinetic evaluation was incorporated [58]. Similar to previous
kinetic evaluation of micafungin, CSF concentrations were
undetectable. However, parenchymal and meningeal concentrations of micafungin exceeded the MIC90 of the infecting
organisms. In fact, the micafungin concentrations in the
meningeal tissues were 10-fold greater than the brain parenchyma. The relationship between parenchymal micafungin
concentrations and reduction in CNS Candida burden in
Expert Opin. Drug Metab. Toxicol. (2007) 3(4)
Kethireddy & Andes
these experiments were strong. Furthermore, the tissue
concentrations in these infected animals were nearly 30%
greater than those previously observed in models without CNS
inflammation [58]. Human CNS kinetic data with these
compounds are not available. However, there are anecdotes
and small case series suggesting clinical efficacy of caspofungin
for patients with CNS fungal infection [59-62].
8.
Expert opinion
Understanding the pharmacokinetics of antimicrobial
compounds at the site of infection is important to optimize
drug choice and dosing regimen design. The CNS represents a
critical tissue site due to poor outcome of fungal infection at
this site and variable kinetics due to the CNS blood barrier.
The CSF kinetics of all available antifungals has been
characterized in the CSF and brain parenchyma in animal
models. Kinetics of these drugs differs markedly in the CSF.
1.
2.
•
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However, each of the available drugs has been demonstrated to
accumulate in the brain parenchyma at concentrations
exceeding the MIC90 values of most infecting pathogens.
Fewer clinical studies are available to corroborate these data.
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Affiliation
Shravan Kethireddy & David Andes†
†Author for correspondence
University of Wisconsin School of Medicine
and Public Health, Madison 600 Highland Ave,
H4/572, Madison, WI 53792, USA
Tel: +1 608 263 1545; Fax: +1 608 263 4464;
E-mail: [email protected]
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