Table 1. Principal activity of ketoconazole, itraconazole, fluconazole and voriconazole against human fungal pathogens. Detailled clinical indications are discussed in the corresponding text paragraphs.

 

KETO

ITRA

FLU

VORI

  Opport. yeasts

 

 

 

 

 - Candida albicans

+

+

+

+

 - Candida tropicalis

+

+

+

+

 - Candida glabrata

+

+/-

+/-

+

 - Candida krusei

+/-

+/-

0

+

 - Cryptococcus neoformans

+

+

+

+

 

 

 

 

 

  Opport. hyaline moulds

 

 

 

 

 - Aspergillus spp.

0

+

0

+

 - Fusarium spp.

0

0

0

+/-

 - Scedosporium spp.

+/-

+/-

0

+/-

 

 

 

 

 

  Dermatophytes

+

+

+/-

+

 

 

 

 

 

  Dimorphic moulds

 

 

 

 

 - Histoplasma capsulatum

+

+

+

+

 - Coccidioides immitis

+

+

+

+

 - Blastomyces dermatitidis

+

+

+

+

 - Parracoccidioides brasiliensis

+

+

+

+

 - Sporothrix schenkii

+

+

+

+

 - Penicillium marneffei

+

+

+/-

+

 

 

 

 

 

  Zygomycetes

 

 

 

 

 - Mucorales

0

0

0

0

 - Entomophthorales

0

+/-

0

?

 

 

 

 

 

  Dematiaceous moulds

+/-

+/-

0

+/-

Rating: 0, no activity; +/-, variable activity; + consistent activity

  

Table 2.  Pharmacokinetic parameters of ketoconazole, itraconazole, fluconazole and voriconazole in healthy adult volunteers at steady state after oral daily dosing with 200 mg (Data compiled from references 18, 26, 46, 84, 87, 88, 96, 103,107, 179).

 

Ketoconazole

Itraconazole

Fluconazole

Voriconazole

 

Oral bioavailability (%)

 

 

75

 

55

 

>90

 

>90

Tmax (h)

1-4

1.5-4

1-2

1-2

Cmax (ug/mL)

3-5

10

10

1.5-2.3

AUC0-24h (ug.h/mL)

12

15.4

170

19.4

Protein binding (%)

> 85

>95

<12

58

VD (L/kg)

1.16

10.7 a

0.7-0.8

2-4

Principal route of elimination

Hepatic

Hepatic

Renal

Hepatic

T 1/2 beta

6-10

21-37

27-37

6

CL (mL/min.kg)

2.75

3.80

0.23

n/a

Unchanged drug in urine (%)

2-4

<1

80

<2

Relative CSF levels (%)

<10

<1

50-90

50-80

          a calculated from an intravenous dose of 100mg.

 

Table 3a.  Profile of common or important adverse effects of ketoconazole and itraconazole in adults at usual dosages (≤ 400mg/day) and dose-limiting toxicity (modified from reference 41, 96 and 253)

 

Ketoconazole

Itraconazole

Gastrointestinal disorders

Nausea, vomiting (<10%); Abdominal pain, anorexia (<5%)

Nausea, vomiting (<5%); Diarrhea (3%); abd. pain (<2%)

 

 

 

Skin and appendages

Pruritus, rash (<5%), potentially exfoliative

Pruritus, rash (<5%), potentially exfoliative

 

 

 

Liver and biliary system

Elevation of hepatic transaminases (<10%): hepatitis (rare)

Elevation of hepatic transaminases (<5%): hepatitis (rare)

 

 

 

Kidney

-

-

 

 

 

Bone marrow

-

 

 

 

Immunologic

Anaphylaxis reported

Anaphylaxis reported

 

 

 

Endocrine system

Adrenal insufficiency; decreased testosterone synthesis; menstrual irregularities and alopecia in women (all rare)

Syndrome of mineralocorticoid excess:

Pedal edema; decreased testosterone syn-

thesis (all rare)

 

 

 

Cardiovascular system

?

Congestive heart failure (rare)

 

 

 

Special senses 

Photophobia

-

 

 

 

Nervous system

Headache

Headache, dizziness

 

 

 

Maximum tolerated dosage in clinical trials and limiting events

> 800 mg/day:

- Endocrinologic effects

- Gastrointestinal intolerance

600-800 mg/day

-   Endocrinologic effects

-   Gastrointestinal intolerance

  

 Table 3b.  Profile of common or important adverse effects of fluconazole and voriconazole in adults at usual dosages (≤ 400mg/day) and dose-limiting toxicity (modified from references 41, 96 and 253)

 

Fluconazole

Voriconazole

Gastrointestinal disorders

Nausea, vomiting (<5%);

Abdominal pain, diarrhea (<2%)

Nausea, vomiting (<5%);

Abdominal pain (<10%)

 

 

 

Skin and appendages

Pruritus, rash (<2%),

potentially exfoliative

Pruritus, rash (<10%),

potentially exfoliative

 

 

 

Liver and biliary system

Elevation of hepatic transaminases (<7%): hepatitis (rare)

Elevation of hepatic transaminases (<15%): hepatitis (rare)

 

 

 

Kidney

-

-

 

 

 

Bone marrow

Neutropenia, agranulocytosis, thrombocytopenia reported

-

 

 

 

Immunologic

Anaphylaxis reported

Anaphylaxis reported

 

 

 

Endocrine system

-

Adrenal insufficiency (rare) 

 

 

 

Cardiovascular system

?

