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`
`Vol 6 N0 2 February 20 5
`
` fi 5
`
`Mike Williams EDITOR
`Stanley Crooke, Annette Doherty, William Hagmann, l0h" K9-mPv lamb I Plattner Co'EDlToRs
`
`/n this issue
`
`Anti-infectives
`- Pathogenic bacteria: How to get them back
`into the line of fire?
`
`I
`
`' Bacterial efflux pump inhibition
`' The use of quorum—sensing blockers to control
`biofilm-associated infections
`
`' New strategies for the treatment of infections
`associated with prosthetic joints
`
`' Protecting APOBEC3G: A promising new
`target for HIV drug discovery
`
`’ Current approaches to developing a
`Preventative HIV vaccine
`
`° H|V—1 assembly and budding as targets for
`drug discovery
`
`° Recent advances in antileishmanial drug
`
`development
`
`' Hepatotoxicity of antifungal agents
`' Telavancin
`.
`
`r
`
`R°taTe“
`' VRX-496
`
`A:
`
`N .
`
`,4 M
`PROPERTY
`NATIONAL
`K
`A Wm LIBRARY or
`A MEDICINE
`..............mum mm.
`
`is mater al was E>D«[J'lEi.‘.l
`atithe F-JLl%:1am:i may be
`
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`

`
`Current Opinion in lnvestigational Drugs
`Copyright © 2005 The Thomson Corporation
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`
`Hepatotoxicity of antifungal agents
`Jessica C Song” & Stanley Deresinskiz
`Address
`
`‘De%artment of Pharmacy Services
`and Division of Infectious Disease
`Santa Clara Valley Medical Center
`San Jose
`CA 95128
`USA
`
`Email: Jessica.Song@hhs.co.santa-c|ara.ca.us
`
`‘To whom correspondence should be addressed
`
`gii|_rrr]en_: Opinion in Invesiigational Drugs 2005 6(2):170-177
`e homson Corporation ISSN 1472-4472
`
`/lntzfungal agents have been implicated in numerous cases of
`hfpatotoxicity throughout
`the past few decades. Hepatotoxic
`reactions to antifungal agents range from slight, asymptomatic
`abnor-malities in liver function tests to potentially fatal fnlminant
`hep!-ltzcfailare. Clinically significant hepatic injury resulting from
`“’mf1”lg”l
`therapy most
`commonly manifests
`as
`acute
`hepatocellular,
`cholestatic or mixed hepatocellular—cholestatic
`reactions.
`In general, reactions usually resolve on cessation of
`therapy, but some antifungal agents may induce chronic liver
`damage. This review will summarize the hepatotoxicity profiles of
`the major
`classes of antifungal
`agents
`and will provide
`recommendations for drug monitoring in order to minimize the
`risk of hepatotoxicity.
`
`Keywords Adverse effect, amphotericin B, amphotericin B
`colloidal
`dispersion,
`amphotericin
`B
`lipid
`complex,
`antifungals,
`caspofungin,
`fluconazole,
`flucytosine,
`griseofulvin, hepatotoxicity,
`itraconazole, ketoconazole,
`liposomal
`amphotericin
`B,
`ravuconazole,
`terbinafine,
`toxicity, voriconazole
`
`and appropriate
`importance in the early rec0gr1ifi01'1
`critical
`toxicity and other
`ession
`management of adverse effects. While r1ePhI°
`I
`systemic effects of amphotericin B, and myelosuptid over
`associated with flucytosine have been well dOcul'Itle9(1;tOwaIdS
`the past few decades, less attention has been d1r€C
`the hepatotoxicity of antifungal agents [2]-
`
`gents range from
`Hepatotoxic reactions to pharmacolcj81C_al a
`function tests l0
`slight, asymptomatic abnormalitiesln l1‘_’91'
`e. The tYPe_ of
`potentially fatal
`fulminant hepatic fall“
`of liver function
`hepatotoxicity can be classified with the 1159
`findings
`l4l~
`tests
`or
`according
`to
`liver
`bl_0P5Y
`that results in
`Pharmacological agents may cause miury he atocenular
`degeneration or necrosis of h9Pat°CYl95_ (-r1}:lI‘V)- Some
`injury) or to arrested bile flow (C_l"‘_’1e5lat]c lcltergzed bya
`drugs may induce a mixed pattern 1flJ“_’Y Chara Hular and
`combination of the features observed 1_n.hePal(?Ce t
`icany
`cholestatic
`injury. Hepatocellular
`lnlury
`lst ytlian 2.
