Continuing Education: Review
`
`Ketoconazole-Associated Liver
`Injury in Drug-Drug Interaction Studies
`in Healthy Volunteers
`
`The Journal of Clinical Pharmacology
`2016, 56(10) 1196–1202
`C(cid:2) 2016, The American College of
`Clinical Pharmacology
`DOI: 10.1002/jcph.711
`
`Peymaan S. Banankhah, MS1, Kyle A. Garnick, BS2, and David J. Greenblatt, MD1,2
`
`Abstract
`Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with
`healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in
`the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the
`primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a
`review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure
`in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed
`in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure.
`All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support
`restriction of ketoconazole as an index CYP3A inhibitor in DDI studies involving healthy volunteers.
`
`Keywords
`ketoconazole, liver injury, healthy volunteers, drug-drug interaction studies, CYP3A
`
`The azole antifungal agent ketoconazole is a potent
`inhibitor of human CYP3A isoforms, and is commonly
`used as an index CYP3A inhibitor in drug-drug interac-
`tion (DDI) studies involving healthy volunteers.1–3 On
`July 26, 2013, the United States Food and Drug Ad-
`ministration (FDA) and the European Medical Agency
`(EMA) released directives imposing limitations on the
`use of oral ketoconazole as a first-line antifungal treat-
`ment, citing a potential risk for acute hepatic injury
`as the primary concern, along with a risk of adrenal
`insufficiency and drug interactions.4,5 These restrictions
`were limited to systemic ketoconazole use, and did not
`apply to topical formulations.4 The communication had
`clear ramifications for clinicians, but the implications
`for investigators conducting DDI studies were not
`immediately evident. On October 16, 2013, the FDA
`further recommended against exposure of study sub-
`jects in DDI studies to ketoconazole, stating that “drug
`companies and researchers [should] avoid using oral
`ketoconazole in drug interaction studies.”6 Regulatory
`agencies in Australia and China followed, discontinuing
`the oral formulation of ketoconazole in late 2013 and
`2015, respectively.7,8
`No specific data analysis was provided to support the
`regulatory decision to single out ketoconazole as having
`hazards beyond what is associated with any azole
`antifungal.2,9 Presumably, data from the FDA Adverse
`Events Reporting System (FAERS) was interpreted
`
`by regulatory agencies as supporting the restrictions
`imposed on the clinical use of ketoconazole as an
`antifungal agent. However, a recent FAERS analysis by
`Raschi et al. indicated that essentially all azole antifun-
`gal agents, including ketoconazole, are associated with
`a risk of liver injury.9
`Standard clinical ketoconazole regimens generally
`consist of 200 mg per day in adults, and treatment
`durations may exceed 6 months. In a recent review of
`ketoconazole-associated hepatotoxicity, liver injury ap-
`peared more likely in treatment regimens that exceeded
`30 days.10 However, DDI studies in healthy volunteers
`typically use systemic ketoconazole schedules of 200 or
`400 mg per day for 5 to 14 days. The FDA prohibition
`assumes that the use of oral ketoconazole for the dura-
`tion of such a study carries a risk of liver injury similar
`
`1Master of Science in Biomedical Sciences Program, Tufts University
`School of Medicine, Boston, Massachusetts, USA
`2Graduate Programs in Pharmacology and Drug Development and
`in Pharmacology and Experimental Therapeutics, Sackler School of
`Graduate Biomedical Science, Tufts University School of Medicine,
`Boston, Massachusetts, USA
`
`Submitted for publication 17 November 2015; accepted 22 January 2016.
`
`Corresponding Author:
`David J. Greenblatt, MD, Tufts University School of Medicine, 136
`Harrison Avenue, Boston, MA 02111
`Email: DJ.Greenblatt@Tufts.edu
`
`1
`
`TEVA1073
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`
`

