Antifungals

1
Antifungals

• Julie Duong, Pharm D candidate 2007
• University of Washington
• School of Pharmacy
• January 25, 2007

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Historical facts
Drug Approval
Nystatin 1954
Amphotericin B deoxycholate 1958
Griseofulvin 1959
Miconazole, clotrimazole (topical) 1969
Flucytosine 1972
Miconazole (IV) 1979
Ketoconazole 1981
Fluconazole 1990
Itraconazole (capsules) 1992
Terbinafine (topical) 1993
Terbinafine (oral), ABLC 1996
ABCD, Liposomal Ampho B, Itraconazole (oral solution) 1997
Caspofungin 2001
Voriconazole 2002
Micafungin 2005
Anindulafungin 2006

• Most recently approved in October 2006,
  Posaconazole.
• Note newer antifungals may have less
  interactions due to the short time period of
  being in the market.

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How do they work?
Polyenes, triazoles, and imidazoles target
ergosterol destroying the cell membranes
integrity. Allylamines inhibit ergosterol
synthesis. ß-3-glucan synthase inhibitor block
the production of the ß-(1,3)-glucan protein
damaging the cell wall. Every component of the
cell wall and membrane can be targeted. Drugs
not available in the market such as Nikkomycin
and Polyoxin target chitin synthase.
Mannoproteins are another potential
target. Other antifungals such as flucytosine
inhibit DNA/RNA synthesis and griseofulvin
inhibit fungal cell mitosis preventing cell
proliferation and function.

• Image from http//www.doctorfungus.org/thedrugs/an
  tif_pharm.htm

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Why is this important?

• 36 of drugs are metabolized by CYP 3A4 and
  antifungals are largely 3A4 inhibitors
• Antifungals can effect up to 60 of all drugs due
  to inhibition of 3A4, 2C9, 2C19, 1A2.

Image from http//www.doctorfungus.org/thedrugs/an
tif_pharm.htm
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Clinical implications

• Most critical interactions can occur in patients
  with immunocompromised status
• Cancer, transplant, HIV, diabetes
• On immunosupressant agents which are mostly 3A4
  substrates or inducers
• On multiple drugs
• Drug interactions can get complicated.

6
GeneMedRx

• A great clinical resource for dosing medications
  in complicated situation with drug-drug
  interactions as well as genetic polymorphisms.

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Classification in GeneMedRx
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GeneMedRx before update
19 Algorithm notes

• Total number of interactions 180
• 154 interactions existed in program
• Notes algorithm30
• Documented through notes only 57
• Correct predictions by algorithm 65
• Incorrect algorithm prediction 1

37 Detected by notes
85 Interaction documented
42 Algorithm Used only
1 incorrect
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Statistics of updating GeneMedRx

• 15 antifungals already in system
• 3 drugs were added
• 26 interactions entered
• Notes
• 59 new notes entered
• 19 existing notes modified
• 35 notes added to document predictions by
  algorithm

15 Interaction added
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General causes of interactions with antifungals

• Decreased absorption
• Increase/decrease plasma levels of other drugs
• Pharmacodynamic interaction

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Polyenes

• Nystatin
• No drug interactions found.
• Mostly topical use and local treatment (oral
  thrush)
• Poor systemic absorption
• Poor oral bioavailability no IV formulation

http//akratiri.com/Meds/nystatin_oral.jpeg
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Polyenes (cont.)

• Amphotericin B
• Metabolism not known
• Excreted by kidney slowly through months
• Side effects include fever, chills, electrolyte
  abnormalities (?K,?Mg), renal dysfunction, and
  hematologic toxicity.
• Potential of increasing potassium
• Regularly monitor Chem 7 or electrolytes and
  treat accordingly
• Caution when administering with drugs that
  increase potassium such as thiazide diuretics
• Potential of increasing nephrotoxicity
• Use vigorous hydration
• Avoid administration with nephrotoxic drugs
  (cyclosporine, tacrolimus, etc.)
• Some have suggested alternate day
  administrationeffective???
• Regularly monitor BUN, Scr, est CrCl, fluid
  intake and excretion (IOs)

http//poisonevercure.150m.com/New_Folder/amphot1.
jpg
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Imidazoles

• Miconazole
• Products available are topical and vaginal,
  negligible topical absorption
• Substrate 3A4
• Inhibits
• Weak 2B6
• Moderate 1A2, 2E1
• Strong 2A6, 2C9, 2C19, 2D6, 3A4
• Interactions occur mostly due to decreased
  metabolism of 3A4
• Increase in cyclosporine (?AUC by 33), fentanyl,
  pimozide, tolterodine, and tremetrexate drug
  levels
• 2C9 interactions Case reports of increase
  bleeding with warfarin and increase levels
  phenytoin.
• Closely monitor levels

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Imidazole (cont.)