`associated with predominant elevations and Srea :rLT) and
`fold increases in serum alanine aminotransferase (
`[4]
`In
`aspartate aminotransferase (AST) C0nC?ntral‘°ns 1
`fi've1
`contrast, cholestatic injury is characterized by’: =7 Gite};
`slight elevations of aminotransferase levels, but Wlt gr/{LP}
`than 4-fold increases
`in alkaline
`pl105Phata5C ,1,( 1).“
`concentrations (often accompanied by increased bi j1r:"1]
`concentrations) and an ALT/ALP ratio of less than 2 [
`,
`t
`Furthermore,
`liver biopsy findings often‘ reveal potr
`inflammation in patients with cholestatic m]111'Yi but no 1“
`patients with hepatocellular injury.
`
`he major
`'triazoles,
`This review will describe the hepatotoxicity of t
`_
`classes of antifungals (ie, polyenes,
`imld3Zf’1e'
`echinocandin, allylamine, flucytosine and griseofulvin)‘ as
`summarized in Table 1. In addition, this review will pligcfvlcle
`recommendations for drug monitoring (when applica e) in
`order to minimize the risk of hepatotoxicity.
`
`introduction
`During the past two decades there has been a dramatic
`increase in the incidence of systemic fungal infections [1].
`This is due to: (i) the increasing number of bone marrow and
`solid
`organ
`transplantation
`patients
`receiving
`chemotherapy, (ii) the spread of AIDS, and (iii) advances in
`medical practice and technology leading to the increased
`utilization of invasive procedures for
`the treatment of
`critically ill patients [1]. Candida and Aspergillus species
`constitute the leading causes of invasive fungal infections,
`with Candida albicans accounting for
`the majority of all
`Candida infections [2]. However, non-albicans Candida spp
`are also increasingly reported as causes of life-threatening
`fungal
`infections. The current antifungal armamentarium
`available for the treatment of patients with invasive fungal
`infections is
`limited to amphotericin B and its
`lipid
`formulations,
`flucytosine,
`ketoconazole,
`the
`triazole
`antifungals itraconazole, fluconazole and voriconazole, and
`the echinocandin caspofungin [2].
`
`Polyenes
`_
`Amphotericin B deoxycholate
`Amphotericin B deoxycholate, a polyene antifungal, has
`been in clinical use for more than 37 years and is rarely
`implicated in cases of acute liver failure. The incidence of
`acute liver failure secondary to amphotericin B deoxycholate
`treatment
`is likely to be extremely low (less than l%
`incidence cited by the manufacturer) [6]. The prescribing
`information for this drug does not include the frequency of
`liver
`function test abnormalities. However,
`in a study
`comparing the efficacy of amphotericin B deoxycholate with
`liposomal amphotericin B as empirical antifungal therapy
`for febrile, neutropenic patients, a 20% frequency (increase
`in ALT or AST) was observed among patients receiving
`either drugs
`[7]. To date, despite the availability of
`amphotericin B deoxycholate in the US for nearly 40 years,
`Hepatic injury due to medications of all types is a concern,
`only three cases of significant hepatotoxicity associated with
`since it is implicated in 15 to 25% of acute liver failure cases
`amphotericin B deoxycholate have been reported in the
`in the US, with case fatality rates ranging from 10 to 50% [3].
`medical literature [80]. The pattern of liver injury observed
`With the increasing prevalence of systemic fungal infections,
`in these cases were mixed hepatocellular-cholestatic or
`some requiring prolonged treatment, an awareness of the
`predominantly hepatocellular, with hepatic injury occurring
`toxicity profiles of the available antifungal agents is of
`1'»-.i.e rv-I-I9wv<rf-Il \Dv“liF rfifiiflfl
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`

`
`Table 1. Hepatotoxic reactions to antifungal agents.