`

`Banankhah et al
`
`1197
`
`to that associated with clinical use of longer duration.
`The present paper reviews recently published DDI
`studies to evaluate the prevalence of ketoconazole-
`associated abnormalities indicative of liver injury.
`
`Methods
`Inclusion and Exclusion Criteria
`A review of
`the literature was conducted through
`PubMed
`using
`search
`terms
`“ketoconazole,”
`“CYP3A,” and “inhibitor.” Studies
`selected for
`review were clinical DDI trials that met the following
`criteria: (1) Oral ketoconazole was given as the sole
`perpetrator drug, along with a victim drug. Exceptions
`were made for studies that utilized multiple perpetrator
`drugs if separate safety analyses were performed for
`each drug. (2) Subjects were healthy volunteers with
`no prior significant medical conditions as defined by
`the investigators of each trial, including any specific
`factors that might predispose to liver injury. Studies
`that included subjects with liver disease, a history
`of alcohol abuse, or other predisposing factors were
`not used in the analysis. (3) Commonly used serum
`chemistry indices of
`liver injury, such as alanine
`aminotransferase (ALT), aspartate aminotransferase
`(AST), and bilirubin, were measured at baseline and
`after ketoconazole exposure, and the relevant results
`were reported. (4) Studies were published between 2005
`and 2015.
`The PubMed search strategy was assumed to yield
`a random selection of existing DDI studies. Analysis
`of the literature was limited to published studies and
`did not include unpublished reports to which we did not
`have access.
`
`Analysis of Data
`For each study, the ketoconazole dosing schedule, the
`daily oral dose, the duration of exposure, and the total
`exposure were recorded. Any clinically relevant changes
`in serum chemistry or other adverse events associated
`with ketoconazole were documented. Evidence of liver
`injury was noted if the subject experienced notable
`adverse symptoms, or if any indicative serum parameter
`was greater than the upper limit of normal (ULN), or
`was ࣙ30% above the baseline value, in accordance with
`FDA guidelines for oral ketoconazole dosing as stated
`in the product label.11
`
`Results
`Characteristics of the Studies Reviewed
`The selected study set consisted of 53 separate DDI
`studies taken from 46 publications between 2005 and
`2015, which included 971 subjects with systemic ke-
`toconazole exposure12–57 (Table 1). A majority of the
`studies were conducted at study centers in the United
`
`States and Germany (Table 2). There was no apparent
`association between study location and occurrence of
`ketoconazole-associated hepatic injury. The median
`total systemic ketoconazole exposure was 2800 mg,
`and the median daily exposure was 400 mg. The study
`period duration varied, ranging from a single day of
`ketoconazole exposure to 28 days. The median duration
`of exposure was 7 days.
`
`Occurrence of Ketoconazole-Associated Abnormalities
`Of the 971 subjects included in the review, 6 subjects in
`6 separate DDI studies had clinically relevant changes
`in laboratory parameters during or after the DDI study,
`possibly indicative of liver injury. Affected individuals
`are referred to as subjects A-F (Table 3). Abnormal
`clinical chemistry values in 3 subjects (A, E, and F)
`were considered likely to be ketoconazole treatment-
`emergent and possibly indicative of acute liver injury.
`Mildly elevated ALT and AST in another subject (D)
`may or may not have been attributable to ketoconazole.
`Elevated serum ALT levels in the remaining 2 subjects
`were considered related to the victim drug as opposed
`to ketoconazole. The 4 cases in which ketoconazole
`was probably or possibly implicated represent 0.41%
`of all subjects included in the study set. None of
`the studies in which abnormal serum chemistry was
`observed were outliers in terms of daily ketoconazole
`dose, study duration, or total ketoconazole exposure,
`and there was no evident association between any of the
`aforementioned variables and serum chemistry abnor-
`malities. There was no reported instance of irreversible
`hepatic dysfunction or liver failure. All abnormalities in
`clinical chemistry values were reversible, and resolved
`on completion of ketoconazole treatment. No serious
`sequelae or deaths were reported.
`
`Consideration of Individual Cases
`Subject A was withdrawn on day 14 of a study by
`Lahu et al19 which evaluated the possible DDI between
`ketoconazole and roflumilast, a phosphodiesterase-4
`inhibitor. The subject had received 200 mg oral ke-
`toconazole daily for the 6 previous consecutive days.
`ALT levels reached 190 U/L (ULN = 60 U/L) on
`study day 14, at which point the subject was withdrawn
`from treatment. ALT levels peaked at 273 U/L (>4.5
`times ULN) on study day 21, and returned to the
`normal range by day 35. Following withdrawal from
`the study, the subject’s AST levels were elevated to
`1.5 to 2 times ULN; however, exact AST values were
`not reported. AST levels returned to the normal range
`by study day 28. The findings were considered to be
`consistent with transient liver injury associated with
`ketoconazole.
`Kotsuma et al21 reported 2 treatment-emergent ad-
`verse effects and an increase in serum ALT levels in
`
`2
`
`

