interactions between azole antifungals and antiretrovirals

21 Pages·2014·0.13 MB·English

INTERACTIONS BETWEEN AZOLE ANTIFUNGALS AND ANTIRETROVIRALS

Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
Kinetic Substrate of CYP3A4 Substrate of Substrate of CYP3A4. Substrate of p- Inhibits CYP3A4. Substrate of
Characteristics (11%)1, p- CYP3A46, p- Inhibits CYP3A4 glycoprotein, Induces CYP3A, 2B CYP2C19 (major),
glycoprotein2. Inhibits glycoprotein2. Inhibits (potent), 2C9, 1A2, p- UGT1A4. Inhibits (preliminary data in CYP3A4, CYP2C9.
CYP3A4, 2C93, CYP3A46, p- glycoprotein7, UGT.4, 5 CYP3A4, p- animal studies). Inhibits CYP3A48,
2C193, UGT4, 5 glycoprotein2. glycoprotein. 2C9, 2C19.
CCR5 Inhibitor
Maraviroc Potential for Potential for When given with Potential for Potential for ↑
fluconazole to ↑ itraconazole to ↑ ketoconazole 400 mg posaconazole to ↑ maraviroc
(metabolized by maraviroc maraviroc QD, maraviroc AUC ↑ maraviroc concentrations due to
CYP3A4 and p- concentrations via concentrations via 5-fold, Cmax ↑ 3.4- concentrations via CYP3A4 inhibition by
glycoprotein.9) CYP3A4 inhibition. CYP3A4 inhibition. fold.10 Reduction of CYP3A4 inhibition. voriconazole. Since
Administration of the Reduction of maraviroc dose by Reduction of voriconazole is
standard maraviroc maraviroc dose by 50% in the presence maraviroc dose by considered a
dose (300 mg BID) 50% in the presence of protease 50% in the presence moderate CYP3A4
should be done with of protease inhibitors/potent of protease inhibitor, the
caution.9 inhibitors/potent CYP3A4 inhibitors is inhibitors/potent magnitude of the
CYP3A4 inhibitors is recommended.9 CYP3A4 inhibitors is interaction is likely
recommended.9 recommended.9 less than with more
potent inhibitors.
Monitor closely for
maraviroc-related
toxicity if maraviroc
300mg twice daily
dose is used.9 It is
unclear whether a
dosage ↓of maraviroc
to 150 mg twice daily
is recommended as it
is with other more
potent CYP3A4
inhibitors (i.e.
ketonazole,
itraconazole,
clarithromycin).9
Integrase Inhibitor
Dolutegravir Interactions are Interactions are Interactions are Interactions are Interactions are Interactions are
(metabolized by unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on
UGT1A1 with some dolutegravir dolutegravir dolutegravir dolutegravir dolutegravir dolutegravir
contribution by metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use
CYP3A4. Inhibits standard doses of standard doses of standard doses of standard doses of standard doses of standard doses of
renal OCT2 both drugs. both drugs. both drugs. both drugs. both drugs. both drugs.
transporter; no
other inhibitory or
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
inductive potential
in vitro.11)
Elvitegravir Potential for ↑ Potential for ↑ In a healthy volunteer Potential for ↑ Potential for ↑ Potential for ↑
(metabolized by fluconazole and/or itraconazole and/or study, subjects posaconazole and/or ravuconazole and/or voriconazole and/or
CYP3A4, elvitegravir and elvitegravir and received elvitegravir elvitegravir and ↑/↓ elvitegravir and elvitegravir and
UGT1A1/3, cobicistat cobicistat 150/ritonavir 100 mg cobicistat cobicistat cobicistat
moderate 2C9 concentrations. concentrations. Do daily alone and then concentrations. concentrations. concentrations.12
inducer) not exceed maximum with ketoconazole 200
Boosted by daily dose of mg BID, each for 10
cobicistat (3A4, itraconazole 200 mg12 days, followed by 4
2D6 substrate, more days of
inhibitor of 3A4, ketoconazole 200 mg
2D6, P- BID alone. In the
glycoprotein) presence of
ketoconazole, modest
increases in
elvitegravir exposures
were observed: 17%
↑ Cmax, 48% ↑ AUC,
67% ↑Cmin. A
maximum
ketoconazole dose of
200 mg once daily is
recommended when
coadministering with
boosted elvitegravir.13
Raltegravir Interactions are Interactions are Interactions are Interactions are Interactions are Interactions are
unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on
(metabolized by raltegravir raltegravir raltegravir raltegravir raltegravir raltegravir
UGT1A1 and has metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use
no inhibitory or standard doses of standard doses of standard doses of standard doses of standard doses of standard doses of
inductive potential both drugs. both drugs. both drugs. both drugs. both drugs. both drugs.
in vitro.14)
NNRTIs
Delavirdine A dual inhibition A dual inhibition A dual inhibition Possible ↑ delavirdine
interaction is possible interaction is possible interaction is possible concentrations due to
(metabolized via via CYP 3A4 inhibition via CYP 3A4 inhibition via CYP 3A4 inhibition CYP3A4 inhibition by
CYP3A4; also by delavirdine and by delavirdine and by delavirdine and posaconazole.
inhibits 3A4, as well fluconazole. No itraconazole. Monitor ketoconazole. No Monitor for delavirdine
as 2C9, 2C19.15) interaction noted.16 for both delavirdine delavirdine dosage toxicity.
Use standard doses and itraconazole adjustment
of both drugs. toxicity (i.e. recommended with
hepatotoxicity). inhibitors of CYP3A4
or CYP2D6.16 Monitor
for both delavirdine
and ketoconazole
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
toxicity (i.e.
hepatotoxicity).
Efavirenz Potential for dual In a pharmacokinetic In a pharmacokinetic Posaconazole AUC ↓ Dual
induction/inhibition study of healthy study of 12 HIV- 50% by efavirenz,24, 25 induction/inhibition
(In vitro is a potent interaction due to subjects, efavirenz infected patients, the likely via efavirenz- interaction likely due
inducer and efavirenz-mediated 600 mg plus kinetics of single-dose mediated induction of to efavirenz-mediated
inhibitor of CYP3A4 induction itraconazole 200 mg ketoconazole 400 mg posaconazole CYP3A4, 2C9, 2C19
CYP3A4. Induces and fluconazole- BID for 14 days led to was measured alone glucuronidation. induction of
2B6.17 Also inhibits related CYP3A4 a 39% ↓ AUC of and after 14 days of voriconazole and
CYP2C9, 2C19.3) inhibition. No itraconazole and 37% efavirenz/3TC/d4T. In Avoid combination voriconazole-related
interaction noted with ↓ AUC of its hydroxyl- the presence of unless the benefits CYP3A4 inhibition of
combination.18 Use metabolite; EFV steady-state clearly outweigh the efavirenz metabolism.
standard doses of exposures were not efavirenz, risks of antifungal 80% ↓ voriconazole
both drugs. affected.19 ketoconazole Cmax ↓ failure. Consider AUC; 43% ↑ efavirenz
44% and AUC ↓ posaconazole TDM to AUC when given as
72%.23 Avoid dose-adjust.22 voriconazole 400 mg
Case report of HIV-
concomitant use; every 12 hours (day
positive male with
consider alternate 1), then 200 mg
disseminated
antiretroviral or every 12 hours and
histoplasmosis with
antifungal therapy. efavirenz 400 mg
undetectable daily x 9 days.26
itraconazole
55% ↓ voriconazole
concentrations and
AUC; 1% ↑ efavirenz
persistently elevated
AUC when given as
urinary Histoplasma
voriconazole 300 mg
antigen levels while
every 12 hours and
on efavirenz and
efavirenz 300 mg
itraconazole 200 mg daily.27
BID. Therapeutic

