Download Making sense of itraconazole pharmacokinetics

Journal of Antimicrobial Chemotherapy (2005) 56, Suppl. S1, i17–i22
doi:10.1093/jac/dki220
Making sense of itraconazole pharmacokinetics
Archibald Grant Prentice1* and Axel Glasmacher2
1
Department of Haematology, Royal Free Hospital, Pond Street, London NW3 2QG, UK;
2
Department of Internal Medicine I, University of Bonn, Bonn, Germany
The triazole, itraconazole, has a wide spectrum of antifungal activity in vitro. Confirming this activity in vivo
has been a long and difficult task because of problems with formulation, delivery and uncertainty about
effective bioavailability. The physicochemical properties of the drug make it insoluble in water but strongly
protein bound. The absorption and blood levels of the original capsular formulation were predictable with
non-linear, saturation kinetics in normal volunteers. Tissue penetration was high and sustained. In neutropenic patients with haematological malignancies, levels were very variable and the doses required to
achieve effective antifungal levels were higher than predicted from normal subjects’ results. The solubility
of the drug and predictability of blood levels were improved by the formulation of an oral solution with
cyclodextrin. Wash-out times were prolonged in patients with this new formulation implying that tissue
penetration was maintained. A high volume of distribution suggests that loading may be necessary. An
intravenous cyclodextrin solution is also now available allowing rapid loading and avoidance of the wellknown gut side effects of the oral solution. Clinical studies have suggested minimum bioavailable dosage
and minimum trough blood levels for effective prophylaxis against systemic fungal infection. Interactions
are also now well documented and manageable. The drug can be measured reliably, quickly and comparatively cheaply by HPLC in serum and plasma. The frequency of such testing in clinical practice depends on
the need to ensure adequate levels and to avoid unwanted toxicity.
Keywords: drug levels, systemic fungal infections
Introduction
The azole group of synthetic aromatic compounds (imidazoles and
triazoles) are all structurally similar with a five-membered azole
ring and a complex side chain. They have a broad range of mostly
fungistatic activity which varies significantly between the
members of the group and two in vitro studies have shown that
itraconazole may be fungicidal against certain species in certain
concentration ranges.1,2 The introduction of these orally administered and systemically active antifungal agents was a major
development in therapeutics but, despite repeatedly encouraging
results from the clinical investigation of itraconazole over more
than 20 years, its use in antifungal prophylaxis has increased relatively slowly. Early anecdotal evidence suggested the efficacy of
capsule formulations, even with relatively poor bioavailability,
provided that adequate serum drug levels could be achieved.
Then improved bioavailability of newer oral and intravenous
(iv) solutions offered potentially greater protection for more
patients. Why has the clinical development of this drug taken so
long whilst it has been shown simultaneously to be so safe and so
effective in so many patients?
While there have been expensive and protracted difficulties in
improving bioavailability, there are still problems of compliance
with the oral solution and the drug has idiosyncratic and more
universal (but manageable) side effects. There is also widespread
scepticism amongst many haematologists and microbiologists
about the need for any anti-infective prophylaxis in our patients.
However, these problems alone do not explain the relative commercial inertia of this drug when compared with the more successful efforts in market penetration of rival products with inferior
evidence of efficacy. The clinical activity of itraconazole is
determined not only by its wide in vitro antifungal spectrum of
activity but also by its handling in vivo.
Physicochemical characteristics
The absorption, metabolism and elimination of any drug are
dependent on the physical and chemical properties of its structure.
The concentration of a drug in any part of the body is determined
by these processes and the time course of drug concentrations in
different parts of the body for any given dose determines the
pharmacokinetic (PK) profile. This profile will affect the clinical
efficacy of the drug.
Itraconazole, like all triazoles, has three nitrogen atoms in
its azole ring which might improve tissue penetration, prolong
.............................................................................................................................................................................................................................................................................................................................................................................................................................
*Corresponding author. Tel: +44-20-7472-6100; Fax: +44-20-7830-2092; E-mail: [email protected]
.............................................................................................................................................................................................................................................................................................................................................................................................................................
