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Managing Drug Interactions inManaging Drug Interactions in the Patient with Aspergillosis the Patient with Aspergillosis

Russell E. Lewis, Pharm.D., FCCPAssociate Professor

University of Houston College of Pharmacy/The University of Texas M.D. Anderson Cancer Center

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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 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?

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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

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“All drugs known to humans are poisons, only the amount or dose determine the effects.”

Paracelsus, 1490 - 1541

Classification of Drug Interactions

Pharmacokinetic∆ in drug absorption,

distribution, metabolism or excretion

Pharmacodynamic∆ of pharmacological effect at standard

drug concentrationsor

∆ of pharmacological effect resulting from altered pharmacokinetic exposures

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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

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

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Azoles are susceptible to pharmacokinetic interactions in the GI tract

NN

N

F

FOH

N

N N

N N

N N

N

CH3F

OHF

F

NNNN

N

OCH3

H3CO

OO

Cl

N

N

N

ClH

Fluconazole pKa 2

Voriconazole pKa 1.63

Itraconazole pKa 3.7 log P-5.66

NNNN

N

OH3C O

O

F

N

N

N

FH

HO

H3C

Posaconazole pKa 3.6 log P-3

Lipid solubility

Aqueous solubility

Dissolution

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Gastrointestinal tract drug interactions-Dissolution and Metabolism

pH interactions (itraconazole-H2 antagonists, PPI, didanosine, antacids) (posaconazole-cimetidine?)

binding interactions (itraconazole-sulcralfate)

pH 2

Small intestine pH 5-7

dissolution

MDR1 (P-gp) Efflux CYP 3A4

Portal vein

OATP

Pre-systemic clearance/metabolism (all azoles)

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Hepatic Drug Interactions

OATP (azoles, echinocandins?) Phase I metabolism (CYP P450)

(itraconazole, voriconazole)

Phase II metabolism (glucoronidation)(posaconazole)

Genetic Disease Diet Drugs Infection

Extraction? Metabolism

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All azoles are inhibitors of CYP

Affinities for specific CYP isoforms are drug dependent

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In Vivo Cytochrome P450 Inhibition Potential vs Other Azoles

1. Wexler D et al. Eur J Pharm Sci. 2004;21:645-653.2. Cupp MJ et al. Am Fam Phys. 1998;57:107-116.3. Drug interactions. Med Letter. 2003;45(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. 2003;31:540-547.7. VFEND [summary of product characteristics]. Kent, UK; Pfizer Ltd; 2005.

CYP3A4 CYP2C8/9 CYP2C19Drug Inhibitor Substrate Inhibitor Substrate Inhibitor Substrate

Fluconazole2,3 Itraconazole2,3,4 Ketoconazole2,3,5 Voriconazole3,6,7 Posaconazole1

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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 >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

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Cyclophosphamide metabolism is affected by azole antifungals

CY

HCYCYP 2B62C9, 2C193A4

ketoCYHPMMCEPM

Itraconazole

DCCYUrine fluconazole

aldoCY

acrolein

Fluconazole

Itraconazole

Marr et al. Blood 2004;103:1557

Cyclophosphamide metabolism changes at different dosages (Timmet al Pharmcogenom J 2005;5:365)

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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, NNRTI’s, 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, NNRTI’s, sirolimus, quinidine and pimozidine, however, published studies are lacking.

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Summary-Important CYP-Azole Interactions

Drug Interaction

Azole + Cytochrome P450

Inducers

Carbamazepine

Phenobarbitol

Phenytoin

Isoniazid

Rifabutin

Rifampin

Nevirapine

Azole + Cytochrome P450

Substrate

Statins

Cyclosporine

Tacrolimus

Sirolimus

Protease inhibitors (saquinavir, ritonavir)

Ca2+ channel blockers (diltiazem, verapamil, nifedipine, nisoldipine)

Azole concentration

Substrate concentration

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Antifungal Serum Drug Concentration Monitoring

Agent Justified in select situations?

Target Range Timing of Sample

Amphotericin B* No N/A N/A Flucytosine Yes- toxicity < 100 mcg/mL 2 hour post-

dose peak Fluconazole No N/A N/A Itraconazole Yes-ensure

absorption, efficacy > 0.5 mcg/mL Trough after 7

days of therapy

Voriconazole Yes-variable metabolism associated with sub-therapeutic and toxic concentrations  drug interactions, pediatrics?

1-2 to 6 mcg/mL

Trough after 7 days of therapy

Posaconazole Yes, ensure absorption, efficacy

> 0.25 mcg/mL?

Trough after 7 days of therapy

Echinocandins No N/A N/A * Including lipid preparations

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Distribution of Poor Metabolizers of CYP P450 2C19 in Various Ethnic Groups

Clin Pharmacokinet 2002;41:913-958.

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%

0

1

2

3

4

5

6

7

8

HomozygousExtensive

metabolizer(n=108)

HeterozygousExtensive

metabolizer(n=39)

HomozygousPoor

metabolizer(n=8)

Influence of CYP2C19 Genotypeon Average Steady-State Plasma Voriconazole Concentrations

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Pharmacogenomic microarray typing-Cleared in U.S. and EU for Diagnostic Use

CYP450 ArrayThe 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)

RC Owens Drugs 2004;64:(10):1091-1124.

DofetilideSotalol

CisaprideTerbinafine

ClarithromycinErythromycin (IV>PO)

SparfloxacinItraconazole

KetoconazolePentamidine

GatifloxacinLevofloxacinMoxifloxacin

Grepafloxacin

Gemifloxacin*Fluconazole

Voriconazole*Telithromycin*

Azithromycin Cotrimoxazole Ciprofloxacin

Schedule I: Highest TdP risk, potent Ikr blockers, TdP risk > 1%

Schedule II: Significant risk for TdP, particularly when co-administered with CYP inhibitors

*New antimicrobials, based on post-marketing data may be re-categorized

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

23HO

NH

O

HO

OH

HN

O

N

H3C

HO

H3C

HO

NH

O

HN

CH3

OH

N

O

OOH

O

NH

O

HO OH

O

H3C

anidulafungin

N

O

NH

OHO

HO

NH

O

OH

HN

H2N

OH

H2N

O

OH

HN

OH

HO

H

H

H HNH O

H

CH3

OH

ONH

O

H3C

CH3 CH3

caspofungin

HO

O

NH

O

HO

OH

HN

O

N

HO

H2N

O

H3C

HO

NH

O

HN

CH3

OH

N

O

OOH

O

NH

O

O

N

HO OH

O

H3C

S

OH

O

O

micafungin

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

N&V, headache, hypokalemia, and GGT

Comparison of the Echinocandin Antifungals-Safety

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.