itraconazole levels
7% ↓ voriconazole
and a decrease in
AUC; 17% ↑
urinary Histoplasma
efavirenz AUC when
antigen levels were
given as
observed after
voriconazole 400 mg
efavirenz was
every 12 hours and
replaced with
efavirenz 300 mg
atazanavir/ritonavir.20
daily. These values
are similar to
In a retrospective monotherapy with
cohort analysis, either agent alone. 27
itraconazole levels
were assessed in 10 Case report in 40
HIV-positive patients year-old male with
with disseminated mild HCV-related
histoplasmosis; 4 cirrhosis and
patients were on PI cryptococcal
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
therapy, 4 on NNRTIs, meningitis requiring a
and 2 on both PIs and dosage adjustment of
NNRTI therapy. All oral voriconazole
NNRTI patients had titrated to 200 mg
undetectable twice daily and
itraconazole efavirenz 300mg
concentrations, vs.1/4 once daily to yield
PI patients. Two therapeutic
patients who switched concentrations of both
from NNRTI to PI drugs and positive
therapy subsequently clinical outcomes.28
had therapeutic
itraconazole levels.21 Contraindicated at
No data using higher standard doses.18
doses of itraconazole. Recommended
dosage adjustment:
↑ voriconazole
Avoid this
maintenance dose to
combination if
400 mg twice daily
possible. If
(from 200mg twice
coadministered,
daily) and ↓ efavirenz
closely monitor
dose to 300mg once
itraconazole
daily (from 600mg
concentration and
once daily). Use the
adjust dose
accordingly.22 capsule formulation to
obtain this dose since
efavirenz 600mg
Use of alternate tablets should not be
antifungal treatment broken.18
may be necessary or
replacement of Short-term co-
efavirenz with a non- administration (i.e. a
inducing class of few days) may not
antiretrovirals such as require empiric
protease inhibitors, dosage adjustments.
integrase or CCR5 When either agent is
inhibitors if possible. discontinued, dosage
readjustments are
required.
Etravirine In healthy volunteers, Possible ↑ etravirine Possible ↑ etravirine Possible ↑ etravirine In healthy volunteers,
coadministration of concentrations and/or plasma concentrations due to coadministration of
(substrate of etravirine 200 mg BID ↓ concentrations of concentrations and/or CYP3A4 inhibition by etravirine 200 mg BID
CYP3A4, CYP2C9, plus fluconazole 200 itraconazole. Dose ↓ plasma posaconazole.29 No plus voriconazole 200
and CYP2C19. mg daily for 9 days adjustments for concentrations of anticipated effect on mg BID for 9 days
Weak inducer of resulted in 109% ↑ itraconazole may be ketoconazole.29 Dose posaconazole resulted in 52% ↑
CYP3A4, weak Cmin, 75% ↑ Cmax necessary.22, 29 adjustments for concentrations. Cmin, 26% ↑ Cmax
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
inhibitor of CYP2C9 and 86% ↑ AUC of Consider TDM of both ketoconazole may be Monitor for etravirine- and 36% ↑ AUC of
and a moderate etravirine, while drugs if possible. necessary. Monitor related toxicity. etravirine, and 23% ↑
inhibitor of fluconazole for ketoconazole Cmin and 14% ↑ AUC
CYP2C19. Also parameters were efficacy. of voriconazole
inhibits p- unchanged compared (although no ↑ was
glycoprotein. No to either drug observed in carriers of
clinically relevant administered alone. CYP2C19*2 allele)
effect on CYP1A2 The combination was compared to either
or CYP2D6.29, 30) well tolerated.31 Use drug administered
standard doses of alone. The
both drugs. Monitor combination was well
for side effects of tolerated.31 Dose
etravirine. adjustments are not
required. Monitor
closely for toxicity.