i17
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Prentice and Glasmacher
Table 1. Basic pharmacokinetic data for itraconazole7,8,10
Volume of distribution (VD SS)
Protein binding
Apparent terminal elimination
half-life in steady state (tg 1/2 SS)
Elimination route
Dose reduction in renal failure
Dose reduction in liver failure
CNS penetration in healthy animals
Relation lung tissue to serum concentration
11 L/kg
99%
34 – 9 h
liver metabolism
no (oral form)
drug monitoring
low
3 : 1
half-life and increase specificity for fungal enzymes.3 The nitrogen
atoms interact with the haem iron of the fungal cytochrome P450
3A (CYP3A), inhibiting the function of lanosine 14a-demethylase
which converts lanosterol to ergosterol, the main sterol in the
fungal cell membrane.4 This inhibits replication and promotes
cell death, or, in the case of yeast cells of Candida albicans, transformation into hypothetically invasive hyphae.5 Itraconazole has
little effect on mammalian cytochrome P450 enzymes even at high
concentrations6 or on the sterol and steroid pathways of the human
pituitary–adrenal–testicular axis.7
Itraconazole is a very weak base (pKa = 3.7), is ionized at a
low pH such as in gastric secretion, and is highly lipophilic being
practically insoluble in water and in dilute acid solutions. Concentrations greater than 10 mg/mL can be achieved in organic solvents
such as dimethyl sulphoxide or acidified polyethylene glycols
(PEGs) and aqueous solutions at a concentration of 5 mg/mL
require the addition of 5% dimethyl-b-cyclodextrin (cyclodextrin).
Thus the physicochemical properties of this drug could both
proffer beneficial broad-spectrum antifungal activity, strong protein binding (99.8%), tissue saturation and prolonged half-life and
limit oral delivery of adequate bioavailability. Pharmacokinetic
studies in animals and humans, and clinical trials illustrate this
conflict and reveal how it may have been resolved. Table 1
gives a summary of the basic pharmacokinetic properties of
itraconazole.
Animal studies
Studies in animals have shown that itraconazole has a much
higher volume of distribution and longer elimination half-life
than other imidazoles, with stable tissue concentrations of itraconazole which were higher than plasma concentrations on repeated
dosing. The ratio of tissue to plasma levels varied from 3 : 1 for
lung to 10 : 1 for liver and over 25 : 1 for fat. These findings
confirmed itraconazole’s potential for penetration of tissues and
therefore continuous and superior bioavailability at sites of tissue
infection.8 Very little drug is found in aqueous body solutions such
as the tears, saliva and CSF but any bodily fluid rich in organic
matter, such as sputum, bronchial exudates and even pus, will
contain high concentrations.
These studies also suggested that oral absorption (and therefore
bioavailability) of itraconazole improved with food and was
dependent on dose. As the dose of itraconazole was increased
from 50 to 200 mg, increases in the area under the curve (AUC)
and maximum concentration (Cmax) were non-linear, implying
saturation of the first pass sites for metabolism by hydroxylation
in the gut mucosa and liver.
At doses of 5 to 10 mg/kg, itraconazole may be superior to
amphotericin B against superficial and systemic infections with
Aspergillus spp., Candida albicans and a range of other moulds9–11
and the cyclodextrin solution was effective intravenously in the
treatment of experimental systemic Aspergillus and Candida
infections in immunocompromised animals.10
Perhaps the most significant result of a pharmacokinetic or
pharmacodynamic animal study was that reported by Berenguer
et al.12 This showed a strong inverse relationship between plasma
concentrations of itraconazole and the pulmonary burden of
Aspergillus fumigatus following therapy for experimental infection
(r = 0.87, P < 0.001). This provided further evidence of the potential for tissue bioavailability of this drug and implied that a minimal
concentration might be needed for effective therapy or prophylaxis.
Studies in normal volunteers
As in animal studies, absorption of itraconazole from oral capsules
has been shown to be improved after food in studies of normal
human volunteers.13 Non-linear, saturation kinetics were confirmed in these studies; the Cmax after a dose of 200 mg per day
was 147% higher than the Cmax after a dose of 100 mg per day at
day 1, but 160% higher at day 15, and the AUC was three or four
times greater for each dosage measured between days 1 and 15.
Extensive tissue binding has been shown in women undergoing
hysterectomy14 after a single 200 mg dose of the drug and in skin
scrapings and hair from normal subjects after 28 days of 100 mg
daily.8 Very little drug has been shown to be excreted unchanged
by the kidney.
