Managing Drug Interactions in the Patient with Aspergillosis

1
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

2
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.

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Patient Case Cont.

• Additional CSF workup
• Gram stain and cultures negative
• PCR CMV, HSV 12, 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?

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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
5
Classification of Drug Interactions
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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

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Pharmacokinetic Interactions of Antifungals
8
Azoles are susceptible to pharmacokinetic
interactions in the GI tract
Dissolution
Aqueous solubility
N
N
N
O
O
N
N
N
N
N
O
O
N
H
N
N
Itraconazole pKa 3.7 log P-5.66
Fluconazole pKa 2
N
N
F
F
F

Voriconazole pKa 1.63
Lipid solubility
9
Gastrointestinal tract drug interactions-Dissoluti
on and Metabolism
pH interactions (itraconazole-H2 antagonists,
PPI, didanosine,
antacids)
(posaconazole-cimetidine?) binding interactions
(itraconazole-sulcralfate)
pH 2
dissolution
Pre-systemic clearance/metabolism (all azoles)
Small intestine pH 5-7
MDR1 (P-gp) Efflux
CYP 3A4
OATP
Portal vein
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Hepatic Drug Interactions
Genetic
Disease
Diet
Drugs
Infection
OATP (azoles, echinocandins?)
Phase I metabolism (CYP P450) (itraconazole,
voriconazole)
Phase II metabolism (glucoronidation) (posaconazol
e)
Extraction?
Metabolism
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All azoles are inhibitors of CYP
Affinities for specific CYP isoforms are drug
dependent
12
In Vivo Cytochrome P450 Inhibition Potential vs
Other Azoles

• Wexler D et al. Eur J Pharm Sci. 200421645-653.
• Cupp MJ et al. Am Fam Phys. 199857107-116.
• Drug interactions. Med Letter. 200345(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.
  200331540-547.
• VFEND summary of product characteristics. Kent,
  UK Pfizer Ltd 2005.

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Itraconazole 3A4 Interactions Affecting
Pharmacokinetics of Other Drugs
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Cyclophosphamide metabolism is affected by azole
antifungals
Fluconazole
fluconazole
DCCY
Urine
CY
CYP 2B6 2C9, 2C19 3A4
HCY
Itraconazole
ketoCY HPMM CEPM
aldoCY
Itraconazole
acrolein
Cyclophosphamide metabolism changes at different
dosages (Timmet al Pharmcogenom J 20055365)
Marr et al. Blood 20041031557
15
Itraconazole 3A4 Interactions and
Anti-Mycobacterial or HIV Drugs
16
Voriconazole Interactions Affecting
Pharmacokinetics/Dynamics of Other Drugs
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, NNRTIs, sirolimus, quinidine and
pimozidine, however, published studies are
lacking.
17
Posaconazole Interactions Affecting
Pharmacokinetics/Dynamics of Other Drugs
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, NNRTIs, sirolimus, quinidine and
pimozidine, however, published studies are
lacking.
18
Summary-Important CYP-Azole Interactions
Azole concentration
Substrate concentration
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Antifungal Serum Drug Concentration Monitoring
Including lipid preparations
20
Distribution of Poor Metabolizers of CYP P450
2C19 in Various Ethnic Groups
Influence of CYP2C19 Genotype on Average
Steady-State Plasma Voriconazole Concentrations
Homozygous Extensive metabolizer (n108)
Heterozygous Extensive metabolizer (n39)
Homozygous Poor metabolizer (n8)
Clin Pharmacokinet 200241913-958.
21
Pharmacogenomic microarray typing-Cleared 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
22
Antimicrobials and QTc Prolongation-Relative
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 (IVPO) Sparfloxacin I
traconazole Ketoconazole Pentamidine
Schedule III Significant risk for TdP,
particularly when
co-administered with CYP
inhibitors
Gatifloxacin Levofloxacin Moxifloxacin Grepafloxac
in
Gemifloxacin Fluconazole Voriconazole Telithromy
cin
Schedule IV Low risk for TdP, case
reports of TdP, mild Ikr blockade,
possible CYP interactions

Schedule V Questionable/minimal
risk for TdP
Azithromycin
Cotrimoxazole
Ciprofloxacin
New antimicrobials, based on post-marketing data
may be re-categorized
RC Owens Drugs 200464(10)1091-1124.
23
O
O
H
O
N
O
H
H
O
H
H
O
O
caspofungin
O
O
N
O
N
O
O
O
O
O
N
O
O
S
O
O
O
micafungin
anidulafungin
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Comparison of the Echinocandin Antifungals-Safety
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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)

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"The person who takes medicine must recover
twice, once from the disease and once from the
medicine." - William Osler, M.D.