Clinical Primer:

Potential Hepatic Complications

With Triazole Therapy

Jointly sponsored by the University of Wisconsin-Madison School of Medicine and

Public Health, School of Pharmacy, and School of Nursing and Fallon Medica LLC

Supported by an educational grant from Pfizer Inc.

Continuing Medical Education/Continuing Education (CME/CE) Information
Statement of Need
Invasive fungal infections (IFIs) present a looming worldwide public health problem and a treatment challenge to physicians, pharmacists, and
other clinicians. Over the past 2 decades, IFIs have become an increasing source of morbidity and mortality in the United States, particularly in
immunocompromised and hospitalized patients with underlying diseases. This US problem is mirrored in the European setting, which recently spurred
international collaboration on the topic to better understand the epidemiology of these infections and move forward with more effective clinical trials
for therapy and outcomes. As newer agents are developed for IFIs, the troublesome effects of resistance and toxicity make the proper clinical selection
of an antifungal agent and specific dosing and administration strategies increasingly important for assuring effectiveness and patient safety.

Target Audience and Scope of Practice

This educational activity has been designed to meet the needs of clinicians and other health care professionals who manage invasive fungal infections.

Elements of Competence
This CME activity has been designed for practice-based learning and improvement, 1 of the 6 competencies embraced by the American Board of
Medical Specialties.

Learning Objectives
Upon completion of this activity, participants should be able to:
•• Identify risk factors for developing triazole toxicity
•• Implement a strategy to use therapeutic drug monitoring (TDM) for appropriate patients on triazole therapy in clinical practice
•• Adjust triazole therapy using TDM, based on the attributes of specific therapies as well as on patient factors
Authors Educational Reviewers
William W. Hope, MD David R. Andes, MD
Clinical Senior Lecturer Associate Professor
University of Manchester Department of Medicine and Medical Microbiology and Immunology
Manchester Academic Health Science Centre Section of Infectious Diseases
NIHR Translational Research Facility in Respiratory Medicine University of Wisconsin
University Hospital of South Manchester NHS Foundation Trust Madison, Wisconsin
Manchester, United Kingdom
Harry A. Gallis, MD
Russell Lewis, PharmD Consulting Professor of Medicine
Associate Professor Internal Medicine/Infectious Diseases
University of Houston College of Pharmacy Duke University
University of Texas M.D. Anderson Cancer Center Durham, North Carolina
Houston, Texas
Julia Greenleaf, MS, MPH, RN
Jeannina A. Smith, MD University of Wisconsin-Madison School of Nursing
Clinical Assistant Professor Madison, Wisconsin
Division of Infectious Diseases
University of Michigan Medical School
Ann Arbor, Michigan

Accreditation Information
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing
Medical Education (ACCME) through the joint sponsorship of the University of Wisconsin School of Medicine and Public Health and Fallon
Medica LLC. The University of Wisconsin School of Medicine and Public Health is accredited by the ACCME to provide continuing medical
education for physicians.

Credit Designation Statement

The University of Wisconsin School of Medicine and Public Health designates this enduring material for a maximum of 1 AMA PRA Category 1
Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Continuing Education Units

The University of Wisconsin-Madison, as a member of the University Continuing Education Association (UCEA), authorizes this program for 0.1
Continuing Education Units (CEUs) or 1 hour.

Pharmacy Information
Extension Services in Pharmacy at the University of Wisconsin-Madison School of Pharmacy is accredited by the Accreditation Council for
Pharmacy Education as a provider of continuing pharmacy education. Participants successfully completing this knowledge-based program
(documented participation based on a completed a program evaluation and posttest with a minimum score of 70%) will be eligible to receive
®

a maximum of 1 hour (0.1 CEUs). A Statement of Credit will be issued online after completion of the activity.

Universal Program Number: 073-999-09-135-H01-P

Nursing Information
The University of Wisconsin-Madison Continuing Education in Nursing is accredited as a provider of continuing nursing education by the American
Nurses Credentialing Center (ANCC) Commission on Accreditation.

Iowa Provider Number: 350

This activity has been planned and implemented using the educational design criteria of the ANCC Commission on Accreditation through the joint
providership of the University of Wisconsin-Madison Continuing Education in Nursing and the other providers. 1.0 ANCC Contact Hours (1.2
Iowa) will be awarded for successful completion of this activity based on documented participation and attainment of minimum score of 70% on
posttest. Awarding of contact hours does not imply product endorsement.

Statement of Policy on Faculty and Sponsor Disclosure

It is the policy of the University of Wisconsin-Madison School of Medicine and Public Health, School of Pharmacy, and School of Nursing that
the faculty, authors, planners, and other persons who may influence content of this CME/CE activity disclose all relevant financial relationships
with commercial interests* to allow CME/CE staff to identify and resolve any potential conflicts of interest. Faculty must also disclose any planned
discussions of unlabeled/unapproved uses of drugs or devices in their manuscript(s). For this educational activity all conflicts of interests have been
resolved, and detailed disclosures are listed below.

Discussion of unlabeled/unapproved
Name Financial relationship disclosures uses of drugs/devices in manuscript?
David R. Andes, MD Principal Investigator: Astellas Inc.; Merck & Co, Inc.; No
Pfizer Inc.; Schering-Plough; Novartis
Harry A. Gallis, MD No relevant relationships to disclose. No

Julia Greenleaf, MS, MPH, RN No relevant relationships to disclose. No

William W. Hope, MD Principal Investigator: Schering-Plough No

Speaker: Pfizer Inc.; Schering-Plough
Russell Lewis, PharmD Investigator: Astellas Inc., Enzon Inc., Merck & Co, Inc. No
Speaker: Merck & Co, Inc.
Jeannina A. Smith, MD No relevant relationships to disclose. No

*The ACCME defines a commercial interest as any entity producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients.
The ACCME does not consider providers of clinical service directly to patients to be commercial interests.

Method of Participation
This monograph should take 1 hour to complete. There are no prerequisites and there is no fee to participate in this activity or to receive a Statement
of Credit. Statements of Credit are awarded upon successful completion of the posttest and evaluation form. The participant is required to receive a
minimum test score of 70% to receive a Statement of Credit.

To Obtain Credit for This Activity

To obtain credit for this activity, you must go to www.doctorfungus.org/triazole and choose the type of credit you are seeking, complete an online
registration on the respective Web site, and review and complete a posttest and evaluation.

This activity will be valid for credit through November 4, 2011. No credit will be given after that date.

Commercial Supporter
The University of Wisconsin-Madison School of Medicine and Public Health, School of Nursing, and School of Pharmacy and Fallon Medica LLC
would like to gratefully acknowledge Pfizer Inc. for providing an educational grant.

Activity Original Release Date:

November 4, 2009

Activity Reviewed and Renewed Date:

November 4, 2010

Expiration Date:
November 4, 2011

© 2010 The University of Wisconsin Board of Regents and Fallon Medica LLC.
Table of Contents

Introduction 1
David R. Andes, MD

Triazole Adverse Effects, Toxicity, and Safety 2

Russell Lewis, PharmD

Therapeutic Drug Monitoring With Triazole Antifungals 8

Jeannina A. Smith, MD

Toxicodynamics of the Azoles: A Focus on Hepatotoxicity 15

William W. Hope, MD
Introduction
David R. Andes, MD, Associate Professor, Department of Medicine and Medical Microbiology and
Immunology, Section of Infectious Diseases, University of Wisconsin, Madison, Wisconsin

Invasive fungal infections represent a serious global health problem. They are associated with increasing morbidity
and mortality, particularly in susceptible patients with underlying disease or compromised immunity.1,2 Although the
introduction of triazole antifungals expanded the therapeutic arena, offering a broader spectrum of activity and the option
of oral therapy,3 management with an appropriate antifungal agent has become more complex as the threat of antifungal
resistance grows and questions arise about the hepatic effects of specific agents.4 For example, questions about the hepatic
effects of a recent second-generation triazole, voriconazole, were raised in 2007 by the European Medicines Agency, the
European equivalent of the US Food and Drug Administration (FDA). These questions arose because of an apparent increase
in the number of hepatotoxic events during the reporting period (March 2006-February 2007).
Current FDA-approved triazole agents (fluconazole, itraconazole, posaconazole, and voriconazole) are widely prescribed
for invasive fungal infections, and several other triazoles are in development (albaconazole, isavuconazole, ravuconazole).
Although the relative risk of liver toxicity with triazoles appears low, dose-limiting toxicities and pharmacokinetic drug-drug
interactions may complicate the use of these agents.5 In the current environment, clinicians should be familiar with the adverse
effects and drug interactions that may occur with triazoles, as well as proactive strategies for the safe and effective use of these
agents, such as therapeutic drug monitoring (TDM).5
This monograph identifies risk factors for developing triazole toxicity, provides guidance on implementing a strategy to use
TDM for appropriate patients on triazole therapy in clinical practice, and describes how to adjust therapy using TDM, based
on the attributes of specific therapies as well as on patient factors.

REFERENCES
1.  faller MF, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007;20(1):133-163.
P
2. McNeil MM, Nash SL, Hajjeh RA, et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis. 2001;33(5):641-647.
3. Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect. 2004;10(suppl 1):1-10.
4. Brüggemann RJ, Donnelly JP, Aarnoutse RE, et al. Therapeutic drug monitoring of voriconazole. Ther Drug Monit. 2008;30(4):403-411.
5. Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Ther. 2009;53(1):24-34.