In addition to dose dependency and a mean absolute bioavailability of 55%, studies with capsules in normal subjects have
shown marked inter-subject variation in plasma concentrations.8,13
Absorption from capsules has been shown to be reduced by a mean
of 20% by concomitant use of the H2-antagonists cimetidine and
ranitidine.15
The potential combination of the capsules’ intrinsically low
bioavailability, poor diet and the use of such antacids in clinical
practice led the development of pharmacokinetic studies of the
cyclodextrin oral solution. In normal subjects, this increased
bioavailability by 30–37% after single dosing and by 23–31% at
steady state with multiple dosing.16 It has been estimated that the
bioavailability of itraconazole from the oral solution taken in fasting conditions may be up to 60% higher than from capsules taken
after food. Studies in normal volunteers have also shown that the
first pass metabolite of the drug, hydroxy-itraconazole, accumulates at approximately twice the rate of the parent drug. This form
of the drug has a similar spectrum of antifungal activity in vitro,
thus increasing overall absolute bioavailability of oral drug further
to at least 80%.17
Pharmacokinetics in haematological patients
In haematological malignancy, the primary aim of pharmacokinetic studies has been to determine whether sufficient levels of drug
could be obtained reliably to provide effective prophylaxis against
systemic fungal infection. When these studies began, there was
evidence that plasma levels above 250 ng/mL could protect against
invasive pulmonary aspergillosis.18 The question of whether the
drug is effective therapy for such infections has been pursued with
less interest. To what extent do studies in animals and normal
i18
Neutropenic antifungal prophylaxis depends on pharmacokinetics of itraconazole
631 – 358 ng/mL to 1292 – 357 ng/mL and from 8770 –
5050 ng·h/mL to 25 154 – 6460 ng·h/mL, respectively. Children
appeared to be the only group of patients in whom the Cmin at
14 days did not usually exceed 500 ng/mL. The co-existence of
even severe mucositis and the concomitant use of H2 antagonists
did not appear to reduce these levels significantly in the adult chemotherapy or transplant patients. In the children at day 14 however,
levels of hydroxy-itraconazole were much higher than those of the
parent drug with Cmin at 437 – 246 ng/mL and AUC at 13 450 –
7190 ng·h/mL.25 In adult studies where hydroxy-itraconazole was
measured, there was confirmation of the greater rate of accumulation
of this first pass metabolite as was first seen in normal volunteers.17
The studies in adults given chemotherapy for acute myeloblastic
leukaemia24 and autologous stem cell transplantation26 showed that
a single daily dose of 5 mg/kg is as effective in achieving adequate
steady-state plasma levels as half this dose given twice daily.
The high volume of distribution of itraconazole suggests that
loading doses are necessary to reach clinically active trough concentrations quickly and reliably. According to standard pharmacokinetic equations, 11 mg/kg of itraconazole must be available
to reach a trough concentration of 1000 ng/mL. Using a combination of capsules (800 mg/day from day 1 to 7) and oral solution
(400 mg per day starting on day 1 until the end of therapy)28 or by
combining the same oral solution dose with intravenous solution
(400 mg per day on day 1 and 2) (A. Glasmacher and C. Hahn,
unpublished observations), the majority of patients can be shown to
reach trough concentrations of itraconazole above 1000 ng/mL at
the end of the first week (Figure 1).
Such serum concentrations are relevant to the published breakpoint of 1000 ng/mL (marking resistance) to test the in vitro susceptibility of itraconazole in Candida spp.29 This breakpoint does
not include the equally active first pass metabolite, hydroxyitraconazole, which accumulates at approximately twice the rate
of the parent drug. Most patients will achieve higher concentrations
of itraconazole provided they receive adequate doses. In the patient
cohort in Bonn, 97.6% of neutropenic patients with haematological
malignancies who received oral itraconazole solution and a loading dose of capsules had combined itraconazole and hydroxyitraconazole trough concentrations over 1000 ng/mL, 92% had
over 1500 ng/mL, 83.5% had over 2000 ng/mL and 49.5%
had over 3000 ng/mL (A. Glasmacher and C. Hahn, unpublished
observations).
4000
Itraconazole (ng/mL, HPLC)
subjects predict the results of pharmacokinetic studies and clinical
trials in patients? The first randomized controlled trial of itraconazole capsules as prophylaxis, in patients being treated for
haematological malignancy, was abandoned in the UK in 1985
because so many patients had undetectable drug in the plasma.
In retrospect, this result could have been predicted and was followed by several pharmacokinetic studies of the capsule in such
patients.