`' Antfgal drug
`lnesd inidence W a f liveijur
`LFTs/liver failure
`
`Polyene
`Amphotericin B
`deoxyoholate
`
`Acute liver failure rarely
`reported
`
`Hepatoceliular and
`hepatocelIularchoiestatic.
`
`Hepatotoxicity of antifungal agents Song 81 Deresinski 171
`
`7 Tim 0 nset ’
`
`H
`
`Preventive tratgy
`
`As early as 4 days
`or after total dose
`of approximately
`5 Q.
`
`Concomitant administration of
`other hepatotoxic antifungals, such
`as itraconazoie and amphotericin
`B, may increase the risk for
`hepatotoxicity due to increased
`Ieakiness of mammalian cell-
`membranes.
`
`Liposomal
`amphotericin B
`
`lmidazole
`Ketoconazole
`
`Triazoles
`Voriconazole
`
`Bi|i=11.1to18.1%;
`ALT = 14.6%; AST =
`12.8%; ALP = 7.1 to
`22.2%
`
`Not reported
`
`Bili = 3 to 19%;
`ALT/AST = 1 to 5%;
`ALP = 3 to 7%
`
`Transaminases = 2 to
`10%
`
`ALT = 10.7 to 18-9%;
`AST = 11.7 to 20.3%;
`ALP = 10.2 to 16%; Bill
`= 4.3 to 19.4%
`
`Hepatoceilular-cholestatic.
`
`Cholestatic.
`
`Hepatoceliular and
`hyperbiiirubinemia.
`
`As early as 10
`days,
`
`Not reported.
`
`Not reported.
`
`Mostly hepatocellular,
`cholestasis and
`he - atooellular-choiestatic.
`
`7 Weeks (range of
`1.5 to 24 weeks).
`
`Hepatocellular-cholestatic,
`hepatocellular and
`cholestatic.
`
`Often within first 10
`days of therapy.
`
`Monitor for CYP3A4, CYP2C9 and
`CYP2C19-mediated drug
`interactions.
`
`Fluconazole
`
`ALT/AST = 1%
`
`Hepatoceilular, hepatic
`necrosis and hepatoce|iuiar-
`cholestatic.
`
`4 to 34 days.
`
`Dose adjust for renal function.
`
`HepatocelIular-cholestatic
`and cholestatic.
`
`5 Days to several
`months.
`
`Not reported.
`
`Usually within 1
`month.
`
`Within 4 to 6
`weeks.
`3 Weeks to 4
`months.
`
`Adjust dose for renal function;
`maintain peak levels of 50 to 100
`/ml.
`
`i1
`1‘
`1
`1
`
`i
`Monitor ALP levels in patients who 1
`develo heaticd sfunction.
`Avoid a second course of
`treatment if patient experiences
`course.
`facial edema/pruritis during first
`
`i
`)
`
`ltraconazole
`
`Echinocandin
`Caspofungm
`acetate
`
`Flucytosine
`
`ALT = 2 to 3%; AST =
`1 to 2%; ALP = 1 to
`2%; Bill = 4 to 6%
`
`ALT = 10.8 to 13%;
`AST = 10.5 to 10.8%;
`Bili = 2.3%
`Transaminases = 0 to
`41%
`
`Hepatocelluiar and
`hyperbilirubinemia.
`
`Hepatocelluiar, cholestatic,
`hyperblllrubinemia and
`heatic necrosis.
`
`Allylamine
`Terbinallne
`
`Griseofulvin
`
`Transaminases = 4%
`
`Not reported
`
`Hepatoceliular, cholestatic
`and fulminant heatic failure,
`Cholestatic.
`
`Aacn amphotericin B colloidal dispersion, ABLC amphotericin B lipid complex, ALP alkaline phosphatase, ALT alanine aminotransferase,
`AST aspartate aminotransferase, Bili total bilirubin, LFTs liver function tests
`
`after the administration of cumulative doses ranging from
`200 mg to 5 g. The exact pathophysiology of amphotericin B
`deoxycholate-induced hepatic injury is unknown, but
`interference with the hepatic cytochrome P450 enzyme
`system and non—selective cellular disruption have been
`suggested [8.,9o]. Non-selective disruption of mammalian
`cells increases the permeability of cells, thereby facilitating
`the entry of other drug entities into the intracellular
`compartment. The risk of hepatic injury may then possibly
`be increased by the administration of amphotericin_B
`deoxycholate in combination with potentially hepatotoxic
`agents.