`

`1198
`
`The Journal of Clinical Pharmacology / Vol 56 No 10 2016
`
`Table 1. DDI Studies Reviewed in the Present Analysis
`
`Reference
`Number
`
`Victim Drug
`
`Publication Year
`
`12
`13
`14
`14
`15
`16
`17
`18
`19
`19
`20
`21
`22
`23
`24
`25
`26
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`36
`37
`38
`39
`40
`41
`42
`43
`44
`44
`45
`46
`47
`48
`48
`49
`50
`51
`51
`52
`53
`54
`55
`56
`57
`
`Solifenacin
`Dexloxiglumide
`Prasugrel
`Clopidogrel
`Cinacalcet
`Cinitapride
`Praziquantel
`Aliskiren
`Roflumilast (1)
`Roflumilast (2)
`Temsirolimus
`Pactimibe
`Maraviroc
`Maribavir
`Ciclesonide
`Ambrisentan
`Saquinavir/Ritonavir (1)
`Saquinavir/Ritonavir (2)
`Udenafil
`Sotrastaurin
`Tolvaptan
`Tamsulosin
`Alitretinoin
`Neratinib
`Bosutinib (1)
`Nilotinib
`BMS 690514
`Vilanterol Tri
`Fluticasone Furoate + VI
`Safinamide
`Bosutinib (2)
`Buprenorphine
`Ruxolitinib
`Risperidone
`Midostaurin
`Macitentan
`Rivaroxaban (1)
`Rivaroxaban (2)
`Ponatinib
`Vorapaxar
`Lenvatinib
`GSK239512 (1)
`GSK239512 (2)
`Dabrafenib
`Apixaban
`Vilazodone (1)
`Vilazodone (2)
`PF-04449913
`CG100649
`Apremilast
`Teneligliptin
`Fentanyl
`Cabozantinib
`
`2005
`2005
`2006
`2006
`2007
`2007
`2007
`2008
`2008
`2008
`2008
`2008
`2008
`2008
`2008
`2009
`2009
`2009
`2010
`2010
`2011
`2011
`2011
`2011
`2011
`2011
`2012
`2012
`2012
`2012
`2012
`2012
`2012
`2012
`2013
`2013
`2013
`2013
`2013
`2013
`2014
`2014
`2014
`2014
`2014
`2014
`2014
`2014
`2014
`2014
`2014
`2015
`2015
`
`N
`
`16
`23
`18
`18
`24
`16
`10
`20
`26
`16
`17
`18
`12
`20
`14
`16
`29
`13
`12
`18
`17
`23
`16
`23
`24
`25
`17
`20
`18
`14
`48
`15
`16
`10
`27
`10
`12
`20
`22
`12
`18
`6
`16
`16
`18
`15
`21
`13
`26
`18
`16
`16
`27
`
`Ketoconazole Daily
`Dose (Mean, mg)
`
`Duration of
`Exposure (Days)
`
`Total Exposure
`(mg)
`
`200
`200
`400
`400
`400
`400
`400
`400
`200
`400
`400
`400
`400
`400
`400
`400
`200
`200
`400
`400
`200
`400
`200
`400
`400
`400
`400
`400
`400
`400
`400
`382
`400
`200
`400
`400
`200
`400
`400
`400
`400
`400
`400
`400
`400
`200
`200
`400
`400
`400
`400
`400
`400
`
`20
`6
`9
`9
`7
`7
`5
`4
`1
`13
`7
`7
`9
`1
`7
`7
`14
`20
`3
`6
`3
`5
`3
`5
`5
`6
`9
`6
`11
`6
`5
`11
`4
`3
`10
`24
`4
`5
`5
`28
`17
`9
`9
`4
`6
`14
`14
`7
`5
`7
`5
`2
`28
`
`4000
`1200
`3600
`3600
`2800
`2800
`2000
`1600
`200
`5200
`2800
`2800
`3600
`400
`2800
`2800
`2800
`4000
`1200
`2400
`600
`2000
`600
`2000
`2000
`2400
`3600
`2400
`4400
`2400
`2000
`4200
`1600
`600
`4000
`9600
`800
`2000
`2000
`11,200
`6800
`3600
`3600
`1600
`2400
`2800
`2800
`2800
`2000
`2800
`2000
`800
`11,200
`
`subject B, although exact ALT levels were not provided.
`This study evaluated the possible DDI of ketoconazole
`with pactimibe, an ACAT-1 inhibitor that failed to
`reach the market. The ketoconazole dosing schedule
`
`was 400 mg daily for 1 week. The reported abnormal-
`ities were not exclusive to the ketoconazole treatment
`period, and resolved without any action taken. These
`events were considered to be unrelated to ketoconazole.
`
`3
`
`