1
 Triazole Adverse Effects, Toxicity, and Safety
Russell Lewis, PharmD, Associate Professor, University of Houston College of Pharmacy,
University of Texas M.D. Anderson Cancer Center, Houston, Texas

INTRODUCTION OH
N N
N CH2 C CH2 N
The introduction of triazole antifungals (fluconazole, N F N
itraconazole, voriconazole, and posaconazole) into clinical
practice was a milestone achievement in antifungal
chemotherapy. With triazole antifungals, oral medication for F

the reliable treatment of invasive fungal infections was possible Fluconazole38

for the first time. Additionally, triazoles are as effective as MW=306
amphotericin B for common pathogens1,2 yet exhibit significantly pKa=2
less nephrotoxicity. log P=0.2
Triazoles expanded the therapeutic options for effective
prophylaxis in solid organ3 and hematopoietic stem cell Cl Cl
transplant recipients.4,5 In addition, they have a proven ability CH2
N N *
to reduce the risk of serious morbidity or death from invasive O O
N
candidiasis4,6 and aspergillosis.7 * N
Although triazoles are safe for most patients, their use in H CH2O N N N
N
*CHCH2CH3
medically complex cases can be complicated further by dose- Itraconazole 39 O

limiting toxicities and pharmacokinetic drug-drug interactions. If MW=706

CH3

recognized early and appropriately managed, these adverse effects pKa=3.7

rarely lead to serious problems. Therefore, it is important for log P=5.7
prescribers to be familiar with the adverse effects of triazoles and
strategies for the proactive management of pharmacokinetic drug-
drug interactions in this widely prescribed class of antifungals. O
CH3
F F O N N N N
BIOPHARMACEUTICAL ASPECTS N OH
OF THE TRIAZOLE ANTIFUNGALS H 3C
O Posaconazole 40

N N MW=701
The triazole antifungals (see Figure) were developed with the
N pKa=3.6
goal of enhancing the affinity of the azole pharmacophore for
log P>3
fungal cytochrome P450 (CYP450) enzymes and improving
on the pharmacokinetic limitations of older agents such as
ketoconazole.8 N
N
N CH3 F

Fluconazole OH

Fluconazole, the narrowest-spectrum triazole antifungal, F N N

is highly water-soluble and circumvents much of the hepatic

metabolism required for elimination with other, more lipophilic F
triazoles. Consequently, fluconazole is excreted primarily (80%) Voriconazole32
in the urine as unchanged drug, with 2 inactive metabolites MW=349
accounting for the remaining dose.9 The hepatic metabolism of pKa=1.8
fluconazole becomes more extensive with increasing daily doses, log P=1.8
which can interfere with the clearance of other drugs metabolized
through CYP450 pathways (eg, cyclosporine).10 Similarly, MW=molecular weight; pKa=acid dissolution constant;
log P=logarithm of octanol-water partition constant.
inducers of mammalian CYP450, such as rifampin, increase
hepatic clearance of fluconazole, resulting in a ~50% reduction Figure. Pharmaceutical characteristics and spectrum of
in serum drug concentrations.11 triazole antifungals.

2
 The hydrophilic characteristics of fluconazole allow for
an intravenous (IV) formulation without the need for a
solubilizing agent, as well as an oral formulation featuring
excellent bioavailability (>90%) and absorption that does
not depend on acidic gastric conditions or food intake.12
Itraconazole, voriconazole, and posaconazole
Impact of gastric pH on absorption
Itraconazole, voriconazole, and posaconazole are more
lipophilic than fluconazole and, depending on the value
of their acid dissociation constant (pKa), may require
acidic gastric conditions and coadministration with food
for adequate absorption. Itraconazole (pKa 3.7) and
posaconazole (pKa 3.6) are weakly basic drugs with limited
water solubility that are best absorbed in the solid- or
suspension-dosage form when gastric pH is 1 to 4.13
Absorption of voriconazole is less affected by gastric
pH because of the drug’s improved aqueous solubility and
lower pKa value.14 Accordingly, potent acid-suppressing
therapies, such as histamine-2 receptor antagonists and
protein pump inhibitors, can significantly reduce the
absorption and dissolution of the solid-dosage formulations
of itraconazole and posaconazole, while having a relatively
minor impact on voriconazole.
The development of an oral solution formulation of
itraconazole, predissolved in 40% hydroxypropyl--
cyclodextrin, overcomes the problems of incomplete
dissolution of the capsules at a higher gastric pH, which
allows concurrent administration of the triazole and acid-
suppressive medication.14 Although the solution formulation
has improved absorption compared with the capsule (ie,
under fasted conditions, there is a 60% greater area under
the plasma concentration-time curve from 0 to 24 hours),
the gastrointestinal (GI) discomfort associated with the
unabsorbed cyclodextrin vehicle offsets this benefit. In fact,
about a third of patients discontinue itraconazole solution
because of GI intolerance.15,16
Renal metabolism and potential for toxicity
Cyclodextrin solutions have been used to develop IV
formulations of itraconazole (removed from market in
2008), voriconazole, and more recently, posaconazole
(in development). One concern with IV administration
of cyclodextrin is that the vehicle is cleared through the
kidney and will accumulate in patients with diminished
renal function. In animal studies, accumulation of high
cyclodextrin concentrations elicited osmotic damage to
the genitourinary system—ie, swelling and vacuolation
of renal proximal cortical cells and the urothelium of the
pelvis and urinary bladder.17 This toxic effect is believed to
be a transient, adaptive effect, similar to that observed with
plasma expanders, hypertonic sugar solutions, and dextrans.17
Although these effects have not been shown to produce
impaired renal function in humans, current labeling does
not recommend the use of IV voriconazole in patients
with moderate-to-severe renal impairment (ie, estimated
creatinine clearance <50 mL/min), unless the benefit
justifies the potential increased risk of toxicity.
Hepatic metabolism and toxicity risks
Itraconazole, voriconazole, and posaconazole undergo
varying degrees of hepatic metabolism before being
excreted as (primarily) inactive metabolites. Posaconazole
is excreted chiefly (~66%) as unchanged drug in the
feces, although a portion of the drug undergoes
glucuronidation before excretion in the urine.18,19
Itraconazole is extensively metabolized by intestinal and
hepatic CYP3A4, resulting in the formation of an active
metabolite, hydroxyitraconazole.20
The hepatic metabolism of voriconazole is more complex
than that of other triazoles, involving CYP2C19, CYP3A4,
and, to a lesser degree, CYP2C9. However, metabolism
through CYP2C19 is the most important determinant
of voriconazole plasma drug exposures because of genetic
variability in the metabolic capacity of this pathway.21,22
Patients who are homozygous poor metabolizers of
CYP2C19 will experience, on average, 4-fold higher
serum concentrations with standard voriconazole doses,
compared with patients who are heterozygous extensive or
homozygous extensive metabolizers.22 (Approximately 3%
to 5% of Caucasians and between 15% and 35% of Asian
populations in the United States carry a homozygous
allele for poor CYP2C19 metabolism.23) Recently, the
homozygous poor metabolism genotype has been linked
to an increased risk of hepatic toxicity during voriconazole
therapy in Japanese patients.24
PHARMACOKINETIC DRUG-DRUG
INTERACTIONS WITH TRIAZOLES
All triazole antifungals are reversible inhibitors of
CYP enzymes in humans.14 This is a collateral effect
of their antifungal mechanism of inhibiting the fungal
CYP450 enzyme involved in ergosterol biosynthesis—
14-demethylase. The most important drug interactions
seen with azole antifungals arise from their inhibition
of mammalian CYP3A4, which is responsible for the
metabolism of a third of all drugs prescribed for
cardiovascular, endocrine, psychiatric, or neurological
disorders, chemotherapy, or immunosuppression in
transplant patients.23
Although fluconazole is a relatively weak inhibitor
of CYP3A4 at lower doses, the hydrophilic azole is a
substrate and inhibitor of CYP2C8/9— the major
3
 metabolic pathway of warfarin elimination.25,26 Other more
lipophilic azoles (itraconazole, voriconazole, and
posaconazole) are potent inhibitors of CYP3A4. A
summary of important triazole interactions with other
drugs is presented in Table 1.
The clearance of itraconazole, voriconazole, and
posaconazole increases significantly in patients receiving
concomitant medications that accelerate CYP450
metabolism. Concomitant use of drugs such as rifampin
can result in low11 or undetectable concentrations of the
triazole in the bloodstream, raising the likelihood of
treatment failure.27-30 Increasing the triazole dose may
overcome the effects of weaker inducers (ie, phenytoin) but
may not be feasible with more potent CYP450-inducing
medications such as rifampin. Table 2 describes the
mechanisms of the enzyme induction in drug classes that
reduce serum triazole concentrations.
ADVERSE EFFECTS WITH
TRIAZOLE ANTIFUNGALS
In general, triazoles are well-tolerated antifungal agents
with relatively few dose-limiting toxicities (Table 3).
Adverse effects common to all triazoles include rash
(2%-9%), nausea or GI intolerance (2%-39%; higher with
itraconazole solution and posaconazole suspension), and
headache (1%-4%).
Drug-specific adverse reactions
Use of itraconazole has been associated occasionally
with negative inotropic effects and a unique triad of
hypertension, hypokalemia, and edema, especially in older
adults.31 Accordingly, itraconazole is not recommended in
patients with underlying congestive heart failure.
Several adverse effects are relatively unique to
voriconazole, including visual disturbances, hallucinations,
encephalopathy (at high drug exposures), and cutaneous
phototoxicity.32 Visual disturbances may develop in up to
a third of patients after the first dose of voriconazole,
possibly because of dose-dependent reversible changes in
conduction through photoreceptors of the retina.33 Visual
disturbances typically manifest as photopsia (ie, appearance
of bright lights, color changes, or wavy lines) or, less
commonly, chromatopsia (ie, yellow haze). These visual
disturbances are usually mild and transient, and abate
with continued treatment. Hallucinations and more severe
forms of central nervous system toxicity are less common
but may indicate excessive drug exposure.34,35 Additionally,
phototoxic rash has been reported in up to 8% of
voriconazole-treated patients with sunlight exposure.
Although the rash is not preventable with sunscreen, it
typically reverses after discontinuation of therapy.36
4
Hepatotoxic reactions
Hepatotoxic reactions are among the most common,
and potentially serious, adverse effects associated with
triazole therapy.37 The mechanism of hepatotoxicity is
classified typically according to liver function test (LFT)
results, although liver biopsy may be required to confirm
the diagnosis.
Reactions resulting in degeneration or necrosis of
hepatocytes (hepatocellular injury) typically manifest
with significant elevations (>3-fold) in serum alanine
aminotransferase (ALT) and aspartate aminotransferase
(AST) concentrations.37 In contrast, hepatotoxic reactions
that result in arrested bile flow (cholestatic injury) are
characterized by relatively modest serum ALT elevations,
but >4-fold alkaline phosphatase (ALP) elevations, in
addition to increases in bilirubin. Occasionally, triazole
therapy may be associated with a mixed pattern of liver
injury (hepatotoxic and cholestatic).37
Drug-specific hepatotoxicity
In triazole clinical trials, LFT elevations are the most
common treatment-related adverse effects that lead
to discontinuation of therapy. The overall incidence of
clinically significant transaminase abnormalities
reported in triazole clinical trials ranges from 1% in
fluconazole-treated patients to 12.4% in voriconazole-
treated patients.32,38-40
With voriconazole, higher serum drug concentrations
and/or doses have been associated with increased risk of
abnormal LFTs.41 Abnormal LFTs during triazole therapy
typically resolve as treatment is continued, or following
dose adjustments or discontinuation. Rare cases of
serious hepatitis and liver failure leading to patient death
have been reported for fluconazole, itraconazole,
voriconazole, and posaconazole.37 In most cases, patients
had other serious underlying medical conditions that
contributed to the poor outcome.33
Assessing and managing hepatotoxicity
Because drug-induced liver injury may occur with a variety
of other medications and overlaps with other syndromes
encountered in immunosuppressed patients (ie, graft-versus-
host disease, viral hepatitis, etc), a high index of suspicion
for triazole hepatotoxicity is important for establishing a
diagnosis. Patients in whom triazole antifungal therapy is
initiated should undergo serial measurements of AST, ALT,
ALP, and total bilirubin. Abnormalities in these serum
biochemistries during triazole therapy may be indicative of
triazole-associated hepatotoxicity if:
•• triazole exposure precedes the onset of evidence of
liver injury, although the latent period may range
from days to months;
Table 1. Major triazole CYP450-mediated drug interactions.

