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Managing Drug Interactions in
the Patient with Aspergillosis
Russell E. Lewis, Pharm.D., FCCP
Associate Professor
University of Houston College of Pharmacy/
The University of Texas M.D. Anderson Cancer Center
1
Patient Case
 44 y/o male with myelodysplastic syndrome s/p
matched unrelated donor Allo-HSCT (Day +210)
admitted with mental status changes and GvHD of
the skin
 Recent PMH:
 Ambisome 5 mg/kg 3x weekly, valganciclovir (maint
dose), levofloxacin, TMP/sulfa prophylaxis, and
vancomycin (catheter infection)
 Extensive flair of GvHD involving skin, started on
steroids in addition to current tacrolimus therapy
 New ground glass opacities and nodular opacities in
lower lung lobes
 DC Ambisome, start voriconazole
 Reduce tacrolimus dose by 30%
 On admission:




Patient confused, disoriented but responsive
Whole blood tacrolimus 6.9 ng/mL [5-15 ng/mL]
Serum electrolytes WNL, CSF normal
CT: Moderate parieto-occipital cerebral atrophy
without focal abnormalities.
2
Patient Case Cont.
 Additional CSF workup:
 Gram stain and cultures negative
 PCR CMV, HSV 1&2, HHV 6, EBV, Varicella, JC/BK
 Tacrolimus
 MRI
 Areas of high signal throughout the white matter
particularly involving the parietal regions with some
extension on the right to the frontal lobe
 Tacrolimus concentration:
 Serum 6.2 ng/mL
 CSF 42 ng/mL!
 Diagnosis:
 Tacrolimus associated Posterior Reversible
Encephalopathy Syndrome (PRES)
 Exacerbated by voriconazole?
3
Factors that Increase the Potential for Serious
Drug Interactions with Antifungal Therapy





Polypharmacy
Underlying renal or hepatic dysfunction
Drugs with narrow therapeutic index
Debilitation /malnutrition/ chronic immunosuppression
Genetic predisposition (I.e. poor metabolizer)
Risk is cumulative, and the relative impact
each factor at different timepoints in unknown
4
Classification of Drug Interactions
Pharmacokinetic
∆ in drug absorption,
distribution, metabolism
or excretion
Pharmacodynamic
∆ of pharmacological effect at standard
drug concentrations
or
∆ of pharmacological effect resulting from
altered pharmacokinetic exposures
“All drugs known to humans are poisons, only the
amount or dose determine the effects.”
Paracelsus, 1490 - 1541
5
Pharmacodynamic Interactions
of Antifungals
 Beneficial:
 Synergy (e.g., echinocandin + triazole)
 Suppression of resistance (e.g., 5-FC + amphotericin B)
 Detrimental:
 Antagonism (e.g., triazole + amphotericin B)
 Overlapping toxicities
 Amphotericin B + other nephrotoxic drugs
 Amphotericin B nephrotoxicity  accumulation of renally-eliminated
drugs  electrolyte disturbances  diuretics  enhanced toxicity of
steroids  digoxin, skeletal muscle relaxants
 Azoles + steroids  adrenal suppression
 All antifungals  hepatic toxicity
6
Pharmacokinetic Interactions
of Antifungals
Decreased absorption from GI tract
• Alterations in pH
• Complex formation with ions
• Interference w/transport protein (i.e. P-gp)
• Pre-systemic enteric metabolism
Changes in hepatic metabolism
• Interference with transport proteins
• Interference with phase I or II drug metabolism
Decreased renal excretion
• Interference with glomerular filtration, tubular
secretion or other mechanisms
7
Azoles are susceptible to pharmacokinetic
interactions in the GI tract
Dissolution
Aqueous solubility
N
N
N
N
CH3
F
O
O
H3C
N
N
N
N
N
N
N
N
N
O
O
N
N
OH
Fluconazole
pKa 2
F
N
N
N
F
H
N
OH
F
Cl
N
N
H3C
CH3
N
F
Voriconazole
pKa 1.63
Cl
Itraconazole
pKa 3.7
log P-5.66
O
O
H3C
N
HO
N
N
N
O
N
H
F
F
Posaconazole
pKa 3.6
log P-3
Lipid solubility
8
Gastrointestinal tract drug interactionsDissolution and Metabolism
pH 2
pH interactions (itraconazole-H2 antagonists, PPI,
didanosine, antacids)
(posaconazole-cimetidine?)
binding interactions (itraconazole-sulcralfate)
dissolution
Pre-systemic clearance/metabolism (all azoles)
Small intestine pH 5-7
MDR1 (P-gp) Efflux
CYP 3A4
OATP
Portal vein
9
Hepatic Drug Interactions
Genetic
Disease
OATP (azoles,
echinocandins?)
Diet
Drugs
Infection
Phase I metabolism (CYP P450)
(itraconazole, voriconazole)
Phase II metabolism (glucoronidation)
(posaconazole)
Extraction?
Metabolism
10
All azoles are inhibitors of CYP
Affinities for specific CYP isoforms are drug dependent
11
In Vivo Cytochrome P450
Inhibition Potential vs Other Azoles
CYP3A4
Drug
Substrate
Inhibitor
Itraconazole2,3,4