**see also entry for
darunavir/ritonavir
plus etravirine plus
voriconazole
Nevirapine In a study of 24 HIV+ In a healthy volunteer, Ketoconazole levels Possible ↑ nevirapine Potential ↓
subjects, combination cross-over study of sig. reduced (63% ↓ concentrations due to voriconazole AUC
(substrate and of nevirapine 200 mg itraconazole 200 mg AUC, 40% ↓ Cmax,) CYP3A4 inhibition by and ↑ nevirapine
potent inducer of BID and fluconazole QD, nevirapine 200 15-20% ↑ NVP posaconazole. No AUC. Avoid
CYP3A4 and 2B6 200 mg daily resulted mg QD or the concentrations.36 anticipated effect on combination if
enzymes.2) in ~100% ↑ AUC of combination (each for Avoid concomitant posaconazole possible. If using the
nevirapine compared 7 days), itraconazole use; consider concentrations. combination, consider
with historical data; Cmax ↓ 38% and alternate antiretroviral Monitor for TDM of both agents to
25% of subjects also AUC ↓ 61% in the or antifungal therapy. nevirapine-related dose-adjust. Monitor
developed elevated presence of toxicity. for nevirapine toxicity
liver transaminases nevirapine. and voriconazole
>5 times upper limit of Nevirapine efficacy.
normal. Nevirapine parameters were not
did not affect the changed.35
pharmacokinetics of
fluconazole.32 In a
retrospective study of Avoid combination if
122 HIV-infected possible. If
patients receiving coadministered,
nevirapine, those also monitor
taking fluconazole 200 itraconazole
or 400 mg daily concentration and
(n=41) had NVP Cmin adjust dose
76% higher compared accordingly.22
to those not taking
fluconazole. One
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
patient on fluconazole
developed clinical
hepatitis.33 In a
prospective placebo-
controlled trial, low-
dose fluconazole
(200mg 3x/weekly)
resulted in a 29% ↑
AUC of nevirapine.
There was no
additional risk of
hepatotoxicity with the
combination.34
Use combination with
caution. Monitor
closely for nevirapine
associated adverse
effects including
hepatotoxicity.
Rilpivirine Fluconazole is the Potential for increased In healthy subjects, Potential for increased Potential for increased
preferred azole option concentrations of steady-state concentrations of concentrations of
(metabolized for patients taking rilpivirine and coadministration of rilpivirine and rilpivirine and
primarily by rilpivirine. Potential decreased azole rilpivirine 150 mg QD decreased azole decreased azole
CYP3A4, as well as for increased concentrations with plus ketoconazole 400 concentrations with concentrations with
CYP2C19, 1A2, concentrations of concomitant mg QD, rilpivirine concomitant concomitant
2C8/9/10 (minor). rilpivirine and administration. No AUC ↑ 49%, Cmax ↑ administration. No administration. No
Moderate inducer of decreased azole rilpivirine dose 30% and Cmin ↑ rilpivirine dose rilpivirine dose
CYP2C19, slight concentrations with adjustment is 76%, while adjustment is adjustment is
inducer of CYP1A2, concomitant required. Monitor for ketoconazole AUC ↓ required. Monitor for required. Monitor for
2B6 and 3A4. A administration. No breakthrough fungal 24%, Cmax ↓ 15% breakthrough fungal breakthrough fungal
clinically relevant rilpivirine dose infections.22, 39 and Cmin ↓ 66% infections.39 infections.39
effect on CY3A adjustment is
compared to each
activity is required. Monitor for agent alone.40
considered unlikely breakthrough fungal