Drug Class
Chemotherapy agents
(vinca alkaloids, tamoxifen,
docetaxel, etoposide, paclitaxel,
cyclophosphamide, busulfan,
irinotecan, teniposide, imatinib)
Pharmacokinetic/
Pharmacodynamic Change
Serum concentration of chemotherapy agents
increased; alteration in the production of active
and toxic metabolites affecting drug efficacy and/
or toxicity.
Comment
Increased toxicity has been described with
coadministration of itraconazole with vinca alkaloids44,45
and cyclophosphamide.46 Concomitant use should be
avoided when possible.

Immunosuppressants Serum concentrations of immunosuppressants Trough concentrations of cyclosporin are increased

(cyclosporine, tacrolimus, sirolimus)
increased >2-fold, leading to toxicity.
2-fold47; cyclosporin doses should be reduced by 50%
(voriconazole) or 75% (itraconazole, posaconazole) and
serum drug concentrations monitored.
A two-thirds reduction in the tacrolimus dose is
recommended in patients started on mold-active triazoles
with follow-up serum drug concentration monitoring.48,49
Sirolimus concentrations increased by 90%.
Coadministration with voriconazole is contraindicated.48

Antiviral agents Likely increases in serum concentrations; may Avoid combination if possible, or closely monitor for
(protease inhibitors) result in increased toxicity. signs of toxicity.50,51
Antidepressants, antipsychotics Increased serum concentrations of Consider using lower starting doses of risperidone and
(risperidone, zolpidem, antidepressants, possibly resulting in more paroxetine and escalate slowly.32,48
paroxetine, haloperidol) side effects.
Cardiovascular agents Increased serum concentrations leading to Patients may require lower doses and careful monitoring
(HMG-CoA reductase inhibitors, increased potential for adverse effects. for adverse effects. Pravastatin, fluvastatin, or rosuvastatin
amiodarone dihydropyridine can be substituted for other HMG-CoA reductase
Itraconazole may exert additive negative
calcium channel blockers) inhibitors.48
inotropic effects with calcium channel blockers.
Anticonvulsants Increased serum concentrations, prolonged Check phenytoin concentrations when starting or
(phenytoin, benzodiazepines) sedation, or adverse effects with phenytoin. stopping triazoles.52
Analgesics Prolonged clearance resulting in Generally, long-acting formulations or agents should
(methadone, fentanyl, increased effects. be avoided with azoles. If necessary, analgesic should be
ergot alkaloids) initiated at lower doses.53
Ergot alkaloids are contraindicated with itraconazole,
voriconazole, and posaconazole.

Sulfonylureas Increased serum concentrations and risk
(glyburide, glipizide) for hypoglycemia.
Anticoagulants CYP2C9 is the major metabolic pathway for
(warfarin) warfarin. Decreased elimination will lead to
increases in INR and potential bleeding.
Gastric acid suppression Omeprazole serum concentrations are increased
(omeprazole) by 50% due to inhibition of CYP2C19
(voriconazole) and CYP3A4.
Corticosteroids 1.5- to 4-fold increases in serum AUC;
(methylprednisone, examethasone, possibility of increased immunosuppression
prednisone, budesonide) and/or metabolic effects.
Oral contraceptive agents Increased serum concentrations through
inhibition of CYP3A4 and 2C9.
Drugs with potential Increased serum concentrations leading to
for QTc prolongation inhibition of the myocardial potassium channels
(cisapride, terfenadine, astemizole, (Ikr) and premature ventricular complexes or
pimozide, quinidine, dofetilide, etc) self-sustaining ventricular arrhythmia (Torsades
de Points).
HMG-CoA=3-hydroxy-3-methylglutaryl-coenzyme A; INR=international normalized ratio; QTc=QT interval corrected for heart rate;
AUC=area under the concentration-time curve; Ikr=delayed rectifier potassium current.
Interaction occurs through CYP2C9; may be more
prominent with fluconazole and voriconazole.
Monitor coagulation status when any triazole is started
or stopped in patients receiving warfarin and adjust
doses accordingly.
Reduce omeprazole doses by 50% if dosed at >40 mg in
patients receiving voriconazole.
No clear guidelines for dose adjustment, but dosage
reduction may be considered.
Monitor for hormone side effects.
Triazoles are contraindicated in any patient receiving
drugs with potent inhibitory potential for myocardial
potassium channels (Ikr).

5
 Table 2. Drug classes that reduce serum •• other causes of underlying liver disease, including infection,
triazole concentrations. have been excluded;
•• evidence of improvement in liver function emerges after
Drug Class Triazole Comment triazole discontinuation, although in some cases serum
Rifabutin, Fluconazole, Induction of biomarkers may continue to worsen after discontinuation
rifampicin itraconazole, CYP3A4 results before improvement is noted; and
voriconazole, in 50%-90%
posaconazole reduction in •• there is evidence that liver injury recurred more rapidly and
serum triazole severely after repeated exposure.42
concentrations
and substantially
reduced efficacy.
Patients should not be routinely rechallenged with the suspected
offending triazole, however, to establish a diagnosis. The primary
Carbamazepine Itraconazole, Induction of treatment for suspected triazole hepatotoxicity is drug withdrawal.
and long-acting voriconazole, CYP450 may Recovery is expected in the majority of patients after drug
barbiturates posaconazole substantially reduce discontinuation. There is also some evidence that patients who
the efficacy of
triazoles.
develop signs of hepatotoxicity during therapy with one triazole
may safely tolerate other triazoles.43
Antivirals: Voriconazole Induction of
nonnucleoside CYP2C9 may CONCLUSION
reverse transcriptase result in substantially
inhibitors, decreased serum In conclusion, the expansion of the triazole class in the last decade
darunavir, concentrations of
didanosine, voriconazole. has significantly improved prophylaxis and treatment options for
lopinavir patients who develop invasive fungal infections. However, the
possibility for drug interactions and adverse effects, such as drug-
Histamine-2 Itraconazole Reduced oral induced liver injury, should be considered in any patient in whom
receptor antagonists capsules, bioavailability may triazole therapy is initiated. Drug interactions and toxicities, if
and proton posaconazole result in inadequate
pump inhibitors suspension serum concentration
recognized early and managed proactively, rarely lead to serious
of itraconazole or sequelae. Appropriate intervention may allow patients to continue
posaconazole. therapy or to transition to oral systemic antifungal therapy for
serious mycoses.