A double-blind cross-over study of PEG and pelleted forms of
the itraconazole capsule (200 mg daily) in patients receiving remission induction therapy for acute myeloblastic leukaemia showed
that a significant number of patients had levels below 250 ng/mL
and that there was wide inter- and intra-patient variation in levels
with both preparations.19 This study also showed that the day 14
median Cmax was approximately half that obtained with half the
dose used in normal volunteers,8 even with good compliance, and
compliance was in fact variable. In another study, even with daily
doses of 400 and 600 mg of the capsule, plasma levels of greater
than 250 ng/mL were not reliably obtained by day 10 in patients
receiving chemotherapy for acute leukaemia or in those receiving
an autologous bone marrow transplant.20
Despite these discouraging results, one key retrospective comparative study of the use of the capsule form of the drug during
chemotherapy for acute leukaemia (76 patients and 148 courses)
versus no systemic prophylaxis (47 patients and 112 courses) did
suggest both that higher plasma levels can be obtained with higher
doses and that these significantly reduce the risk of systemic fungal
infections.21 The end point was death from proven systemic fungal
infection, which was reduced in the itraconazole patients from
8.8% to 0.9% (P = 0.005). In those patients given 400 mg daily,
the median trough plasma concentration was 520 ng/mL (range
230–793 ng/mL) and in those given 600 mg daily 760 ng/mL (370–
1200 ng/mL). Another retrospective analysis of incidence rates of
breakthrough proven or probable systemic fungal infection in the
treatment of haematological malignancy receiving itraconazole
prophylaxis showed that trough (Cmin) plasma itraconazole concentrations of less than 500 ng/mL carried a significantly increased
risk (P = 0.039) of invasive yeast but mainly pulmonary aspergillosis infections.22 Many of the patients in this last study
had received the capsule form of the drug. In vitro, most Candida
and Aspergillus spp. are inhibited by itraconazole concentrations
greater than 1000 ng/mL.23 The co-existence of equally effective
hydroxy-itraconazole, at concentrations approximately twice that
of the parent drug,16 should ensure such overall antifungal activity
in vivo. These human studies also confirm the animal model correlating plasma itraconazole levels with the pulmonary burden of
aspergillosis.12
Dissatisfaction with the reliability of bioavailability of the capsule form of the drug in neutropenic patients with haematological
malignancy led to pharmacokinetic studies in these patients of the
cyclodextrin solution which had provided much greater Cmax and
AUC values in normal volunteers. There have now been pharmacokinetic studies of the cyclodextrin solution in patients receiving intensive chemotherapy for acute myeloblastic leukaemia,24
children treated for a variety of haematological malignancies,25
patients receiving stem cell autografts for haematological malignacies26 and those receiving allogeneic stem cell transplants for
leukaemia.27 By day 14 or 15 after daily doses of 5 mg/kg, means
(– standard deviation) of Cmin range from 223 – 145 ng/mL in the
children to 845 – 221 ng/mL in the adults treated for acute
myeloblastic leukaemia. The Cmax and AUC values range from
3000
2000
1000
0
Day 3
Day 7
Day 11
Day 20
Figure 1. Itraconazole trough concentration after combining 400 mg/day
itraconazole oral solution (starting on day 1) with itraconazole iv solution
(400 mg/day on day 1 and 2). The line marks 500 ng/mL (A. Glasmacher and
C. Hahn, unpublished observations).
i19
Prentice and Glasmacher
When either formulation is used alone, all studies suggest that
the oral solution is more bioavailable than the capsule form.
Loading as described above will reduce inter-patient variation
and increase the probability of high levels. Variation in PK profiles
is due not only to variable bioavailability but also to interindividual variation of the cytochrome P450 genotypes which
express phenotypically variable rates of metabolism of all azoles.
In addition, a significant proportion of patients will not tolerate the
taste of the oral itraconazole solution30 and variable ingestion is a
powerful determinant of variation of bioavailability of any oral
preparation. In clinical practice, it is not clear how often blood
levels should be measured but in patients at high risk of systemic
fungal infections, where absorption or compliance are uncertain or
where unnecessarily high levels are possible, weekly measurement
of trough levels is recommended. The application of the HPLC
method would require a small investment compared with the overall cost of care and to the likely benefit of reducing risk.
The intravenous preparation of the cyclodextrin solution circumvents all the problems of bioavailability and poor compliance
although it cannot influence cytochrome P450-determined rates of
metabolism. In two pharmacokinetic studies of switching from oral
to iv use, the iv preparation has been used to either load patients
quickly at induction of neutropenia before switching to oral solution31 or to substitute for the oral solution should compliance fail.32
The latter study illustrated that levels of drug continued to rise with
a daily dose of 200 mg iv and that the rate of rise of hydroxyitraconazole slows on switching to the iv preparation, presumably
because the rate of exposure to hepatic hydroxylation is reduced.
These results indicate that less than 200 mg daily iv may provide
adequate bioavailability and support further the need for measurement of plasma levels.
Interactions
Although itraconazole exhibits greater specificity for fungal than
for human and other mammalian CYP450, its binding to nonfungal types has been extensively investigated in vitro and in vivo.