`

`Banankhah et al
`
`Table 2. Origin of the Reviewed DDI Studies
`
`1199
`
`Country of Origin
`
`Number
`of Studies
`
`Number of
`Subjects
`
`Ketoconazole
`Exposure Duration
`(Mean, Days)
`
`Total Ketoconazole
`Exposure (Mean, mg)
`
`Instances of Ketoconazole-
`Associated Serum Chemistry
`Abnormalities
`
`United States
`Germany
`Netherlands
`France
`South Korea
`United Kingdom
`Australia
`Canada
`Thailand
`Spain
`Israel
`
`24
`12
`4
`2
`2
`2
`2
`1
`2
`1
`1
`
`455
`218
`100
`42
`38
`28
`22
`22
`20
`16
`10
`
`9
`6
`11
`17
`4
`8
`9
`5
`4
`7
`24
`
`3322
`2133
`3300
`3400
`1600
`3200
`3600
`2000
`1300
`2800
`9600
`
`1
`1
`0
`0
`0
`0
`2
`0
`0
`0
`0
`
`Table 3. Summary of Biochemical Abnormalities Observed in the Reviewed Studies
`
`Study Reference
`Number
`
`Affected
`Subject
`
`Event
`
`Assessment of Causality
`
`Outcome
`
`19
`
`21
`
`28
`
`47
`
`48
`
`48
`
`A
`
`B
`
`C
`
`D
`
`E
`
`F
`
`Elevated serum ALT (273 U/L,
`ULN = 60 U/L) and AST (exact
`values not reported, 1.5-2 × ULN)
`Elevated serum ALT (exact values
`not reported)
`Elevated serum ALT (74 U/L, ULN =
`60 U/L)
`
`Elevated serum ALT and AST (exact
`values not reported, mild severity)
`Elevated serum ALT (144 U/L, ULN=
`60 U/L)
`Elevated serum bilirubin (40 mmol/L,
`ULN=17 mmol/L)
`
`Ketoconazole-associated
`
`Unrelated to ketoconazole
`
`Unrelated to ketoconazole
`
`Possibly ketoconazole-associated
`
`Ketoconazole-associated
`
`Ketoconazole-associated
`
`ALT and AST levels returned to normal
`range 21 days after treatment
`discontinuation
`ALT levels spontaneously returned to
`normal range
`ALT levels returned to normal range
`within 60 days after treatment
`discontinuation
`ALT levels spontaneously returned to
`normal range
`ALT levels returned to normal range
`after treatment discontinuation
`Bilirubin levels returned to normal
`range after treatment discontinuation
`
`Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
`
`In a study investigating the kinetics of sotrastaurin
`with CYP3A inhibition conducted by Kovarik et al,28
`elevated ALT levels were observed in subject C after
`completion of the ketoconazole dosing regimen. Treat-
`ment consisted of 200 mg oral ketoconazole twice daily
`for 6 days, along with a single dose of sotrastaurin on
`study day 4. ALT levels were reported at 74 U/L (>20%
`elevation over ULN) at the end of the study period.
`The investigators were not able to reassess the affected
`subject for 60 days, at which point ALT levels were
`within the reference range. The investigators considered
`these abnormalities likely related to sotrastaurin.
`Elevated serum ALT and AST levels were reported
`in subject D in the study by Shumaker et al.47 The trial
`evaluated the kinetics of lenvatinib, a novel VEGFR2
`and VEGFR3 kinase inhibitor, when given with 400
`mg ketoconazole for 17 consecutive days. Exact ALT
`and AST serum levels were not presented, but the
`investigators considered the changes to be of mild
`severity. The relation to ketoconazole treatment was not
`established.
`
`In a study conducted by Xu et al,48 GSK239512,
`an experimental H3-receptor antagonist, was the victim
`drug. Peak ALT levels of 144 U/L (>2 times ULN)
`were reported in subject E. ALT levels began to decrease
`at the termination of ketoconazole treatment, and
`returned to normal. In a separate cohort of the same
`study, subject F experienced transient asymptomatic
`hyperbilirubinemia (40 mMol/L, ULN = 17 mMol/L).
`Both study cohorts received 400 mg oral ketoconazole
`daily for 9 days. The investigators considered the abnor-
`malities in both cases to be related to ketoconazole.
`
`Discussion
`Less than half of 1% (0.41%) of subjects included in the
`present review had evidence of ketoconazole-associated
`hepatic injury. In all cases the findings consisted of
`asymptomatic abnormalities in commonly used serum
`chemistry indices of
`liver injury, and all resolved
`on treatment discontinuation with no specific medi-
`cal intervention. This may reflect the relatively short
`
`4
`
`