Ketoconazole2,3,5



Voriconazole3,6,7


Posaconazole1

Fluconazole2,3
1.
2.
3.
4.
5.
6.
7.
Inhibitor
CYP2C8/9
Wexler D et al. Eur J Pharm Sci. 2004;21:645-653.
Cupp MJ et al. Am Fam Phys. 1998;57:107-116.
Drug interactions. Med Letter. 2003;45(W1158B):46-48.
Sporanox IV [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; 2005.
Nizoral tablets [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; 2001.
Hyland R et al. Drug Metab Dispos. 2003;31:540-547.
VFEND [summary of product characteristics]. Kent, UK; Pfizer Ltd; 2005.
Substrate

CYP2C19
Inhibitor
Substrate

12
Itraconazole 3A4 Interactions Affecting
Pharmacokinetics of Other Drugs
Drug
Effect
Alternatives/Management
HMG-CoA reductase
(lovastatin, simvastatin, atorvastatin)
3-20 fold  Cmax, AUC0-24, t1/2
Fluvastatin, pravastatin, rosuvastin
Cmax, AUC, t1/2, F,
 clearance
Oxazepam, estolazam, temazepam
Anxiolytics, sedatives
(buspirone)
13-fold  Cmax, AUC0-24
Zolpidem
Antipsychotics
(Haloperidol)
 30% AUC
Clozapine
Immunosuppressants
CsA
Tacrolimus
 Cmin >50%
 Cmin 5-fold
Empirically reduce dosage by 50%
and monitor levels
Corticosteroids
Methylprednisolone, dexamethazone
Prednisolone
 3-4x increase in AUC
 15-30% increase in t1/2
Adrenal-suppressant effects
Calcium channel blockers
Felodipine
 6-8x fold increase in AUC
Avoid
Chemotherapy
(Cyclophosphamide, busulfan, vinca alkaloids)
 Css > 25-50%
Avoid concomitant use, especially for
conditioning therapy
Benzodiazepines
(midazolam, triazolam, diazepam)
13
Cyclophosphamide metabolism is
affected by azole antifungals
Urine
DCCY
fluconazole
Fluconazole
CY
HCY
Itraconazole
ketoCY
HPMM
CEPM
CYP 2B6
2C9, 2C19
3A4
Itraconazole
aldoCY
acrolein
Cyclophosphamide metabolism changes at
different dosages (Timmet al Pharmcogenom J 2005;5:365)
Marr et al. Blood 2004;103:1557
14
Itraconazole 3A4 Interactions and
Anti-Mycobacterial or HIV Drugs
Drug
NNRTI
(delavirdine, nevirapine, efavirenz)
Protease inhibitors
(Indinavir, aprenavir, saquinavir)
(lopinavir, ritonavir)
Rifabutin
Effect
Alternatives/Management
Decreased metabolism of
NNRTIs,
Nevirapine and efavirenz may
induce itraconazole
metabolism
Monitor for antiviral toxicity and
antifungal efficacy/ itraconazole
trough concentrations
Increased PI concentrations
Increased ITRA
concentrations
Indinavir 600 mg q8h
Monitor for toxicity
Rifabutin induces metabolism
of itraconazole, itraconazole
inhibits metabolism of
rifabutin
Rifabutin uveitis, antifungal
efficacy/ itraconazole trough
concentrations
15
Voriconazole Interactions Affecting
Pharmacokinetics/Dynamics of Other Drugs
Drug
(Enzyme)
Effect
Management
Inhibits primary metabolic
pathway, increases PD effect by
41%
Monitor INR and adjust dose
accordingly
Immunosuppressants
(3A4)
• Cyclosporin
• Tacrolimus
• Sirolimus
 Cmin 248%, AUC 70%
 Cmin
 Cmin
Reduce dose by 50%, monitor
Reduce dose by 33%, monitor
Contraindicated
Miscellaneous
(2C9, 3A4)
• Phenytoin
• Omeprazole
• Prednisolone
• Rifabutin
 Cmax 70%, AUC 80%
