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.

3
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?

4
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
6
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
CYP3A4 CYP3A4 CYP2C8/9 CYP2C8/9 CYP2C19 CYP2C19
Drug Inhibitor Substrate Inhibitor Substrate Inhibitor Substrate
Fluconazole2,3 ? ?
Itraconazole2,3,4 ? ? ?
Ketoconazole2,3,5 ? ? ?
Voriconazole3,6,7 ? ? ? ?
Posaconazole1 ?

1. Wexler D et al. Eur J Pharm Sci. 200421645-653.
2. Cupp MJ et al. Am Fam Phys. 199857107-116.
3. Drug interactions. Med Letter. 200345(W1158B)46-
   48.
4. Sporanox IV summary of product characteristics.
   Bucks, UK Janssen-Cilag Ltd 2005.
5. Nizoral tablets summary of product
   characteristics. Bucks, UK Janssen-Cilag Ltd
   2001.
6. Hyland R et al. Drug Metab Dispos.
   200331540-547.
7. VFEND summary of product characteristics. Kent,
   UK Pfizer Ltd 2005.

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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
Benzodiazepines (midazolam, triazolam, diazepam) ?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 gt50 ? 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 gt 25-50 Avoid concomitant use, especially for conditioning therapy
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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
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Itraconazole 3A4 Interactions and
Anti-Mycobacterial or HIV Drugs
Drug Effect Alternatives/Management
NNRTI (delavirdine, nevirapine, efavirenz) Decreased metabolism of NNRTIs, Nevirapine and efavirenz may induce itraconazole metabolism Monitor for antiviral toxicity and antifungal efficacy/ itraconazole trough concentrations
Protease inhibitors (Indinavir, aprenavir, saquinavir) (lopinavir, ritonavir) Increased PI concentrations Increased ITRA concentrations Indinavir 600 mg q8h Monitor for toxicity
Rifabutin Rifabutin induces metabolism of itraconazole, itraconazole inhibits metabolism of rifabutin Rifabutin uveitis, antifungal efficacy/ itraconazole trough concentrations
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Voriconazole Interactions Affecting
Pharmacokinetics/Dynamics of Other Drugs
Drug (Enzyme) Effect Management
Warfarin (CYP 2C9) 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
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.
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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, NNRTIs, sirolimus, quinidine and
pimozidine, however, published studies are
lacking.
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Summary-Important CYP-Azole Interactions
Drug Interaction Drug Interaction
Azole Cytochrome P450 Inducers Carbamazepine
Azole Cytochrome P450 Inducers Phenobarbitol
Azole Cytochrome P450 Inducers Phenytoin
Azole Cytochrome P450 Inducers Isoniazid
Azole Cytochrome P450 Inducers Rifabutin
Azole Cytochrome P450 Inducers Rifampin
Azole Cytochrome P450 Inducers Nevirapine
Azole Cytochrome P450 Substrate Statins
Azole Cytochrome P450 Substrate Cyclosporine
Azole Cytochrome P450 Substrate Tacrolimus
Azole Cytochrome P450 Substrate Sirolimus
Azole Cytochrome P450 Substrate Protease inhibitors (saquinavir, ritonavir)
Azole Cytochrome P450 Substrate Ca2 channel blockers (diltiazem, verapamil, nifedipine, nisoldipine)
Azole concentration
Substrate concentration
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Antifungal Serum Drug Concentration Monitoring
Including lipid preparations
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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 (n108)
Heterozygous Extensive metabolizer (n39)
Homozygous Poor metabolizer (n8)
Clin Pharmacokinet 200241913-958.
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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
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Antimicrobials and QTc Prolongation-Relative
Risk for Torsades de Pointes (TdP)
Schedule I Highest TdP risk, potent Ikr
blockers, TdP risk gt 1
Dofetilide Sotalol
Cisapride Terbinafine
Schedule II Significant risk for TdP,
particularly when
co-administered with CYP inhibitors
Clarithromycin Erythromycin (IVgtPO) 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.
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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
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 histamine-rxn with infusion, phlebitis, Asymptomatic ? transaminases NV, headache, hypokalemia, and ?GGT
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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.