`
`One reported case involved a 26-year-old Caucasian male
`with pulmonary Blastomyces dermatilidis infection [80]. Initial
`treatment employed oral itraconazole (200 mg twice daily);
`intravenous amphotericin B deoxycholate (25 mg on the first
`day,
`followed by 50 mg once daily) was added to the
`therapeutic regimen 6 days later. Asymptomatic e1€Vafi01’i5
`in ALT, AST and ALP concentrations were noted after the
`patient
`received four doses of amphotericin B and a
`cumulative dose of 3200 mg of itraconazole. Peak levels of
`ALT, AST and ALP occurred the next day and were 518, 294
`and 205 U/1, respectively, thus prompting discontinuation
`of amphotericin B therapy. Within 4 days, the patient's hvel‘
`This rnateri al w‘as»m«pie»1:l
`at the NL!sr1a.nd may be
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`

`
`172 Current Opinion in lnvestigational Drugs 2005 Vol 6 No 2
`
`function tests normalized, despite continuation of itraconazole
`therapy. The patient described in this study likely experienced
`hepatocellular injury, as the liver damage primarily manifested
`as increases in ALT and AST. A possible adverse drug
`interaction with amphotericin B deoxycholate and itraconazole
`was postulated based on the enhanced entry of itraconazole
`into the intracellular compartment.
`
`Two previous cases of possible amphotericin B-related
`hepatotoxicity occurred after considerably higher
`total
`closes: a patient receiving amphotericin B for cryptococcal
`meningitis developed hepatotoxicity after a cumulative dose
`of almost 5 g while he was also receiving chlorpromazine, a
`recognized hepatotoxic agent; another patient developed
`reversible
`increases
`in transaminases and ALP after
`receiving a cumulative dose of 571 mg [80].
`
`Liposomal amphotericin B
`the only lipid
`Liposomal
`amphotericin B (AmBisome),
`formulation of amphotericin B that represents a liposomal drug
`delivery system, has been licensed for use in the US for seven
`years [10,11]. The incidence of elevations in bilirubin, ALT, AST
`and ALP levels associated with this agent in various clinical
`trials was 11.1 to 18.1, 14.6, 12.8 and 7.1 to 22.2%, respectively
`[10]. Of note,
`the safety data were primarily derived from
`clinical trials with febrile, neutropenic patients, a severely ill
`population in whom such abnormalities
`are
`frequently
`observed. At present, one case of mixed hepatocellular-
`cholestatic reaction secondary to liposomal amphotericin B has
`been reported in the medical literature [120]. The mechanism by
`which liposomal amphotericin B induces hepatotoxicity is
`believed to be due to the lipid component of this product, as the
`drug is preferentially sequestered in the reticuloendothelial
`tissue [120]
`
`Mohan et al described a study involving a 9-year-old patient
`who developed hepatic dysfunction after
`receiving a
`cumulative dose of 168 mg of liposomal amphotericin B over
`7 clays [12o]. Liposomal amphotericin B was discontinued
`after 11 days when the patient's ALT, AST and ALP were
`found to be 364, 1112 and 1254 U/l, respectively. Within 7
`days of discontinuing the drug, the patients liver function
`tests normalized. The liver
`function test abnormalities
`observed in this patient indicated a mixed hepatocellular-
`cholestatic injury. A retrospective report on the use of
`liposomal amphotericin B in 133 episodes of
`fungal
`infections
`lends support
`to the mixed hepatocellular-
`cholestatic pattern of injury associated with this drug [13].
`Mills et ul reported that hepatotoxicity occurred in up to 17%
`of fungal infection episodes; two cases were severe enough
`to warrant discontinuation of liposomal amphotericin B. The
`median peak concentrations of the patients‘ AST, ALP and
`bilirubin were 103 U/l (58 to 510), 582 U/1 (302 to 1362) and
`55 umol/ l (15 to 310), respectively [13].