 Cmax 2.5 fold, AUC 3.8 fold
 AUC 13-30%
 AUC, 2-fold
Monitor phenytoin levels
Reduce dose by 50%
Monitor
Warfarin
(CYP 2C9)
Voriconazole may also increase the plasma concentrations of several drugs including benzodizepines, calcium channel
blockers, HMG-CoA reductase inhibitors, vinca alkaloids, busulfan, cyclophosphamide sulfonylureas, protease inhibitors,
NNRTI’s, sirolimus, quinidine and pimozidine, however, published studies are lacking.
16
Posaconazole Interactions Affecting
Pharmacokinetics/Dynamics of Other Drugs
Drug
Effect
Management
Immunosuppressants
(3A4)
• Cyclosporine
• Tacrolimus
 Cmin 14-24%
 AUC 360%
Monitor
Reduce dose by 50%, monitor
Miscellaneous
(3A4)
• Phenytoin
• Rifabutin
• Ritonavir
 AUC 15%, Posa  50%
 AUC 82%, Posa  50%
 AUC 30%
Monitor phenytoin levels
Avoid if possible, monitor for uveitis
Clinically significant?
Posaconazole may also increase the plasma concentrations of several drugs including benzodizepines, calcium channel
blockers, HMG-CoA reductase inhibitors, vinca alkaloids, busulfan, cyclophosphamide, sulfonylureas, protease inhibitors,
NNRTI’s, sirolimus, quinidine and pimozidine, however, published studies are lacking.
17
Summary-Important
CYP-Azole Interactions
Drug Interaction
Azole +
Cytochrome P450
Inducers
Carbamazepine
Phenobarbitol
Phenytoin
Isoniazid
Azole concentration
Rifabutin
Rifampin
Nevirapine
Azole +
Cytochrome P450
Substrate
Statins
Cyclosporine
Tacrolimus
Sirolimus
Substrate concentration
Protease inhibitors (saquinavir, ritonavir)
Ca2+ channel blockers (diltiazem, verapamil,
nifedipine, nisoldipine)
18
Antifungal Serum Drug
Concentration Monitoring
Agent
Justified in select
situations?
No
Yes- toxicity
Target Range
Fluconazole
Itraconazole
No
Yes-ensure
absorption, efficacy
N/A
> 0.5 mcg/mL
Voriconazole
Yes-variable
metabolism associated
with sub-therapeutic
and to xic
concentr ations drug
interact ions,
pediatrics?
Yes, ensure
absorption, efficacy
1-2 to 6
mcg/mL
No
N/A
Amphotericin B*
Flucytosine
Posaconazole
Echinocandins
* Including lipid preparations
N/A
< 100 mcg/mL
> 0.25
mcg/mL?
Timing of
Sample
N/A
2 hour postdose peak
N/A
Trough after 7
days of
therapy
Trough after 7
days of
therapy
Trough after 7
days of
therapy
N/A
19
Distribution of Poor Metabolizers of CYP
P450 2C19 in Various Ethnic Groups
Influence of CYP2C19 Genotype
on Average Steady-State Plasma
Voriconazole Concentrations
Genotype
Caucasian
Blacks
Japanese
Chinese
Homozygous
poor metabolizer
2%
2%
19%
14%
Heterozygous
extensive
metabolizer
26%
28%
46%
43%
Homozygous
extensive
metabolizer
73%
70%
35%
43%
Homozygous
Extensive
metabolizer
(n=108)
Clin Pharmacokinet 2002;41:913-958.
Heterozygous
Extensive
metabolizer
(n=39)
Homozygous
Poor
metabolizer
(n=8)
20
Pharmacogenomic microarray typingCleared in U.S. and EU for Diagnostic Use
CYP450 Array
The world's first pharmacogenomic microarray designed for
clinical applications that provides comprehensive coverage
of gene variations – including deletions and duplications –