with phase III infections.39.
No rilpivirine dose
dose.37 No effect
adjustment is
on CYP2E1
required. Monitor for
activity.38)
breakthrough fungal
infections.39
PIs
Atazanavir In healthy subjects, Potential for ↑ In a healthy volunteer Atazanavir: 268% ↑ Paradoxical
coadministration of concentrations of PIs study, AUC atazanavir when interaction displaying
(Primarily atazanavir 300/rtv 100 and/or itraconazole coadministration of given as 300 mg daily short-term inhibition
metabolized by mg QD plus via CYP 3A4 inhibition 400 mg atazanavir x 14 days with followed by induction
CYP3A4; also fluconazole 200 mg by both agents. plus 200 mg posaconazole 400 mg at steady-state.
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
inhibits CYP3A and QD for 10 days did Clinical significance ketoconazole daily did twice daily x 7 days • Short-term: ↑
UGT1A1.41 not result in changes unclear, monitor for not result in significant Atazanavir/RTV: voriconazole
Atazanavir alone to pharmacokinetic dose-related toxicities. changes in atazanavir 146% ↑ AUC concentrations
does not induce parameters of either concentrations.44 atazanavir when given initially due to
glucuronidation, ATV, rtv or Dosage adjustment as 300 mg/100 mg RTV-related
while atazanavir/ fluconazole.43 Use not necessary with daily x 14 days with CYP3A4
ritonavir does standard doses of unboosted atazanavir. posaconazole 400 mg inhibition,
induce both drugs. twice daily x 7 days.24, particularly in
glucuronidation.42) 25 CYP2C19 poor
Empiric dosage metabolizers.
adjustments are not • Steady-state: ↓
recommended. voriconazole
Monitor for concentrations
atazanavir-related due to
toxicity. In cases of CYP2C19/2C9
suspected toxicity, induction.
TDM may be useful to
dose-adjust. With RTV 100 mg
twice daily: 39% ↓
voriconazole AUC;
14% ↓ RTV AUC45, 46

Use of low boosting
doses of RTV (i.e.
100mg twice daily)
combined with any of
the other PIs should
be avoided unless
the benefits outweigh
the risks of antifungal
failure.41, 46