`
`Amphotericin B lipid complex
`the first
`Amphotericin B lipid complex (ABLC; Abelcet),
`lipid formulation of amphotericin B to receive approval by
`the US Food and Drug Administration (FDA) for use in
`amphotericin B deoxycholate-refractory/intolerant patients,
`is comprised of amphotericin B complexed with two lipids
`in a 1:1 drug-to-lipid molar ratio [11,14]. The Liposome
`Company does not specify the frequency of liver function
`
`in ALT, AST, ALP and
`(elevations
`test abnormalities
`bilirubin) associated with this product. However, a'1_a1”89
`analysis of open—label multicenter trials of amphotericin B
`deoxycholate-refractory/intolerant
`patients
`(n
`=
`55])
`receiving ABLC for invasive fungal infections, showed a 1‘1Se
`in bilirubin occurring in 33% of evaluable cases, of whom
`25% had normal baseline values [15]. ABLC appeaf5 *0
`induce cholestatic hepatic injury in some patients, as shown
`by the significant elevations in bilirubin and ALP levels
`reported in the analysis conducted by Walsh et (11. To our
`knowledge, the pathogenesis of ABLC—induced choles-tasis
`has not been elucidated. The pivotal safety and efficacy
`analysis included 551 patients, of whom 80% had elther
`failed
`previous
`systemic
`antifungal
`therapy (mamly
`amphotericin
`B
`deoxycholate)
`or
`developed
`renal
`impairment secondary to amphotericin B deoxycholate l15l-
`l-lematological malignancy was
`the most C0mm0n
`underlying condition and was present in approximately 30%
`of cases. The mean serum bilirubin concentration increased
`by 41% from baseline at the end of therapy (p = 0.0001) and
`the mean serum ALP concentration increased by 17% from
`baseline at the end of therapy (p = 0.0015). Interestingly, the
`mean serum ALT level was not significantly altered at the
`end of treatment. Of note, patients enrolled in this study
`were diagnosed with numerous conditions such as sepsis,
`graft-versus-host disease (GVHD), veno-occlusive disease
`and end—organ damage due to chemotherapy that could
`have
`contributed
`to
`elevations
`in
`serum bilirubin
`concentrations. A similar pattern of hepatic injury was
`reported in a small retrospective analysis of 15 pediatric
`cancer patients, four (27%) of whom discontinued ABLC due
`to hyperbilirubinemia [16].
`
`Amphotericin B colloidal dispersion
`Amphotericin B colloidal dispersion (ABCD) is a colloidal
`dispersion of disc—shaped particles
`that
`received FDA
`approval for use in the US in December 1996 [11]. Rises in
`serum aminotransferases and bilirubin have occurred
`during ABCD therapy, but
`the
`true
`incidence
`of
`hepatotoxicity is confounded by the presence of competing
`causes for liver toxicity such as GVHD in many patients
`prior to treatment [1,17,18]. The incidence of elevations in
`bilirubin, ALT, AST and ALP levels associated with this
`agent in various clinical trials was 3 to 19, 1 to 5, 1 to 5 and 3
`to
`7,
`respectively
`[14]. Hepatocellular
`injury
`and
`hyperbilirubinemia
`represented
`the most
`commonly
`reported liver function test abnormalities in major clinical
`trials. Further
`research is needed to determine
`the
`mechanism responsible for its hepatotoxic effects.
`
`A randomized, double-blind, multicenter trial in which the
`efficacy of ABCD was compared with amphotericin B
`deoxycholate for the treatment of invasive aspergillosis (n =
`174) showed that hyperbilirubinemia occurred in 4.5 and 10.5%
`of ABCD- and amphotericin B-treated patients, respectively (p
`value not reported) [17]. Similarly, a phase I study of ABCD for
`the treatment of invasive fungal infections showed elevations in
`serum bilirubin concentrations in patients receiving ABCD at
`2.5 to 4.0 mg/kg/day (p = 0.002) and ABCD at 4.5 to 6.0
`mg/kg/ day (p = 0.009). Rises in AST and ALT occurred in 9
`and 13% of patients treated with ABCD, respectively, in an
`open—label trial that enrolled patients (n = 168) with systemic
`mycoses [1].