• Clotrimazole
• Liver metabolized but not by CYP P450 enzymes
• Inhibits
• Weak 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1,
• Moderate 3A4
• Topical, vaginal, oral troche
• Interactions primarily through 3A4 inhibition
  with ergot derivatives, fentanyl, sirolimus,
  tacrolimus (?Cmax 2 fold)
• Monitor drug levels, sedation, etc.

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Imidazole (cont.)

• Ketoconazole
• Substrate of CYP3A4
• Inhibits
• Weak 2B6, 2C8
• Moderate 2A6, 2C19, 2D6
• Strong 1A2, 2C9, 3A4
• Interactions
• Decrease absorption due to increase in pH by
  aluminum, calcium, magnesium containing antacids,
  PPI, H2 blockers
• Increased drug levels of other drugs due to 3A4
  inhibition
• Increases risk of QTc prolongation
• Avoid other QTc inducing drugs (astemizole, etc.)
  /monitor EKG
• Increases risk of rhabdomyolysis when used with
  statins
• Monitor creatine kinase, signs and symptoms
• Excessive sedation with BZD
• Alprazolam Cmax? slightly ?31 clearance
• Lorazepam is suggested as an alternative.

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Triazoles

• This is only a list of the general trends of drug
  interactions.
• Refer to GeneMedRx for more details.
• Fluconazole
• Inhibits
• Weak 1A2
• Moderate 3A4
• Strong 2C9/19
• Interactions Generally same concerns as
  ketoconazole
• Itraconazole
• Substrate 3A4
• Inhibitors
• Strong 3A4
• Interactions Generally same concerns as
  ketoconazole
• Voriconazole
• Oral absorption NOT effected by gastric pH
• Substrate 2C9/19 major 3A4 minor
• Susceptible to 2C19 polymorphismsno
  pharmacogenomic dosing suggested

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Triazoles (cont.)

• Posaconazole
• UDP Glucuronidated, Pgp
• Effected by rifampin , phenytoin (both ? Cmax by
  around 40)
• 3A4 inhibitor
• Interactions
• Oral absorption NOT effected by gastric pH
• Except cimetidine (Cmax?39)
• Increase of other drug levels through 3A4
  inhibition
• Increased levels of tacrolimus (Cmax ?121),
  sirolimus, cyclosporine (? 29), midazolam (AUC
  ?83)
• QTc prolongation

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Allylamines

• Naftifine
• Only available as a gel or cream
• Poor systemic absorption 4-6
• No interactions found.
• Terbinafine
• Substrate 1A2, 2C9/19, 3A4
• Cimetidine decreased clearance by 33
• Rifampin increased clearance by 100
• Avoid combination
• Inhibitor 2D6 strong
• Increased nortriptyline levels, paroxetine
  (Cmax?1.9 fold), amitriptyline (t1/2 ? to 400
  hrs), desipramine (Cmax ? 2 fold).
• Avoid combination or adjust dosages accordingly.
• Inducer 3A4 weak
• Increased metabolism of cyclosporine by 15
• Monitor cyclosporine levels
• Butenafine
• Only topical use with minimal systemic
  absorption.

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ß-glucan synthase inhibitors

• Caspofungin
• Metabolized by hydrolysis and N-acetylation
• Not inhibitor/inducer/substrate of CYP
• Enzymes induced by carbamazepine, cyclosporine,
  dexamethasone, efavirenz, nelfinavir, nevirapine,
  phenytoin, rifampin
• Dose of Caspo increased to 70mg daily
• Tacrolimus Cmax reduced by 16
• Micafungin
• Substrate 3A4 minor weak inhibitor of 3A4
• Increased levels of nifedipine Cmax and AUC 42
  and 18 and sirolimus AUC 21
• Increased monitoring for toxicity and dosage
  adjustment needed.
• Anidulafungin
• Not inhibitor/inducer/substrate of CYP
• Degrades at normal pH and condition to an
  open-ringed peptide
• Cyclosporine induced AUC 22
• Monitor effectiveness in antifungal treatment