Table 3. Frequency of common triazole adverse effects reported in multidose studies.a

Incidence Rate
Adverse Effect Fluconazole, % Itraconazole, % Voriconazole, % Posaconazole, %
Hepatotoxicity (>2-fold AST, 1 ALT, 2-3 ALT, 10.7-18.9 ALT, 2-3
elevation of AST or ALT, ALT, 1 AST, 1-2 AST, 11.7-20.3 AST, 2-3
or doubling of TBIL) TBIL, 1 TBIL, 4-6 TBIL, 4.3-19.4 TBIL, 2-3
ALP, 10.2-16 ALP, 2-3
Nausea, vomiting, 1.7 11 (capsules) 5.4 7
or diarrhea 24-39 (oral solution)
Rash 1.8 9 5.3 3

Visual disturbance - - 18.7 -

Headache 1.9 4 3 2

Hallucinations - - 2.4 -

CHF - Postmarketing reports of - -

negative inotropic effects
in older adults; use in CHF
patients not recommended.
Data extracted from US package insert labeling.
a

AST=aspartate aminotransferase; ALT=alanine aminotransferase; TBIL=total bilirubin; ALP=alkaline phosphatase; CHF=congestive heart failure.

6
REFERENCES
1. H  erbrecht R, Denning DW, Patterson TF, et al; Invasive Fungal Infections
Group of the European Organisation for Research and Treatment of Cancer and
the Global Aspergillus Study Group. Voriconazole versus amphotericin B for
primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415.
2. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole
with amphotericin B for the treatment of candidemia in patients without
neutropenia. Candidemia Study Group and the National Institute. N Engl J Med.
1994;331(20):1325-1330.
3. Pelz RK, Hendrix CW, Swoboda SM, et al. Double-blind placebo-controlled
trial of fluconazole to prevent candidal infections in critically ill surgical patients.
Ann Surg. 2001;233(4):542-548.
4. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole
prophylaxis for fungal infections after bone marrow transplantation: a prospective,
randomized, double-blind study. J Infect Dis. 1995;171(6):1545-1552.
5. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for
prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):
335-347.
6. Rex JH, Anaissie EJ, Boutati E, Estey E, Kantarjian H. Systemic antifungal
prophylaxis reduces invasive fungal infections in acute myelogenous leukemia:
a retrospective review of 833 episodes of neutropenia in 322 adults. Leukemia.
2002;16(6):1197-1199.
7. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole
or itraconazole prophylaxis in patients with neutropenia. N Engl J Med.
2007;356(4):348-359.
8. Maertens JA. History of the development of azole derivatives. Clin Microbiol
Infect. 2004;10(suppl 1):1-10.
9. Brammer KW, Coakley AJ, Jezequel SG, Tarbit MH. The disposition and
metabolism of [14C] fluconazole in humans. Drug Metab Dispos. 1991;19(4):
764-767.
10. LÓpez-Gil JA. Fluconazole-cyclosporine interaction: a dose-dependent effect?
Ann Pharmacother. 1993;27(4):427-430.
11. Nicolau DP, Crowe HM, Nightingale CH, Quintiliani R. Rifampin-fluconazole
interaction in critically ill patients. Ann Pharmacother. 1995;29(10):994-996.
12. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration
of fluconazole in humans. Rev Infect Dis. 1990;12(suppl 3):S318-S326.
13. Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics.
J Antimicrob Chemother. 2005;56(suppl 1):i17-i22.
14. Gubbins PO, McConnell SA, Amsden JR. Antifungal agents. In: Piscitelli SC,
Rodvold KA, eds. Drug Interactions in Infectious Diseases. 2nd ed. Totowa, NJ:
Humana Press; 2005:289-338.
15. Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole
for prevention of fungal infections in patients receiving allogeneic stem cell
transplants. Blood. 2004;103(4):1527-1533.
16. Stevens DA. Itraconazole in cyclodextrin solution. Pharmacotherapy.
1999;19(5):603-611.
17. Gould S, Scott RC. 2-Hydroxypropyl-b-cyclodextrin (HP-b-CD): a toxicology
review. Food Chem Toxicol. 2005;43(10):1451-1459.
18. Courtney R, Sansone A, Smith W, et al. Posaconazole pharmacokinetics, safety,
and tolerability in subjects with varying degrees of chronic renal disease. J Clin
Pharmacol. 2005;45(2):185-192.
19. Nagappan V, Deresinski S. Reviews of anti-infective agents: posaconazole:
a broad-spectrum triazole antifungal agent. Clin Infect Dis. 2007;45(12):
1610-1617.
20. Heykants J, Van Peer A, Van de Velde V, et al. The clinical pharmacokinetics of
itraconazole: an overview. Mycoses. 1989;32(suppl 1):67-87.
21. Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450
enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos.
2003;31(5):540-547.
22. Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M.
Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status.
Clin Pharmacol Ther. 2004;75(6):587-588.
23. Kashuba DM, Bertino JS. Mechanisms of drug interactions I. In: Piscitelli SC,
Rodvold KA, eds. Drug Interactions in Infectious Diseases. 2nd ed. Totowa, NJ:
Humana Press; 2005:13-39.
24. Matsumoto K, Ikawa K, Abematsu K, et al. Correlation between voriconazole
trough plasma concentration and hepatotoxicity in patients with different
CYP2C19 genotypes. Int J Antimicrob Agents. 2009;34(1):91-94.
25. Crussell-Porter LL, Rindone JP, Ford MA, Jaskar DW. Low-dose fluconazole
therapy potentiates the hypoprothrombinemic response of warfarin sodium. Arch
Intern Med. 1993;153(1):102-104.
26. Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis.
1990;12(suppl 3):S327-S333.
27. Albengres E, Le Louët H, Tillement JP. Systemic antifungal agents. Drug
interactions of clinical significance. Drug Saf. 1998;18(2):83-97.
28. Drayton J, Dickinson G, Rinaldi MG. Coadministration of rifampin and
itraconazole leads to undetectable levels of serum itraconazole. Clin Infect Dis.
1994;18(2):266.
29. Krishna G, Parsons A, Kantesaria B, Mant T. Evaluation of the
pharmacokinetics of posaconazole and rifabutin following co-administration
to healthy men. Curr Med Res Opin. 2007;23(3):545-552.
30. Tucker RM, Denning DW, Hanson LH, et al. Interaction of azoles with
rifampin, phenytoin, and carbamazepine: in vitro and clinical observations.
Clin Infect Dis. 1992;14(1):165-174.
31. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with
itraconazole. Lancet. 2001;357(9270):1766-1767.
32. VFEND Tablets/VFEND I.V. [prescribing information]. New York, NY:
Pfizer Inc. Pharmaceuticals; 2002.
33. Pfizer Inc. 2001. NDA 21-266, Vfend (voriconazole) Tablets and NDA
21-267, Vfend I.V. (voriconazole) for infusion.
34. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole
in the treatment of acute invasive aspergillosis. Clin Infect Dis. 2002;34(5):
563-571.
35. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole
therapeutic drug monitoring in patients with invasive mycoses improves
safety and efficacy outcomes. Clin Infect Dis. 2007;46(2):201-211.
36. Dodds Ashley ES, Lewis RE, Lewis JS 2nd, Martin C, Andes D. Pharmacology
of systemic antifungal agents. Clin Infect Dis. 2006;43:S28-S39.
37. Song JC, Deresinski S. Hepatotoxicity of antifungal agents. Curr Opin Investig
Drugs. 2005;6(2):170-177.
38. Diflucan [prescribing information]. New York, NY: Roerig Division of Pfizer
Inc.; 1998.
39. Sporanox [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals;
2000.
40. Noxafil oral suspension [prescribing information]. Kenilworth, NJ: Schering-
Plough; 2006.
41. Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of
the potential relationships between plasma voriconazole concentrations and
visual adverse events or liver function test abnormalities. J Clin Pharmacol.
2006;46(2):235-243.
42. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med.
2006;354(7):731-739.
43. Spellberg B, Rieg G, Bayer A, Edwards JE Jr. Lack of cross-hepatotoxicity
between fluconazole and voriconazole. Clin Infect Dis. 2003;36(8):1091-1093.
44. Gillies J, Hung KA, Fitzsimons E, Soutar R. Severe vincristine toxicity in
combination with itraconazole. Clin Lab Haematol. 1998;20(2):123-124.
45. Jeng MR, Feusner J. Itraconazole-enhanced vincristine neurotoxicity in a
child with acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2001;18(2):
137-142.
46. Marr KA, Leisenring W, Crippa F, et al. Cyclophosphamide metabolism is
affected by azole antifungals. Blood. 2004;103(4):1557-1559.
47. Romero AJ, Le Pogamp P, Nilsson LG, Wood N. Effect of voriconazole
on the pharmacokinetics of cyclosporine in renal transplant patients.
Clin Pharmacol Ther. 2002;71(4):226-234.
48. Saad AH, DePestel DD, Carver PL. Factors influencing the magnitude and
clinical significance of drug interactions between azole antifungals and select
immunosuppressants. Pharmacotherapy. 2006;26(12):1730-1744.
49. Sansone-Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S, Mant
TG. Effect of oral posaconazole on the pharmacokinetics of cyclosporine and
tacrolimus. Pharmacotherapy. 2007;27(6):825-834.
50. Koks CH, Crommentuyn KM, Hoetelmans RM, et al. The effect of
fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected
individuals. Brit J Clin Pharmacol. 2001;51(6):631-635.
51. Purkins L, Wood N, Kleinermans D, Love ER. No clinically significant
pharmacokinetic interactions between voriconazole and indinavir in healthy
volunteers. Brit J Clin Pharmacol. 2003;56(suppl 1):62-68.
52. Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A.
Coadministration of voriconazole and phenytoin: pharmacokinetic
interaction, safety, and toleration. Brit J Clin Pharmacol. 2003;56(suppl 1):
37-44.
53. Liu P, Foster G, Labadie R, Somoza E, Sharma A. Pharmacokinetic
interaction between voriconazole and methadone at steady state in patients
on methadone therapy. Antimicrob Agents Chemother. 2007;51(1):110-118.
7
 Therapeutic Drug Monitoring With Triazole Antifungals
Jeannina A. Smith, MD, Clinical Assistant Professor, Division of Infectious Diseases,
University of Michigan Medical School, Ann Arbor, Michigan
INTRODUCTION
The incidence of invasive mycoses continues to rise,
and the spectrum of infection-causing pathogens has
broadened considerably.1-3 Despite recent advances in
antifungal therapy, invasive fungal infections remain a
significant cause of morbidity and mortality, particularly in
patients with compromised immunity.3
Historically, options for the treatment of invasive fungal
infections have been limited, but the introduction of
the triazole class of antifungals has greatly expanded the
antifungal armamentarium. The triazoles share a similar
mechanism of action: inhibition of the fungal cytochrome
P450 (CYP450) oxidase–mediated synthesis of ergosterol.
Compared with earlier antifungal agents, triazoles are less
toxic and have a broader spectrum of activity, targeting
pathogens for which no effective treatment previously
existed. In addition, triazoles offer the advantage of
oral dosing.
Currently available triazole antifungal drugs include
fluconazole, itraconazole, voriconazole, and posaconazole.
Despite their similarities, triazoles have important
differences in bioavailability, metabolism, penetration into
protected sites (such as the central nervous system and
eye), and spectrum of activity. Therapeutic drug monitoring
has been proposed to optimize the use of many of
the triazoles.
THERAPEUTIC DRUG MONITORING
Therapeutic drug monitoring, or TDM, is defined as the
assessment of a drug’s concentration at specified intervals
Table. Indications for TDM with triazole agents.
Concentration-
Dependent
Triazole Variable Levels Efficacy?
Fluconazole No Yes
Itraconazole Yes Yes
Voriconazole Yes Yes
Posaconazole Yes Yes
TDM=therapeutic drug monitoring; HPLC=high-performance liquid chromatography.
8
to determine if changes in dosing are required to optimize
therapy. For most drug therapies, TDM is unnecessary.
Most drugs already have undergone extensive testing to
show that drug concentrations in the majority of patients
are predictable, as well as sufficient to achieve the
therapeutic effect without approaching a toxic range. For
most drugs with a demonstrated concentration-associated
effect, titration based upon clinical response is acceptable.
However, for drugs with variable concentrations and a
narrow therapeutic index, TDM may be warranted.
Specifically, TDM is useful when a drug meets the
following criteria:
•• First, the drug must have unpredictable absorption,
elimination, or significant drug-drug interactions that
cause important variations in the concentration of the
drug from patient to patient.
•• Second, there must be a correlation of the drug
concentration to efficacy and/or toxicity. This
correlation must be sufficiently important that titration
by effect, or monitoring separately for adverse effects,
would be inappropriate.
•• Finally, there must be a valid assay available to the
clinician, and the results must be accessible in a suitable
time frame to guide clinical decision-making.