`
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`

`
`lmidazoles
`Ketoconazole
`a well—documented complication of
`Liver
`toxicity is
`ketoconazole administration [19-0]. The hepatic reaction to
`the drug is usually limited to an asymptomatic increase in
`serum transaminases, with an estimated frequency of 2 to
`10% [20]. Ketoconazole therapy has resulted in symptomatic
`hepatitis in approximately 1:15,000 to 1:10,000 recipients
`[19o0]. The pattern of
`liver
`injury
`is most
`often
`hepatocellular, butlcholestasis and hepatocellular-cholestatic
`injury may also occur. The mechanism of hepatotoxicity
`induced by ketoconazole has not been established, but
`interference with membrane sterol synthesis and inhibition
`of hydrogen peroxidase degrading enzymes may be
`involved in promoting this reaction [210-]. The mean time-
`to-onset of hepatic injury is usually within 7 weeks of
`treatment initiation, but patients may experience hepatic
`dysfunction as early as 1.5 weeks or as late as 24 weeks of
`therapy.
`
`A cohort study that included 69,830 patients, compared the
`risk of acute hepatotoxicity among users of antifungal
`agents,
`including ketoconazole,
`itraconazole,
`fluconazole,
`griseofulvin and terbinafine, with that of non-users. The
`diagnosis of acute liver injury in the study was based on the
`presence of symptoms suggestive of liver dysfunction (ie,
`nausea, vomiting, abdominal pain and/or jaundice) and
`increases in ALT, AST, ALP and bilirubin exceeding twice
`the upper limit of normal range. The relative risk of acute
`liver injury was 228.0 (95% confidence interval; range 33.9 to
`933.0) for ketoconazole, compared with the risk for non-
`users. In contrast, the relative risks of acute hepatotoxicity
`for itraconazole and terbinafine were considerably lower,
`and were shown to be 17.7 (range 2.6 to 72.6) and 4.2 (range
`0.2 to 24.9), respectively [21n].
`
`A retrospective analysis of 33 cases of ketoconazole-induced
`hepatic injury in the US showed that hepatocellular injury
`was evident in 55% of cases, whereas cholestatic injury and
`hepatocellular—cholestatic injury were evident in 15 and 27%
`of cases, respectively [190-]. One death was attributed to
`ketoconazole, with
`liver
`biopsy
`showing massive
`hepatocellular
`necrosis. Normalization of biochemical
`abnormalities and clearing of jaundice were noted 1 to 16
`weeks after discontinuation of ketoconazole therapy, with
`most patients experiencing resolution of hepatic injury
`within 7 weeks.
`
`Hepatotoxicity of antifungal agents Song 8. Deresinski 173
`
`progression or underlying immunocompromise, one patient
`died of liver failure that was judged to be associated with
`voriconazole therapy. Elevations in ALT, AST, ALI’ and
`bilirubin levels reported in clinical trials occurred at rates of
`10.7 to 18.9, 11.7 to 20.3, 10.2 to 16 and 4.3 to 19.4%,
`respectively [24]. The pattern of liver injury observed in one
`clinical
`trial
`included mixed hepatocellular—cholestatic,
`hepatocellular, or cholestatic, with hepatic injury usually
`occurring within the first 10 days of
`therapy [250-].
`Mechanisms underlying the development of hepatic injury
`associated with the use of voriconazole have not been
`elucidated.