`

`1200
`
`The Journal of Clinical Pharmacology / Vol 56 No 10 2016
`
`treatment duration and low overall ketoconazole expo-
`sure in DDI studies as compared to a clinical treatment
`course. The incidence of ketoconazole-associated liver
`injury found in this review is consistent with a recent
`report by Lo Re et al.58
`Ketoconazole produces rapid and reversible CYP3A
`inhibition, and DDI studies with ketoconazole preex-
`posure durations as short as 1-2 days produce maximal
`inhibition of CYP3A metabolic activity.2,3,59,60 In the
`present analysis, subjects who experienced probable or
`possible ketoconazole-associated abnormalities (A, D,
`E, and F) had been exposed to ketoconazole for longer
`than the median study length of 1 week (13, 17, 9,
`and 9 days, respectively) prior to discontinuation of
`ketoconazole treatment. All studies involved healthy
`subjects without hepatic disease or other predisposing
`factors, and excluded individuals with a history of
`alcohol abuse.
`Our review has the limitation that we assumed the
`studies we identified to be representative of the larger
`data base. In addition, we did not have access to unpub-
`lished data. Nonetheless, we evaluated reports of close
`to 1000 healthy volunteers who received ketoconazole
`in the course of clinical DDI studies. The findings
`indicate that systemic ketoconazole use in this context
`carries minimal risk of hepatic injury.
`A number of alternative index CYP3A inhibitors
`have been proposed, for use in DDI studies. Itra-
`conazole and clarithromycin have been proposed, but
`do not produce in vivo CYP3A inhibition compa-
`rable to ketoconazole.2,61–63 Itraconazole is associ-
`ated with incidence rates of hepatic injury similar to
`ketoconazole.2,9,58 Ritonavir produces in vivo CYP3A
`inhibition similar to or greater than ketoconazole,
`and is the most appropriate perpetrator drug to serve
`as an alternative to ketoconazole in DDI studies of
`healthy volunteers.2,63,64 Cobicistat is closely related to
`ritonavir,65 and is another option to serve as an index
`CYP3A inhibitor.61,63,64
`
`Conclusions
`Ketoconazole should continue to serve as the standard
`CYP3A inhibitor in DDI studies involving healthy
`volunteers. The risk of liver injury in this context is
`minimal, and can be further mitigated by using short
`durations of ketoconazole exposure.
`
`Disclosures
`The authors have no disclosures to report.
`
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`7
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`

`

`Editor: Joseph S. Bertino, Jr., Schenectady, NY
`
`Associate Editors:
`Hartmut Derendorf, University of Florida, Gainsville, FL
`Michael D. Reed, Orange Village, OH
`
`Managing Editor: Marjory M. Spraycar, Philadelphia, PA
`
`Assistant Managing Editor: Elizabeth Marshall, Towson, MD
`
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`McKeen Cattell
`Deborah L. Keefe
`Daniel S. Sitar
`John C. Somberg
`Lisa L. von Moltke
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`Guohua An, Iowa City, IA
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