Although not all of the triazole antifungals require
TDM, many of them meet the aforementioned criteria
(Table). Several of the triazole agents—eg, itraconazole,
voriconazole, and posaconazole—have marked interpatient
variability in drug concentration. Furthermore, triazoles are
used for severe and life-threatening infections in which an
association between adequate drug exposure and efficacy
Concentration- Available
Dependent Concentration
Toxicity? Testing TDM Indicated?
No HPLC No
No HPLC and bioassay Yes
Yes HPLC Yes
No HPLC Yes
has been demonstrated. In addition, one of the triazoles,
voriconazole, has significant drug toxicity related to drug
exposure. Therefore, to optimize the use of itraconazole,
voriconazole, and posaconazole, TDM may be indicated.
SPECIFIC TRIAZOLE AGENTS AND TDM
Fluconazole
Fluconazole is a triazole antifungal compound with
excellent activity against most Candida species. It is also
useful in treating infections caused by Cryptococcus and the
endemic fungi, but it has little or no activity against mold
infections, such as those caused by the Aspergillus species or
the class Zygomycetes. The drug is available in intravenous
(IV) and oral preparations.
In most patients, fluconazole has excellent bioavailability
and is almost completely absorbed within 2 hours.
The absence of an acidic gastric environment does not
significantly affect absorption. Fluconazole has a wide
therapeutic index, as well. Based on these features, there is
little indication to perform TDM for this agent.4
Itraconazole
Itraconazole is a triazole compound with activity against
a broad range of pathogens, including Candida species,
endemic fungi, dermatophytes, Sporothrix schenckii, and
molds such as Aspergillus. It is considered the agent of choice
for the treatment of mild-to-moderate endemic fungal
infections. Itraconazole is available in 2 oral formulations,
capsule and solution. The half-life of itraconazole is long
(24 hours), and because elimination occurs by a saturable
mechanism, the drug maintains a stable concentration once
it reaches steady state.5
Variability in itraconazole levels
Itraconazole concentrations have marked interpatient
variability.6 Most of this variability is related to the
absorption of the drug from the gastrointestinal (GI)
tract. Some of it is formulation-dependent; there is greater
variability with the capsule than with the solution. Blood
concentrations are also approximately 30% higher in patients
receiving the solution.7 This effect is greater in patients whose
GI absorptive function may be impaired.8,9
Absorption of the itraconazole capsule is pH-dependent,
and optimal absorption requires an acidic environment.10-12
Proton pump inhibitors (PPIs) to lower gastric pH—which
are often administered in patients who have the greatest risk
of developing an invasive fungal infection—may markedly
reduce absorption of itraconazole in capsule form.13 The oral
solution of itraconazole, in contrast, has a more predictable
absorption that is enhanced by administration in a fasted
state and well maintained even with PPI usage.10,14
An additional factor that may influence drug concentration
and account for interpatient variability is that itraconazole
has multiple important drug interactions, most notably with
CYP450-inducing medications.5
A study of various doses of itraconazole administered
as prophylaxis for invasive fungal infections in immune-
compromised patients revealed that standard dosing did
not provide the target trough concentration of .5 g/mL in
nearly 60% of patients. Additionally, despite the improved
absorption available with the solution form of itraconazole,
20% of patients did not achieve the target trough
concentration with the standard dosage of the solution.7
Clinical significance of variable itraconazole levels
Efficacy. Itraconazole has concentration-dependent
efficacy for prophylaxis and treatment of invasive fungal
infections. This relationship has been demonstrated in
animal models of invasive aspergillosis15 as well as in human
disease.16 There is also a correlation between itraconazole
concentration and therapeutic efficacy in the treatment of
a number of other fungal infections, including cryptococcal
meningitis,17 coccidiomycosis,18 and mucosal candidiasis
affecting patients with human immunodeficiency virus.19
A relationship between the concentration and the efficacy
of itraconazole as prophylaxis has been noted. For example,
the incidence of invasive fungal infections was >50% in
neutropenic patients with itraconazole levels <.25 g/mL,
compared with slightly more than 30% in patients with levels
>.25 g/mL.20 In another study of itraconazole prophylaxis,
trough concentrations were >.5 g/mL in all of the patients
who did not develop an invasive fungal infection. Only 47%
of patients who developed an invasive fungal infection had
trough levels >.5 g/mL.21
Toxicity. A recent analysis suggests that increased
concentrations of itraconazole are associated with an
increasing incidence of toxicity. Itraconazole concentrations
>17.1 g/mL (measured by bioassay) were associated with a
greater risk of adverse events. Therefore, this level should be
considered the upper range of the drug’s therapeutic index.22
Recommendations for TDM with itraconazole
TDM is vital to ensure clinical efficacy when itraconazole
is used for the prophylaxis and treatment of invasive fungal
infections. In fact, monitoring itraconazole levels is currently
part of treatment guidelines outlined by the Infectious
Diseases Society of America (IDSA) for the management
of the endemic fungal infections histoplasmosis and
blastomycosis.23,24
The initial assessment of drug levels should be performed
at the start of itraconazole therapy to ensure adequate
absorption. Because of itraconazole’s long half-life, however,
this first assessment should be obtained approximately
9
 2 weeks after therapy has begun to ensure that the drug
has attained steady state.5 After this point, drug levels
may be random rather than peak or trough, and they
should be assessed once per month as well as after any
changes in drug dosage or delivery, after the addition or
withdrawal of interacting medications, and/or for the
purpose of determining the cause of perceived disease
progression or toxicity.
The optimal itraconazole level depends on several factors,
including the method of testing. For example, because
itraconazole has an active metabolite, the bioassay method
provides concentrations that are 7-fold higher than those
generated by high-performance liquid chromatography
(HPLC).25 Additionally, the ideal itraconazole level may
depend on the infecting organism. For example, the
minimum inhibitory concentration (MIC) of itraconazole
to Histoplasma is very low, but higher MICs are seen with
some Candida species or mold infections, which may
therefore require higher itraconazole levels.
As previously mentioned, the maximal level of
itraconazole is 17.1 g/mL, measured by bioassay. The
minimal level for efficacy in the treatment of fungal infection
is, in most instances, >1 to 2 g/mL when HPLC is used,
whereas the target level with bioassay should be >6 g/mL.
For prophylaxis of fungal infection, some authors recommend
a lower level, .5 g/mL (by HPLC).26
Summary of TDM recommendations for itraconazole:
•• Random drug levels are acceptable.
•• Obtain the first drug level 2 weeks after starting therapy.
•• Obtain follow-up levels once monthly.
•• Reasons for checking drug levels more frequently include:
any changes in the dosage or delivery of itraconazole,
the addition or withdrawal of interacting medications,
and/or perceived disease progression or toxicity.
•• HPLC goal is >.5 g/mL for prophylaxis and >1 to
2 g/mL for treatment of fungal infection.
•• If low drug levels are detected with capsule
administration, consider switching to the solution.
Avoid acid suppression with the capsule. You may also
increase the dose to 200 mg 3 times a day if low levels
are detected.
Voriconazole
Voriconazole is a newer triazole compound with enhanced
antifungal activity against the Aspergillus species. It is now
considered the agent of choice for invasive Aspergillus
infection.27 Voriconazole also has proven efficacy against a
number of unusual and emerging fungal pathogens highly
resistant to all previously available antifungal agents.
These include Fusarium species, as well as Scedosporium
apiospermum (asexual form of Pseudallescheria boydii), for
10
which voriconazole is the only treatment approved by the
US Food and Drug Administration (FDA). Voriconazole
is available in IV and oral preparations, and oral
bioavailability is excellent. Voriconazole exhibits nonlinear
pharmacokinetics; its concentration does not increase at a
predictable rate with escalations of the dose. Additionally,
administration with high-fat meals reduces drug levels.28
The half-life of voriconazole is approximately 6 hours but
increases in tandem with drug concentration, probably
because of saturation of the hepatic metabolism of the drug.29
Variability in voriconazole levels
As with itraconazole, striking interpatient variability in
drug levels occurs with voriconazole.30-33 Unlike itraconazole,
this variability is not due primarily to erratic absorption.
Rather, it can be attributed largely to interpatient differences
in the elimination of the drug via the CYP450 system—in
particular, to allelic polymorphisms at CYP2C19. Among
different populations, there is considerable variation in the
proportion of people who are poor or extensive metabolizers
of CYP2C19, a variation that can have a significant impact
on voriconazole drug levels.29 For example, up to about
5% of US Caucasian populations are homozygous poor
metabolizers of CYP2C19, whereas 75% are homozygous
extensive metabolizers. In contrast, in patients of Asian
descent, roughly 20% of individuals are homozygous poor
metabolizers of CYP2C19, and only 35% are homozygous
extensive metabolizers.34
Variability in voriconazole levels has been observed in
multiple different patient populations, including patients
with bone marrow or solid organ transplants and intensive
care patients.28,35-39 In studies of these groups, a substantial
proportion of patients had very low or undetectable levels,
whereas a significant proportion had high levels. In most
cases, this effect was not predictable.
Several recent studies have suggested that prominent
fluctuations can occur in drug concentrations during
voriconazole therapy, even in patients whose serum
concentrations were acceptable previously.36,40,41 Finally,
a number of medications commonly administered to
patients at risk for invasive fungal infections, including
sirolimus, cyclosporine, tacrolimus, rifamycins, protease
inhibitors, and phenytoin, may greatly alter voriconazole
concentrations. Caution must be exercised when using any
of these agents concurrently with voriconazole, and
performing TDM with voriconazole and the other agents
may promote safer administration.
Clinical significance of variable voriconazole levels
Efficacy. There is mounting evidence of a correlation
between drug concentration and the efficacy of voriconazole
prophylaxis and treatment. This correlation was first
suggested in animal models.42 Later, a relationship between
adequate voriconazole concentrations and efficacy was noted
in a series of studies in human invasive fungal infections.43-45
In the first prospective trial to assess the relationship of
voriconazole serum concentrations to efficacy, slightly more
than 50% of patients with voriconazole levels <1 g/mL
responded to therapy, whereas >90% patients with levels
>1 g/mL had a favorable clinical response.46 A study of
voriconazole prophylaxis also revealed a correlation between
breakthrough infection and low voriconazole levels.35
Although efficacy studies have not consistently described
whether the reported drug levels were peak, trough, or
random, trough levels are preferable for assuring adequate
drug exposure throughout the dosing interval.
Toxicity. Toxic reactions, including visual changes, liver
function abnormalities, and encephalopathy, are associated
with higher levels of voriconazole.46-51
Recommendations for TDM with voriconazole
Given the aforementioned concerns about variable
and unpredictable voriconazole levels, in addition to
the correlation of drug levels to efficacy and toxicity, the
IDSA has recommended voriconazole TDM in its recent
guidelines for the treatment of invasive aspergillosis.52
TDM may also be useful during therapy for a variety of