`
`The issue of hepatotoxicity associated with the use of
`voriconazole was
`addressed by Denning et
`:11, who
`conducted an open-label study that evaluated the safety and
`efficacy of voriconazole in the treatment of acute invasive
`aspergillosis
`[25--]. Twenty patients (15%) experienced
`elevations in excess of 3- to 5-fold the upper limit of normal
`serum aminotransferases, ALP or bilirubin. Denning and
`colleagues suggested that liver function test abnormalities
`may have been associated with higher voriconazole serum
`concentrations, as biochemical abnormalities or hepatic
`failure occurred in six out of the 22 patients with plasma
`concentrations
`exceeding
`6000 ng/ml. Voriconazole
`undergoes
`extensive metabolism through
`numerous
`cytochrome P450 (CYP)
`isoenzymes,
`including CYPZC9,
`CYP2Cl9 and CYP3A4 [22]. Concomitant administration of
`voriconazole with inhibitors or substrates of CYPZC9,
`CYPZC19 or CYP3A4 will result in elevated voriconazole
`plasma concentrations, potentially increasing the risk of
`hepatic dysfunction in susceptible patients. In View of the
`potential
`pharmacokinetic
`drug
`interactions With
`voriconazole,
`it would be prudent to adjust the dose of
`voriconazole accordingly when it is co—administered with
`inhibitors of CYPZC9, CYPZC19 and CYP3A4.
`
`How does the hepatotoxicity profile of voriconazole fare
`against other antifungal agents? The US FDA Antiviral
`Drugs Advisory Committee reported a greater incidence of
`liver function test abnormalities among voriconazole-treated
`patients compared with fluconazole-treated patients with
`esophageal candidiasis [23]. In contrast,
`the incidence of
`hepatotoxicity among voriconazole-treated patients was
`comparable
`to
`that
`of patients who received lipid
`formulations of amphotericin B or amphotericin B (plus
`another antifungal agent) as empiric treatment for invasive
`aspergillosis.
`
`Flucanazole
`
`Triazoles
`Voriconazole
`Fluconazole may cause abnormalities of liver function tests
`(elevations in AST/ALT > 8-fold the normal levels) in 1% Of
`a
`is
`that
`triazole antifungal agent
`Voriconazole is a
`derivative of
`fluconazole [22]. Pooled data from 2090
`patients, but significant hepatic injury is rare [26]. To date,
`only four cases of fatal hepatic necrosis and seven Cases Of
`patients
`administered
`voriconazole
`in
`clinical
`and
`non-fatal hepatotoxicity due to fluconazole have been
`pharmacological trials indicated discontinuation rates of 1.4,
`1.0, 0.7 and 0.5% secondary to elevations in ALP, serum
`reported in the literature [50-,27]. Hepatocellular-cholestatic
`injury was evident in all four cases of fatal hepatitis, with
`aminotransferase (> 3-fold the upper limit of normal),
`time-to-onset of hepatic dysfunction ranging from 10 to 21
`bilirubin (> 1.5-fold the upper
`limit of normal) and
`days [50-,27]. Liver function test abnormalities observed in
`cholestatic jaundice, respectively [23]. In addition, 19 cases
`the non-fatal cases of hepatic dysfunction included (1)
`(0.9%) of hepatic failure leading to death occurred in the
`elevations in AST, ALT and bilirubin, (ii) increase in AST,
`voriconazole group during clinical and pharmacological
`trials. Although hepatic failure may have reflected disease
`and (iii) elevations in AST, ALT and ALP [5--1 The d“ra“°“
`Thi= rnanncrial ma: e‘-rrrsiznai
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2179 - 6/10
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2179 - 6/10
`
`

`
`174 Current Opinion in Investigational Drugs 2005 Vol 6 No 2
`
`therapy prior to the occurrence of non-fatal hepatic
`of
`dysfunction ranged from 4 to 34 days. Of note,
`the
`hepatotoxicity observed in two of the fatal hepatic necrosis
`cases and three of the non-fatal cases could have been
`attributed to the use of concomitant potentially hepatotoxic
`drugs
`(eg,
`antituberculosis
`agents
`and
`cimetidine).
`However,
`the
`sequential
`association with fluconazole
`administration and withdrawal pointed to this agent as the
`most likely cause of liver injury [5--]. The mechanism of
`fluconazole-induced hepatic injury is unknown, but is likely
`to differ from other triazole antifungals, as it is primarily
`excreted unchanged in the urine [26].