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Other

• Griseofulvin
• Liver metabolized
• Induces 1A2, 2C9, 3A4 weakly
• Decreased effectiveness of cyclosporine (?40),
  estrogens, warfarin
• Monitor effectiveness of treatment
• Phenobarbital and omeprazole decreased absorption
• May require increases in dose
• Theophylline dose reduction when administered
  with Griseofulvin
• Flucytosine
• Renally eliminated unchanged in urine.
• Interactions
• QTc prolongations with Levo Alpha Acetyl
  Methadone
• Decrease in levels due to cytarabineunknown
  mechanism
• Increase in levels due to amphotericin Bdecrease
  in renal excretion increase cellular uptake
• Tolnaftate
• Available as cream, powder, solution, swabs.
• No interactions found.

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Genetic polymorphism of 3A4

• According to a small study (N26) of people with
  12 genetic variations of 3A4, no significant
  alterations in drug metabolism of Midazolam was
  found.
• A combination of genetic polymorphism of other
  enzymes in addition to use of a 3A4 inhibitor may
  dramatically influence levels of drugs
  metabolized by multiple enzymes.

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Genetic Polymorphism and 3A4 inhibition
Genetics N Voriconazole levels (Ritonavir)
1 Control 20 ?Cl 43 ?Cmax 17 ? AUC 4.6 fold
2 2C19 1/1 Homozygous EM 8 ?Cl 34Cmax NC ? AUC 1.5 fold
3 2C19 1/2 Heterzygous EM 8 ?Cl 45 ?Cmax 28 ? AUC 1.9 fold
4 2C19 2/2, 2/3, 3/3 PM 4 ?Cl 86 ?Cmax 30 ? AUC 9 fold
Not statistically significant NC No change
This is a randomized, double-blinded, crossover
study. Patients were given one dose of
Voriconazole and 4 doses of ritonavir. Levels
were measured throughout 48 hours. Avoid using
voriconazole and ritonavir or any potent 3A4
inhibitors in 2C19 PM.
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Genetic Polymorphism and 3A4 inhibition

• Tolterodine substrates 3A4, 2D6 (major)
• This is a open, nonrandomised, crossover,
  multiphase study. N6 whom are 2D6 PM
• 1st phase (N8)
• After washout period of 4 days, each received 4
  days of ketoconazole 200mg PO daily and
  tolterodine 2mg one time on day 2 of ketoconazole
  administration.
• 2nd phase (N6)
• After washout period of 3 months, each received 5
  doses of ketoconazole at same dosage as previous
  and tolterodine 1mg twice daily for 4.5 days.
• Day 3 blood drawn and in the evening received two
  1mg loading doses of tolterodine and
  ketoconazole.
• Day 4,5 ketoconazole 200mg and tolterodine were
  given
• Day 6,7 only ketoconazole 200mg daily
• General results decrease in oral clearance of
  tolterodine by 60 and 2.1 fold increase in AUC
  with concurrent use of ketoconazole

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References
Black, D Fall 2007 Pharmacy 560 Antifungal Drugs Lecture. Brynne N, et al. Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Pharmacol. 1999 Oct48(4)564-72. Drew, RH, et. Al. Overview of Flucytosine. internet Wellesley (MA) UpToDate c2007 updated 2006,Apr 18access 2007, Jan 20 Available http//www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKeyantibiot/2067typeAselectedTitle428 He P, et. Al. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther. 2005 May77(5)373-87. Luna, B. Overview of Imidazole. internet Wellesley (MA) UpToDate c2007 updated 2004,Aug 9access 2007, Jan 20 Available http//www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKeyantibiot/6341typeAselectedTitle366 Luna, B. Overview of Triazoles. internet Wellesley (MA) UpToDate c2007 updated 2004,Aug 9access 2007, Jan 20 Available http//www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKeyantibiot/9969 Mikus G, et al. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther. 2006 Aug80(2)126-35. Epub 2006 Jul 3. Product information for Diflucan Product information for Sporanox Product information for Grifulvin V Product information for Vfend Product information for Eraxis Product information for Mycamine Product information for Pinoxifil Product information for Naftin Gel Product information for Ketoconazole tablets Product information for Amphocin Product information for Lamisil Thomson Micromedex, Greenwood Village, CL. 2007. Available at http//www.thomsonhc.com. Accessed January 20. 2007. For additional references on specific drug interactions, please refer to GeneMedRx.
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• Howard Coleman
• Kristine Ashcraft
• Jessica Oesterheld
• Richard Patterson
• And all the staff at Genelex!!