other serious invasive fungal infections.53
Voriconazole trough concentrations should be obtained
toward the end of the first week of therapy to determine
whether levels are adequate to treat the infection and to
identify patients whose higher drug concentrations may
pose an increased risk of liver or central nervous system
adverse effects. Voriconazole levels should be reassessed
once or twice monthly, as well as in the following cases:
a patient has not responded as well as expected to the
drug; an interacting medication has been introduced or
withdrawn; the route of administration of voriconazole
has changed (eg, from an mg/kg dosing schedule for
IV therapy to a fixed dosing schedule for oral therapy);
deteriorating hepatic function is noted; and/or toxicity
is suspected.
An ideal voriconazole target trough concentration has
not been identified but is likely to be in the range of .5 to
2 g/mL, depending on the known or predicted MIC of
the infecting pathogen or whether the infection is located
in a pharmacologically inaccessible place such as the brain
or eye (in which case trough concentrations >2 g/mL may
be necessary). Trough levels should be titrated to remain
<5.5 g/mL to reduce the risk of neurotoxicity.46
If low levels are detected in patients on oral therapy,
consider checking a peak and a trough concentration. If
the peak is elevated but the trough is undetectable or
very low, one can surmise that the level is low because of
rapid metabolism, and an increased dose of oral drug may
be indicated. If, on the other hand, both levels are very
low and the patient has known or suspected GI absorptive
impairment, IV dosing may be considered until disease
stability is established.
Summary of TDM recommendations for voriconazole:
•• Obtain the first drug level at the end of the first week
of therapy.
•• Follow-up levels may be obtained once or twice monthly.
•• Trough levels are preferred, with target of .5 to
2 g/mL (lower end for prophylaxis). This goal
should be higher (≥2 g/mL) for central nervous
system or eye infection.
•• Levels >5.5 g/mL should prompt dose reduction
to minimize risk of neurotoxicity and hepatotoxicity.
Decrease daily dose by 100 mg and recheck the level
in 1 week.
•• If the drug level is less than desired with oral therapy,
increase the daily dose by 100 mg and recheck the level
in 1 week. The patient may also be advised to avoid
taking the medication with meals.
•• Reasons for checking levels more frequently include
changes in the dosage or delivery of voriconazole, the
addition or withdrawal of interacting medications,
and perceived disease progression or toxicity.
Posaconazole
Posaconazole is the most recently marketed triazole
agent. Posaconazole is attractive because of its enhanced
antifungal spectrum, especially its activity against
the Zygomycetes. Posaconazole is available in an oral
formulation only. Despite its prolonged elimination half-
life (>24 hours), the compound is optimally administered
multiple times daily (eg, 2 to 4) because it features
saturable absorption.54
Variability in posaconazole levels
Posaconazole is another triazole that has significant
interpatient variability.55-58 As with itraconazole,
interpatient variability with posaconazole is related to
a marked variability in absorption. A number of factors
impact the absorption of posaconazole. For example,
administering posaconazole with food, particularly with
high-fat meals, enhances absorption.59
The saturable absorption of posaconazole means that
the drug concentration can improve considerably when the
total daily dosage of posaconazole is divided into smaller,
evenly distributed doses throughout the day. In a study of
healthy volunteers, the fractionation of an 800-mg/d dosage
into 400 mg administered twice daily doubled posaconazole
exposure. Administering a 200-mg dose 4 times daily
11
 increased exposure by 220%.60 However, the utility of
administering posaconazole with food or in smaller,
divided doses is limited for ill, hospitalized patients unable
to take the medication with meals. Indeed, in clinically
relevant patient populations, greater variation (and often
reductions) in drug levels have been noted.58,61
As with itraconazole, an acidic gastric environment fosters
posaconazole absorption.62,63 Numerous medications, if
used concurrently with the drug, reduce the concentration
of posaconazole apparently by enhancing GI transit and
increasing gastric pH, which can impair posaconazole
absorption. Finally, lower posaconazole concentrations have
occurred when the drug was administered via nasogastric
tube, which may represent a significant limitation in
posaconazole’s usefulness for critically ill patients.64
In a recently published assessment of samples of serum
posaconazole concentrations obtained from a fungal-
testing reference laboratory, almost 70% of samples fell
short of a cutoff level for efficacy, suggesting an increased
risk of breakthrough fungal infection or disease with
posaconazole prophylaxis or treatment. In addition, 16.3%
of posaconazole levels were undetectable.65
Clinical significance of variable posaconazole levels
Efficacy. Posaconazole has a concentration-dependent
efficacy in animals and humans. In a study of posaconazole
for the treatment of aspergillosis, a clinical response was
observed in slightly more than 20% of patients whose
average drug plasma concentration was ≤.13 g/mL,
compared with >70% of patients who had an average
steady-state concentration of ≥1.25 g/mL.66 In studies
of posaconazole for the prevention of fungal infections
in patients with severe graft-versus-host disease,
posaconazole concentrations were 2 times lower in the
few patients who developed an invasive fungal infection
than in those who did not, although the difference was
not statistically significant.56
Toxicity. The relationship of posaconazole drug
concentration to toxicity has not been adequately explored
at this time.
Recommendations for TDM with posaconazole
Although clinical experience with posaconazole is
limited because of its recent introduction to the market,
TDM may be important based on the drug’s variability
in absorption. Trough concentration monitoring should
be considered toward the end of the first week of therapy,
especially in patients who have impaired gastric acidity or
GI mucosal absorption, are administered posaconazole
by nasogastric tube, or receive the drug on a twice-daily
or divided daily dosing schedule.62,64 A trough level
assessment should be repeated to ascertain the etiology of
12
inadequate clinical response, after the addition or withdrawal
of an interacting medication, or with changes in dosage.
The target posaconazole trough level should be .5 to
1.5 g/mL for patients being treated for invasive fungal
infection. Some authors propose that the goal for
prophylaxis may be lower than the level necessary
for treatment and may be sufficient at >.5 g/mL.26
Additionally, an FDA briefing document for posaconazole
recommends a posaconazole average serum drug
concentration target of >.7 g/mL.67
If low drug levels are found, changing to a dosing regimen
of 200 mg 4 times daily with a fatty meal and acidic beverage
may improve the levels. However, some patients may not
respond to this change and may continue to have low levels
despite all efforts to enhance absorption.
Summary of TDM recommendations for posaconazole:
•• Obtain the first level at the end of the first week
of therapy.
•• Follow-up levels may be obtained once or twice monthly.
•• Trough levels are preferred, with a goal of >.5 to
1.5 g/mL (lower end for prophylaxis).
•• If low levels are found, the level may be improved
by switching to a dosing regimen of 200 mg 4 times
daily (which will generally result in higher levels than
400 mg twice daily), administered with a fatty meal and
acidic (carbonated) beverage, such as cola. Use of acid
suppression should be avoided.
•• Increasing the dose above 200 mg 4 times daily will
not increase the drug level, as posaconazole has
saturable absorption.
•• Reasons for checking levels more frequently include
any changes in dosage; the addition or withdrawal of
interacting medications, particularly PPIs; perceived
disease progression; as well as development of mucositis,
diarrhea, or vomiting.
CONCLUSION
The triazoles are an important addition to the antifungal
formulary. Several of the triazole agents have some
of the cardinal indications for TDM. For example,
significant interpatient variability exists with itraconazole,
voriconazole, and posaconazole. An increasing body
of literature suggests that TDM may be useful both to
minimize toxicity and to optimize efficacy with these
agents. In fact, TDM has been recommended in
guidelines for treating a variety of fungal infections.
TDM may be particularly useful for patients who have
the greatest risk of disease progression when therapy is
inadequate, or who are likely to develop toxic reactions to
antifungal drug therapy.
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Toxicodynamics of the Azoles: A Focus on Hepatotoxicity
William W. Hope, MD, Clinical Senior Lecturer, University of Manchester, Manchester Academic
Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University
Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom
INTRODUCTION
The azole class of drugs has revolutionized antifungal
therapy. Azoles are safe, effective, orally bioavailable
compounds with broad-spectrum antifungal activity. The
imidazoles (eg, ketoconazole) and triazoles (eg, fluconazole,
itraconazole, voriconazole, and posaconazole) have the same
mechanism of action, but their antifungal spectrum and
clinical pharmacokinetics are determined by structural
differences unique to each compound. The ratio of the
area under the concentration-time curve to the minimum
inhibitory concentration is the pharmacodynamic index
that best links triazole drug exposure to antifungal effect.1-4
In contrast, however, the toxicodynamic relationships for
these compounds are less well understood. This review
summarizes the exposure-toxicity relationships for the
triazoles, with a focus on hepatotoxicity.
AN OVERVIEW OF AZOLE-INDUCED
HEPATOTOXICITY
All of the triazoles are associated, at least to some degree,
with the development of hepatotoxicity that manifests
as abnormalities of liver function tests (LFTs), clinical
hepatitis, or fatal cases of fulminant hepatitis. The
mechanism of azole-induced liver injury is not well
understood. Although hepatotoxicity is clearly a drug
class–specific effect, the triazoles differ in their propensity
for causing liver damage and may not always be cross-
reactive.5,6 The absence of peripheral eosinophilia, fever,
and rash suggests that hepatotoxicity arises from a direct
toxic effect rather than via immunologically mediated
mechanisms. Potential mechanisms underlying hepatoxicity
include the production of toxic metabolites, mitochondrial
toxicity,7 and inhibition of mammalian sterol synthesis,
but the role of these mechanisms has never been
substantiated in a rigorous manner. Hepatocellular
damage appears to be the predominant pattern of injury,
whereas a cholestatic or mixed pattern of liver injury is
observed less commonly.
Ketoconazole
Ketoconazole was the first orally bioavailable azole that
could be used to treat systemic fungal infections. However,
with the advent of modern triazoles, which have an improved
safety profile and a broader spectrum of antifungal activity,
ketoconazole is now used rarely.
Ketoconazole causes concentration-dependent damage
in an in vitro model of Sprague-Dawley rat hepatocytes8
and is associated with a mild elevation in liver enzymes in
approximately 3% to 5% of patients. There do not appear to
be any long-term sequelae of asymptomatic LFT elevations,
provided therapy is promptly stopped. Liver enzymes usually
return to normal within 3 months.9 A hepatocellular pattern
of liver injury is usually seen, but a cholestatic or mixed
picture may also be present.9 Much less commonly, clinical
hepatitis (approximate incidence 1:15,000) and fulminant
hepatitis have been reported.9,10 The latter is caused by
hepatocellular necrosis and occurs in patients without
preexisting liver disease. Deaths resulting from fulminant
hepatitis have been reported following the continued
administration of ketoconazole, despite the presence of
jaundice and other clinical features of hepatitis.
Some have argued that it may be reasonable to continue
ketoconazole in patients with asymptomatic elevation
of LFTs, as long as patients can be carefully monitored.11