for the 2D6 and 2C19 genes, which play a role in the
metabolism of about 25% of all prescription drugs. It is
intended to be an aid for physicians in individualizing
treatment doses for patients on therapeutics metabolized
through these genes.
Cost- ~ $500/ test
21
Antimicrobials and QTc ProlongationRelative Risk for Torsades de Pointes (TdP)
Schedule I: Highest TdP risk, potent Ikr blockers, TdP risk > 1%
Dofetilide
Sotalol
Cisapride
Terbinafine
Schedule II: Significant risk for TdP, particularly when
co-administered with CYP inhibitors
Clarithromycin
Erythromycin (IV>PO)
Sparfloxacin
Itraconazole
Ketoconazole
Pentamidine
Schedule III: Significant risk for TdP, particularly
when co-administered with
CYP inhibitors
Schedule IV: Low risk for TdP, case
reports of TdP, mild Ikr blockade,
possible CYP interactions
Schedule V: Questionable/minimal
risk for TdP
Gatifloxacin
Levofloxacin
Moxifloxacin
Grepafloxacin
Azithromycin
Gemifloxacin*
Fluconazole
Voriconazole*
Telithromycin*
Cotrimoxazole
Ciprofloxacin
*New antimicrobials, based on post-marketing data may be re-categorized
22
RC Owens Drugs 2004;64:(10):1091-1124.
H2N
NH
OH
O
HO
O
NH
H
H2N
N
H
O
N
O
OH
HN
H3C
H
H
NH
HO
H
O
CH3
CH3
CH3
O
H
N
H
OH
OH
O
OH
caspofungin
HO
OH
O
HO
HO
O
NH
H3C
HO
NH
H2N
N
O
O
HN
H3C
NH
O
O
HO
NH
O
O
NH
N
OH
OH
O
HO
N
CH3
O
O
H3C
HN
H
N
HO
HO
NH
O
OH
OH
O
OH
O
H
N
HO
O
CH3
N
O
S
OH
N
O
H3C
O
O
OH
O
OH
HO
micafungin
O
anidulafungin
HO
H3C
23
Comparison of the Echinocandin AntifungalsSafety
Caspofungin
Micafungin
Anidulafungin
CYP 3A4 inhibitor?
No
No
No
Drug interactions
OATP1B1 transporter?
Tacrolimus 20%
CSA  CASPO 35%
RIF or other inducers
 CASPO 30%
No effects on
tacrolimus,cyclosporine,
prednisolone or effects
of rifampin.
 Sirolimus, nifedipine
AUC 20%
No effects on
tacrolimus,cyclosporine,
prednisolone or effects of
rifampin.
Dosage
adjustment in
hepatic dysf.
 To 35 mg/day in
moderate hepatic
insufficiency
No dosage adjustment
No dosage adjustment
Adverse effects
Histamine-rxn with
infusion, phlebitis,
Asymptomatic 
transminases
Occasional histaminerxn with infusion,
phlebitis,
Asymptomatic 
transaminases
N&V, headache,
hypokalemia, and GGT
Summary
• Patients with invasive aspergillosis have many risk factors for
potentially harmful drug interactions, some of which may be
unanticipated
• A pro-active approach is essential to protect patients from
potentially severe interactions
– Better laboratory support may help the management of suspected
interactions (serum drug level monitoring, genotyping?)
• Drug interactions that are always significant:
– Interactions affecting agents with narrow therapeutic index (e.g.,
immunosuppressants, chemotherapy, anti-retrovirals)
– Interactions increasing the metabolism of antifungals used to treat
the Aspergillus infection
– Interactions affecting the QTc (Torsades de pointes)
"The person who takes medicine must
recover twice, once from the disease
and once from the medicine."
- William Osler, M.D.
26