`
`Itraconazole
`Asymptomatic elevations in ALT, AST, ALP and total
`bilirubin have been reported with itraconazole use in clinical
`trials, with rates of 2 to 3, l to 2, 1
`to 2 and 4 to 6%,
`respectively [28]. To date,
`the FDA has received and
`reviewed at least 24 cases of liver failure attributed to the
`use of
`itraconazole in the US, with patterns of injury
`manifested
`as
`cholestatic
`or
`hepatocellular—cholestatic
`[29,30-]. Hepatic dysfunction can occur as early as 5 days
`after
`treatment
`initiation to as late as several months
`[29,31,32]. Recovery from hepatitis may be delayed in some
`patients; resolution of hepatotoxicity did not occur until 5
`months after discontinuation of treatment in one patient
`who developed severe cholestasis related to intraconazole
`[29].
`In addition to causing prolonged cholangiopathy,
`intraconazole use may lead to the development of chronic
`cholestatic syndrome for patients with prior exposure to this
`agent. One study described a patient who developed this
`syndrome two years after experiencing hepatitis related to
`therapy with intraconazole [32]. The exact mechanism of
`itraconazole-induced hepatotoxicity is unknown.
`
`Echinocandin
`
`caspofungin acetate
`Caspofungin acetate has been shown in some clinical studies
`to have
`the potential
`to induce liver
`function test
`abnormalities, but to no greater degree than that observed
`with fluconazole or amphotericin B deoxycholate [33,34].
`Phase II clinical trials in 263 individuals showed that 2.3% of
`caspofungin-treated patients
`experienced elevations
`in
`serum bilirubin concentrations exceeding 3-fold the upper
`limit of normal, but the incidence of hyperbilirubinemia did
`not differ from that observed in fluconazole—treated patients
`[33].
`In addition, a pooled analysis of data from three
`double-blind, randomized studies showed that elevated AST
`and ALT levels occurred in 10.5 to 10.8% and in 10.8 to 13%
`of patients receiving caspofungin at 50 to 70 mg/ day,
`respectively [34]. The incidence of AST/ALT abnormalities
`did not differ between caspofungin—treated patients and
`amphotericin
`B
`deoxycholate
`or
`fluconazole—treated
`patients. At present, the pattern and time of onset of hepatic
`injury,
`along with the pathophysiological mechanism
`responsible for hepatic biochemical abnormalities associated
`with caspofungin are unknown.
`
`theoretically low risk of drug if1f€TflCt1°115 W111‘
`the
`caspofungin given its
`19
`_
`_
`file’
`ther? 15
`evidence of enhanced hepa’t0‘f0><iC1tY W111‘ Coricomltant
`administration of this agent with ciclosfxmn and hlposomal
`amphotericin B [35,36]. In a study of four healthy V0 unteers,
`transient elevations in ALT levels to 2- to 3-fold the IIPPQ1
`limit of normal occurred in three individuals 1 day after the
`addition of ciclosporin to caspofungin. The individuals
`received 9 days of caspofungin therapy (70 1118/C13)’ 1") P1101‘
`to the addition of ciclosporin on day 10 (W70 doses ‘_’f 3
`mg/kg). Moreover,
`in the same study,
`t'_WO Out 01 918111
`individuals who received caspofungin (33 1118/ C1513’) f°1 3
`days plus two doses of ciclosporin (3 I118/kg
`exhibited ALT levels above the upper limit of normal on the
`second day. A retrospective evaluation of the C0r1C0mItaI1t
`use of caspofungin with ciclosporin (40%) 01'
`taC1°11111“5
`(60%) in organ transplant patients (mostly.lung transplafit)
`revealed hepatic biochemical abnormality In two out Of .19
`episodes of caspofungin use [37]. Elevations in ALT (iW1C€
`the upper
`limit of normal) or y-glutamyl
`transferase
`occurred in the
`two patients, but other hepatotoxic
`medications, such as voriconazole and amphotericin B, may
`have induced the biochemical abnormalities. Consequently,
`the prescribing information for caspofungin States that
`concomitant administration of this drug and ciclosporin
`should be reserved for patients for whom the potential
`benefit outweighs the potential risk [35].
`
`A retrospective evaluation of 30 patients with Aspergillus
`pneumonia refractory to liposomal amphotericin [3, showed
`that the addition of caspofungin to this agent was associated
`with mild elevation of ALP levels in 30% of the patients
`(degree of elevation not specified). The underly