Others have suggested this is not a safe strategy, and
the drug should be promptly stopped.12 Given the
availability of other, newer antifungal agents, the latter
would appear prudent.
Fluconazole
Fluconazole remains widely used for the treatment
of superficial and invasive infections caused by Candida
species. Despite limited activity against Candida glabrata
and Candida krusei, the majority of medically important
Candida species remain susceptible to this agent.
When assessed in an in vitro model, fluconazole is less
toxic to hepatocytes than ketoconazole.13 Fluconazole most
commonly causes an asymptomatic increase in LFTs, but
there are occasional reports of fatal fulminant hepatic
necrosis.14,15 Fluconazole hepatotoxicity usually occurs
in patients without preexisting liver disease but can cause
a worsening of liver function in the setting of preexisting
hepatitis.16 See Table for a summary of the LFT
abnormalities that occurred secondary to fluconazole in
selected clinical studies. Despite several case reports,14,17
there is little evidence that fluconazole-associated
hepatotoxicity is dose dependent, although this may reflect
a lack of current data.
15
 In a study of bone marrow transplant recipients, fluconazole
exposure was associated with an increased probability of
developing hepatotoxicity, defined as >3 × upper limit
of normal (ULN) aspartate aminotransferase (AST) or
alanine aminotransferase (ALT) levels or the doubling of
baseline concentrations (odds ratio, 1.99; 95% confidence
interval, 1.21-3.26), with an estimated incidence of .98
cases per 100 patient-days.18
Patients with abnormal LFTs secondary to fluconazole
who continued to receive therapy had variable outcomes.
Approximately 56% of patients had stable or decreasing
LFTs, 32% developed a continued moderate increase,
and a further 12% developed sharply increasing LFTs
to >10 × normal. There was no evidence of an increased
risk of hepatotoxicity associated with increased duration
of exposure. The authors of this study concluded that
deranged LFTs secondary to fluconazole are usually innocuous
and continued therapy is probably reasonable, provided
that close clinical observation and serial measurement
of LFTs continue. For patients whose fluconazole needs
to be discontinued, voriconazole may be a reasonable
alternative, based on a case report that suggests the absence
of cross-reactivity.6
Itraconazole
Hepatotoxicity is a well-described complication of
itraconazole therapy. A meta-analysis of clinical trials
for onychomycosis comparing continuous and pulsed
itraconazole regimens demonstrated a low overall
incidence of LFT abnormalities.19 In that study, the
incidence of elevated LFTs was as follows: elevated
ALT, 1.02% and 1.51% of patients receiving pulsed and
continuous regimens, respectively; elevated AST, .72%
and .66% of patients receiving pulsed and continuous
regimens, respectively; and elevated bilirubin, 1.22%
and 1.47% of patients receiving pulsed and continuous
therapy, respectively.19
Abnormal LFTs induced by itraconazole tend to
normalize with cessation of therapy.20 There are isolated
reports of symptomatic hepatitis due to itraconazole.21,22
Less commonly, itraconazole causes liver failure, which may
be fatal.19 Consequently, LFTs should be monitored and
itraconazole stopped if abnormally high levels are seen.
A growing body of data attests to the importance of
therapeutic drug monitoring (TDM) to ensure effective
itraconazole concentrations, primarily because of the drug’s
erratic bioavailability and considerable pharmacokinetic
variability.23-25 The toxicodynamics of itraconazole were
described in a recent study.25 In this study, the probability of
any adverse event increased progressively with increasing
average itraconazole concentrations. The itraconazole
concentrations were measured by bioassay, making direct
16
comparison with concentrations measured by high-
performance liquid chromatography somewhat difficult.
The majority of adverse events attributable to itraconazole
were related to gastrointestinal intolerance, with a smaller
number due to rarer events such as rash, neurological signs
and symptoms, and fluid retention. There were relatively
few episodes of hepatotoxicity, which probably reflects
the predominance of patients with chronic pulmonary
aspergillosis and other fungal allergy syndromes in the
study population versus profoundly immunocompromised
patients receiving other hepatotoxic compounds.
Patients receiving itraconazole should undergo serial
monitoring of LFTs. Itraconazole should be discontinued
in patients with deranged LFTs. Although there is no
information on cross-reactivity with other triazoles,
voriconazole has been used safely in patients with prior
adverse events attributable to itraconazole.25
Voriconazole
Voriconazole is a structural congener of fluconazole
with antifungal activity against a broad range of medically
important fungal pathogens. Currently, voriconazole is
considered a first-line agent for the treatment of invasive
aspergillosis, and it can be used for the treatment of
disseminated candidiasis.26,27 Voriconazole exhibits classic
Michaelis-Menten (nonlinear) pharmacokinetics, meaning
that dose escalation may cause disproportionately high
systemic exposures, which may, in turn, increase the
probability of concentration-dependent toxicity. Another
effect of its nonlinear pharmacokinetics is that the dosage
of the drug is an even cruder measure of drug exposure
than it is for linear compounds.
Voriconazole more commonly causes a hepatocellular,
as opposed to cholestatic, pattern of liver injury.
Gamma glutamyl transpeptidase (GGT), which may
be the most sensitive marker of cholestasis, has been
used to detect voriconazole hepatotoxicity in a variety of
patient groups.28
The rate of LFT elevations among patients in the
therapeutic studies of the voriconazole development
program was 12.4%.29 The incidence may be higher
outside the setting of clinical trials30,31 as well as compared
with those receiving other triazoles. In a study of esophageal
candidiasis, the proportion of patients with elevated
bilirubin, AST, ALT, and alkaline phosphatase (ALP) was
4.3%, 20.3%, 10.7%, and 10.2% for voriconazole versus
3.8%, 8.1%, 6.5%, and 7.5% for fluconazole, despite a
comparable median duration of exposure.29 Consistent
with the other azoles, LFT abnormalities resolve relatively
promptly after the cessation of drug administration.
The systemic drug exposure resulting from the
administration of voriconazole to patients with moderate
hepatic impairment is significantly higher compared
with patients whose hepatic reserve is normal.32,33 A 50%
reduction in maintenance dosage for patients with mild-
to-moderate hepatic impairment is recommended. A
proportion of patients recruited to the clinical development
program had abnormal baseline LFTs, but these patients
did not necessarily seem to have a higher risk of worsening
LFTs. In lung transplant recipients, patients receiving
voriconazole prophylaxis had a higher incidence of
LFTs compared with those receiving a combination of
itraconazole and nebulized amphotericin B (respectively,
60% versus 41%; 45 versus 15%; and 37% versus 15% for
GGT, ALT, and AST).34
A dose-dependent increase in the incidence of elevated
LFTs has been observed after voriconazole administration
in healthy volunteers. In these studies, no LFT abnormalities
were documented in 14 patients who received—every 12
hours—6 mg/kg intravenous (IV) voriconazole on day 1,
followed by 3 mg/kg for 6 days, followed by 200 mg for
7 days. In contrast, ALT or AST values greater than the
ULN occurred in 5 of the 14 patients who received—every
12 hours—6 mg/kg IV voriconazole on day 1, followed by
5 mg/kg for 6 days, followed by 400 mg for 7 days. No
LFT abnormalities occurred in patients receiving 200
mg IV voriconazole every 12 hours for 14 days. One of 9
patients who received 300 mg IV voriconazole every 12
hours had an AST >3 × the ULN.33 These results were used
to design appropriate dosing regimens for phase 3 trials as
well as to underpin current licensed dosages and schedules
of administration—ie, 6 mg/kg IV for 2 doses, followed
by 4 mg/kg IV every 12 hours, followed by 200 mg orally
every 12 hours. The oral dosage may be increased to 300 mg
every 12 hours if clinically indicated.
The most comprehensive study that has examined exposure-
toxicity relationships for the triazoles was conducted
by Tan and colleagues.35 These investigators described
the relationships between average serum voriconazole
concentrations and the probability of subsequently
developing elevated LFTs. This study included patients
with a range of fungal infections, including invasive
aspergillosis, esophageal candidiasis, scedosporiosis,
fusariosis, and underlying comorbid conditions. A
longitudinal logistic regression analysis was used. Because
of uncertainty about the timing of sample acquisition in
relation to dosage, the mean voriconazole concentrations in
each patient were determined, and these were used as the
independent variable for the logistic regression analysis.
The overall incidence of elevated LFTs was <10% for
the majority of patients, except for patients with average
concentrations >9 mg/L.35 Abnormal LFTs led to the
discontinuation of therapy in 3% of patients.29 Increasing
voriconazole concentrations correlated with a statistically
significant increase in the probability of LFT elevation,
with the exception of ALT elevation. For AST, ALP,
and bilirubin, the probability of an abnormality increased
13.1%, 16.5%, and 17.2% for every 1-mg/L increase in
average voriconazole concentrations. In this study, there
was no cut-off value that clearly separated the patient
population into groups with high and low probability for
deranged LFTs.35 This was cited as evidence that TDM
would not be useful for the management of patients. The
relationship between trough concentrations (not average,
as used in the study of Tan et al) and the probability of
hepatotoxicity was recently confirmed with a logistic
regression model in a small number of Japanese patients
(n=29).31 In 2 small studies, there is no relationship
between the cytochrome P450 2C19 genotype and the
probability of hepatotoxicity.31,36
The use of TDM to prevent hepatotoxicity remains
somewhat debatable. The analysis of Tan et al demonstrates
that there is only a weak relationship between average
voriconazole concentrations and the probability of elevated
LFTs. The majority of patients with relatively high
average voriconazole concentrations will have normal
LFTs. Some have argued that the measurement of LFTs
alone may be a less costly and more convenient way to
detect drug-related toxicity. Serial LFTs can be measured
with progressive dosage escalation, with refinement once
LFTs begin to increase. The measurement of a voriconazole
concentration may be potentially helpful for patients with
high LFTs, for which the cause is unclear. In this context,
a high voriconazole concentration increases the probability
that the high LFTs are related to voriconazole. A trough
concentration of 5 to 6 mg/L has been advocated as a
reasonable upper threshold for TDM.
There is little information regarding appropriate
antifungal therapy for patients that have hepatotoxicity
from voriconazole. A single case report that suggests
there is no cross-reactivity between voriconazole and
posaconazole, although this occurred in a patient with a
cholestatic rather than hepatocellular pattern of liver injury.5
For patients in whom there is a limited choice of alternative
antifungal agents, posaconazole could be used with
assiduous clinical and laboratory monitoring.
Posaconazole
Posaconazole is a broad-spectrum triazole that is
structurally similar to itraconazole. The clinical utility
of this compound has been studied for prophylaxis for
patients with graft-versus-host disease and neutropenia,
as well as for patients with invasive aspergillosis who are
refractory to or intolerant of other antifungal agents.37-39
The administration of posaconazole is associated with
a low incidence of hepatotoxicity and clinical hepatitis
17
 Table. Incidence of LFT abnormalities in selected randomized clinical trials.
Triazole— Comparator—
Study Hepatic Event, % Hepatic Event, % Disease
Herbrecht et al26 Voriconazole followed by other Amphotericin B deoxycholate followed Invasive aspergillosis
licensed antifungal therapy—hepatic by other licensed antifungal therapy—
abnormalities, 3.6 hepatic abnormalities, 2.2

