Antifungals

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

Drug

Approval 1954 1958 1959 1969 1972 1979 1981 1990 1992 1993 1996 1997 2001 2002 2005

Historical facts
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.

Nystatin Amphotericin B deoxycholate Griseofulvin Miconazole, clotrimazole (topical) Flucytosine Miconazole (IV) Ketoconazole Fluconazole Itraconazole (capsules) Terbinafine (topical) Terbinafine (oral), ABLC ABCD, Liposomal Ampho B, Itraconazole (oral solution) Caspofungin Voriconazole Micafungin

Anindulafungin

2006

How do they work?

Polyenes, triazoles, and imidazoles target ergosterol destroying the cell membranes integrity. Allylamines inhibit ergosterol synthesis. -3-glucan synthase inhibitor block the production of the -(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.
Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Other antifungals such as flucytosine inhibit DNA/RNA synthesis and griseofulvin inhibit fungal cell mitosis preventing cell proliferation and function.

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/antif_pharm.htm

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.

GeneMedRx

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

Classification in GeneMedRx
Antifungals
Polyenes Imidazoles Triazole -3-glucan Allylamines synthase inhibitors
naftifine caspofungin

Other

nystatin

miconazole

fluconazole

griseofulvin

amphotericin B

clotrimazole

itraconazole terbinafine

micafungin

flucytosine

ketoconazole

voriconazole butenafine

anidulafungin

tolnaftate

posaconazole

GeneMedRx before update

19% Algorithm & notes 37% Detected by notes 85% Interaction documented 42% Algorithm Used only 1% incorrect

Total number of interactions = 180

154 interactions existed in program
Notes & algorithm=30 Documented through notes only= 57 Correct predictions by algorithm= 65 Incorrect algorithm prediction= 1

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

General causes of interactions with antifungals

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

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

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

http://poisonevercure.150m.com/New_F older/amphot1.jpg

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 (I&Os)

Miconazole

Imidazoles

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 2C9 interactions: Case reports of increase bleeding with warfarin and increase levels phenytoin.
Closely monitor levels Increase in cyclosporine (AUC by 33%), fentanyl, pimozide, tolterodine, and tremetrexate drug levels

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.

Imidazole (cont.)

Ketoconazole

Substrate of CYP3A4 Inhibits:

Interactions:

Weak: 2B6, 2C8 Moderate: 2A6, 2C19, 2D6 Strong: 1A2, 2C9, 3A4 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.

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:

Interactions: Generally same concerns as ketoconazole

Strong 3A4

Voriconazole
Oral absorption NOT effected by gastric pH Substrate 2C9/19 major; 3A4 minor
Inhibitors:
Susceptible to 2C19 polymorphismsno pharmacogenomic dosing suggested Weak 2C9/19 Moderate 3A4 (less than ketoconazole and itraconazole)

Interactions: Generally same concerns as ketoconazole except no pH effect

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 (Cmax39%)

Increase of other drug levels through 3A4 inhibition

Increased levels of tacrolimus (Cmax 121%), sirolimus, cyclosporine ( 29%), midazolam (AUC 83%)

QTc prolongation

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 (Cmax1.9 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. No interactions found.

-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 Tacrolimus Cmax reduced by 16%
Dose of Caspo increased to 70mg daily

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

Other

Griseofulvin

Liver metabolized Induces 1A2, 2C9, 3A4 weakly Decreased effectiveness of cyclosporine (40%), estrogens, warfarin Phenobarbital and omeprazole decreased absorption Theophylline dose reduction when administered with Griseofulvin
May require increases in dose Monitor effectiveness of treatment

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.

Genetic polymorphism of 3A4

According to a small study (N=26) 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.

Genetic Polymorphism and 3A4 inhibition

# 1 2 Genetics Control 2C19 *1/*1 Homozygous EM N Voriconazole levels (+Ritonavir) 20 Cl 43%; Cmax 17%; AUC 4.6 fold 8 Cl 34%;Cmax NC*; AUC 1.5 fold

3
4

2C19 *1/*2 Heterzygous EM

2C19 *2/*2, *2/*3, *3/*3 PM

8
4

Cl 45%; Cmax 28%; AUC 1.9 fold

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.

Genetic Polymorphism and 3A4 inhibition

Tolterodine substrates: 3A4, 2D6 (major) This is a open, nonrandomised, crossover, multiphase study. N=6 whom are 2D6 PM 1st phase (N=8)

2nd phase (N=6)

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. 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

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 Oct;48(4):564-72. Drew, RH, et. Al. Overview of Flucytosine. [internet] Wellesley (MA): UpToDate; c2007 [updated 2006,Apr 18;access 2007, Jan 20] Available: http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/2067&type=A &selectedTitle=4~28 He P, et. Al. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther. 2005 May;77(5):373-87. Luna, B. Overview of Imidazole. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 20] Available: http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/6341&type=A &selectedTitle=3~66 Luna, B. Overview of Triazoles. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 20] Available: http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/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 Aug;80(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.

Thank you!
Howard Coleman Kristine Ashcraft Jessica Oesterheld Richard Patterson And all the staff at Genelex!!