Case report of
positive immunologic
and virologic
response in a patient
with multidrug-
resistant HIV on
atazanavir 300 mg
QD, raltegravir 400
mg BID and
tenofovir/emtricitabine
concurrently with
voriconazole
200 mg twice daily.47

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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole

An open-label
nonrandomized study
assessed the impact
of atazanavir/ritonavir
300/100-mg QD on
the kinetics of
voriconazole in
CYP2C19 extensive
metabolizers (EMs)
and poor metabolizers
(PMs).
Among EMs,
coadministration
resulted in 33% ↓
AUC and ↓ 39% Cmin
of voriconazole, and
12% ↓ AUC and 20%
↓ Cmin of atazanavir.
Among PMs,
coadministration
resulted in ↑
voriconazole Cmax,
AUC and Cmin by
4.4-, 5.6-, and 7.7-
fold, while atazanavir
AUC ↓ 20%, Cmax ↓
19% and Cmin ↓
31%. Ritonavir AUC
and Cmax did not
change substantially
with voriconazole
codosing in either
study group.48

Complex case report
of a female with
CYP2C19*17 allele
(rapid metabolizer)
who achieved target
Cmin voriconazole
concentrations with
concomitant
raltegravir and
TDF/FTC and
esomeprazole
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
(CYP2C19 inhibitor).
The patient was
switched to unboosted
atazanavir with
ranitidine and the
esomeprazole was
stopped.CYP3A4
inhibition by
atazanavir coupled
with uninhibited
CYP2C19 resulted in
subtherapeutic
voriconazole Cmin.
Management involved
replacement with
darunavir/ritonavir and
reintroduction of
esomprazole (double
blockade of CYP3A4
and 2C19 pathways).
The voriconazole
Cmin ↑14-fold and
dose was reduced by
50%.49

Avoid combination
unless the benefits
outweigh the risks of
antifungal failure.
Darunavir Potential for ↑ Coadministration of Coadministration of Possible ↑ PI Paradoxical
concentrations of PIs darunavir 400/100 mg darunavir 400 mg BID concentrations due to interaction displaying
(Primarily and/or fluconazole BID and ketoconazole and ketoconazole 200 CYP3A4 inhibition by short-term inhibition
metabolized by via CYP 3A4 inhibition 200 mg BID led to mg BID in healthy posaconazole. followed by induction
CYP3A4. Inhibits by both agents. 212% ↑ ketoconazole volunteers (n=6) led Monitor for PI-related at steady-state.
CYP3A4.50) Monitor for both PI exposure and 42% ↑ to 155% ↑ AUC, toxicity. • Short-term: ↑
and fluconazole darunavir exposure.51 179% ↑ Cmin of voriconazole
toxicity (i.e. A similar interaction darunavir, and no concentrations
hepatotoxicity). may be possible with significant change in initially due to
itraconazole. Do not ketoconazole levels. RTV-related
exceed 200 mg CYP3A4
itraconazole per day inhibition,
Coadministration of
while on particularly in
darunavir 400/100 mg
darunavir/ritonavir. CYP2C19 poor
BID and ketoconazole
metabolizers.
200 mg BID in healthy
• Steady-state: ↓
volunteers (n=17) led
voriconazole
to 212% ↑
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Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole
ketoconazole concentrations
exposure and 42% ↑ due to
darunavir exposure.51 CYP2C19/2C9
Do not exceed 200 induction.
mg ketoconazole per
day while on With RTV 100 mg
darunavir/ritonavir. twice daily: 39% ↓
voriconazole AUC;
14% ↓ RTV AUC45, 46

Use of low boosting
doses of RTV (i.e.
100mg twice daily)
combined with any of
the other PIs should
be avoided unless
the benefits outweigh
the risks of antifungal
failure.46, 50
Consider voriconazole
TDM or use other
antifungals that do not
interact significantly
with RTV.
Darunavir/r plus Case report of a
etravirine patient on darunavir
900/100 mg QD,
etravirine 200 mg BID,
2 NRTIs and
voriconazole 400 mg
BID for 6 weeks.
Drug levels were
obtained during
voriconazole co-
administration and 3
weeks after
voriconazole
discontinuation.
Therapeutic
voriconazole levels
were achieved, while
etravirine Ctrough ↑
134%, ritonavir
Ctrough was
undetectable and
darunavir Ctrough
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