Itraconazole’s inhibition of rat microsomal enzyme activity was
weak, it did not induce hepatic drug-metabolizing enzymes, and
even at high doses, it did not interact in vitro with coumarins or
methohexital.33,34 It did not change the pharmacokinetics of antipyrine, a marker of microsomal oxidation, when given to normal
volunteers.35
There is, nevertheless, a long list of drugs known to interact with
itraconazole and these interactions can be divided into those which
affect itraconazole levels and those affecting levels or activity of
others.36 Metabolism of itraconazole is induced by rifampicin,
carbamazepine, phenytoin, phenobarbitone and isoniazid. Absorption of itraconazole is potentially reduced by any drug which
reduces gastric acid. These preceding interactions further justify
measurement of plasma levels of itraconazole with subsequent
dose adjustment.
The second group of interactions is perhaps more important. The
metabolism of cyclosporin, tacrolimus and digoxin is reduced and
their concentrations should be monitored to adjust doses as necessary. Midazolam, triazolam, cisapride, terfenadine and astemizole
should be avoided because of potentially dangerous increases in
their levels being induced by itraconazole. Calcium channel blockers should also be avoided if possible or at least there should be
careful monitoring of the ECG because of prolongation of the QT
interval with concomitant use of itraconazole. Coumarin derivatives may also be potentiated, so close monitoring of coagulation
tests is needed. Itraconazole should be avoided in combination with
vincristine and probably other vinca alkaloids because of the risk of
severe neurotoxicity. There are no descriptions yet of the clinical
interactions between itraconazole and the taxanes and busulphan
but there is a theoretical possibility of these and concomitant
administration is best avoided.
The most serious interaction is probably least known since it
has only recently been reported. In a randomized controlled trial of
itraconazole versus fluconazole in bone marrow transplant patients,
an excess of clinically significant renal and hepatic toxicity was
observed in the itraconazole arm with a lower probability of
survival.37,38 The hepatic toxicity was worst in the patients
conditioned with cyclophosphamide and preliminary analysis of
cyclophosphamide pharmacokinetic data suggests that these toxicities are related to an interaction leading to an excess of cyclophosphamide metabolites. When the trial protocol was amended,
from starting itraconazole with conditioning to starting at day 0 on
stem cell infusion, the difference in these toxicities in the two arms
was no longer apparent. It should be noted however that these
patients were given the highest recorded dose of itraconazole
for prophylaxis at 7.5 mg/kg per day, that most patients were
given iv drug and it is not clear how many patients needed dose
reductions if their plasma levels were deemed too high. A similar
comparative study in transplant patients, given itraconazole and
fluconazole only after conditioning therapy, found no excess
toxicity with itraconazole.39
Pharmacokinetic studies have shown that potentially protective
plasma concentrations of itraconazole can be delivered by all the
cyclodextrin preparations of the drug available. The itraconazole
trough concentration should be above 500 ng/mL. Bioavailability is
only absolutely reliable if the drug is given iv but the solution
achieves greater levels than the capsule. It is possible to switch
between the iv and the oral solutions depending on compliance,
but, considering the high volume of distribution of the drug, oral
or iv loading doses are needed to reach protective levels quickly.
Owing to the inter-patient variation of bioavailability and metabolism (which is seen in all azoles), there is no way of predicting
levels in individual patients so these should be routinely measured
to ensure adequate bioavailability. The iv dosing schedule which
will not result in a continuing rise in serum levels is not yet known
and it is not clear from clinical studies if there is a maximum
tolerable level. The contribution of hydroxy-itraconazole to effective bioavailability has been underestimated in many pharmacokinetic and in vitro susceptibility studies. In patients at high risk of
systemic fungal infection, weekly trough level measurements may
be necessary to ensure potentially protective trough levels. There
are serious interactions but with careful management, these can be
either avoided or monitored to reduce their clinical impact.
Understanding the pharmacokinetic properties of itraconazole
has informed attempts to demonstrate its clinical efficacy in reducing the risk of systemic fungal infection in the therapy of haematological malignancy.
Transparency declarations
A. G. P. has received reimbursement for attending advisory boards
and symposia from Janssen-Cilag, Johnson and Johnson, OrthoBiotech, Pfizer, Gilead, Merck and Schering-Plough, for speaking
i20
Neutropenic antifungal prophylaxis depends on pharmacokinetics of itraconazole
from Janssen-Cilag, Gilead, Merck and Pfizer and as a consultancy
fee from Ortho-Biotech/Janssen-Cilag but to his knowledge does
not own directly any shares in any pharmaceutical company.
A. G. has received the following: Gilead (speaker’s honoraria),
Janssen-Cilag/Ortho-Biotech (consultant, research support,
speaker’s honoraria), Merck Sharp & Dohme (consultant, research
support, speaker’s honoraria), Pfizer (research support,
speaker’s honoraria), Schering-Plough (consultant).
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