Cornely et al37 Posaconazole—elevated bilirubin, 2 Fluconazole or itraconazole— Acute myeloid leukemia

elevated bilirubin, 1

Ullman et al38 Posaconazole—elevated bilirubin, 3; Fluconazole—elevated bilirubin, 2; Prophylaxis for graft-

elevated GGT, 3; elevated AST, 3; elevated GGT, 2; elevated AST, 1; versus-host disease
elevated ALT, 3 elevated ALT, 1

Winston et al40 Itraconazole—elevated liver enzymes, 15 Fluconazole—elevated liver enzymes, 10 Prophylaxis for allogeneic
hematopoietic stem cell
transplant recipients

Rex et al41 Fluconazole 800 mg—elevated liver Fluconazole + amphotericin B—elevated Candidemia
enzymes, 9 liver enzymes, 8

Rex et al42 Fluconazole—elevated liver enzymes, 14 Amphotericin B—elevated liver Candidemia

enzymes, 10

Walsh et al43 Voriconazole—elevated bilirubin, 9.6; Liposomal amphotericin B—elevated Empirical therapy for
elevated AST, 8.9; elevated ALT, 7; bilirubin, 10.9; elevated AST, 6.4; neutropenia and fever
elevated ALP, 2.9 elevated ALT, 8.1; elevated ALP, 4.3

GGT=gamma glutamyl transpeptidase; AST=aspartate aminotransferase; ALT=alanine aminotransferase; ALP=alkaline phosphatase.

(see Table). There is no clear association between drug
exposure (average concentrations) and the probability
of toxicity. Elevated LFTs generally normalize with the
cessation of posaconazole. There are rare reports of more
severe hepatitis, hepatic failure, and deaths in patients
with severe underlying medical conditions. Posaconazole
has not been well studied in patients with severe hepatic
dysfunction and probably should be used in this patient
population with significant caution.
LFTs should be serially monitored in patients receiving
posaconazole. If high LFTs are seen, there should be a low
threshold for stopping therapy or substituting an alternative
antifungal agent.
CONCLUSIONS
All of the azole antifungal agents are hepatotoxic, at
least to some degree. The best characterized toxicodynamic
relationships are for voriconazole. The majority of cases of
triazole-induced hepatotoxicity are asymptomatic elevation
of LFTs. While clinical sequelae appear exceedingly rare,
careful consideration must be given to stopping the agent
in question. If the drug is continued, clinical and laboratory
monitoring must be assiduous. LFTs tend to normalize
relatively promptly with the cessation of therapy. Further
work is required to define the toxicodynamic relationships
for this important class of antifungal agent more precisely.
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Clinical Primer:
Potential Hepatic Complications
With Triazole Therapy