Cardiac arrhythmias (<5%)

 

 

 

Special senses

-

Altered/enhanced perception of light; photophobia, blured vision (<30%)

 

 

 

Nervous system

Headache, seizures

Halluzinations, confusion (<10%); headache

 

 

 

Maximum tolerated dosage in clinical trials and limiting events

1200 mg/day:

- Hepatotoxicity

- CNS-toxicity

up to 800 mg/day (10mg/kg/day) have been tolerated without dose-limiting events for a period of 14 days

  

Table 4.  Drug-drug interactions of ketoconazole, itraconazole, fluconazole and voriconazole

Mechanism and Drug Involved

Azole Involved

Comment

 

 

 

Decreased plasma concentration of azole compounds:

 

 

Decreased absorption of triazole

- Antacids, H2-antagonists, omeprazole, sucralfate, didanosine, grapefruit juice

 

KETO, ITRA (capsules)

Take antacids and antifungal agent at least 2 hours apart**

 

 

 

Increased metabolism of triazole

-Isoniazid, rifampin, rifabutin, phenytoin,

phenobarbital, carbamazepine

 

-Nevirapin, efavirenz

 

KETO, ITRA, FLU, VORI**

 

 

VORI

Potential for therapeutic failure; increased potential for hepatotoxicity**

 

Potential for therapeutic failure**

 

 

 

Increased plasma concentration of azole compounds:

-Ritonavir, indinavir

-Delavirdine, efavirenz

-Erythromycin, clarithromycin

 

 

KETO, ITRA, VORI

VORI

KETO, ITRA

 

 

Monitor closely for toxicity and adverse events

 

 

 

Increased plasma concentration of coadministered compounds: 

-Terfenadine, astemizole, cisapride, mizolastine, dofetilide, quinidine, pimozide, domperidon

-Lovastatin, simvastatin, atorvastatin

 

 

 

KETO, ITRA, FLU, VORI

 

 

KETO, ITRA, VORI

 

 

Contraindicated

(QTc prolongation)

 

Contraindicated

(rhabdomyolysis)

-Triazolame, PO midazolame

KETO, ITRA, FLU, VORI

Contraindicated

(oversedation)

-Ergotamin, dihydroergotamin

KETO, ITRA, VORI

Contraindicated(ergotism)

-Alprazolam, brotizolam, IV midazolam

KETO, ITRA, FLU, VORI

Monitor closely

-Buspirone, alfentanil, sildenafil

KETO, ITRA

Monitor closely

-Haloperidol

ITRA

Monitor closely

-Phenytoin

KETO, ITRA, FLU, VORI

Monitor levels **

-Carbamazepine

KETO, ITRA

Monitor levels

-Rifampin, rifabutin

KETO, ITRA, FLU, VORI

Monitor closely

-Clarithromycin

ITRA

Monitor closely

-Indinavir, ritonavir,saquinavir

KETO, ITRA, VORI

Monitor closely

-Vincristine, vinblastine, vindesine

KETO, ITRA, VORI

Avoid concom. use **

-Busulfan

KETO, ITRA

Avoid concom. use

-Docetaxel

KETO, ITRA

Monitor closely

-Trimetrexate

KETO, ITRA

Monitor closely

-All-trans retinoic acid

FLU

Monitor closely

-Dihydropyridine, verapamil

KETO, ITRA

Monitor closely

-Nifedipine, felodipine

ITRA, FLU

Monitor closely

-Cyclosporine A, tacrolimus, sirolimus

KETO, ITRA, FLU, VORI

Monitor levels **

-Sulfonylurea drugs

KETO, ITRA, FLU, VORI

Monitor closely **

-Methylprednisolone

KETO, ITRA

Monitor closely

-Warfarin

KETO, ITRA, FLU, VORI

Monitor prothromb. time**

-Digoxin

KETO, ITRA

Monitor levels

-Ebastin, reboxetin

KETO, ITRA

Monitor closely

-Zidovudine; theophyllin

FLU

Monitor closely

-Omeprazole

VORI

Omeprazole dose reduction

         **major clinical relevance; compiled form references 65,92,96,99,116,253

 

Table 5.  Dosing During Continuous Renal Replacement Therapy (Fluconazole)

CVVH (Continuous venovenous hemofiltration): 200-400mg q24h

CVVHD (Continuous venovenous hemodialysis): 400-800mg q24h

CVVHDF (Continuous venovenous hemodiafiltration) 400-800mg q24h

 Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD

 or CVVHDF which combine dialysis with fluid removal.

 Note: A dose of 800mg is appropriate if the dialysate flow rate is and/or if treating fungal

 species with relative azole resistance such as C. glabrata

 

Table 6.  Dosing during Continuous Renal Replacement Therapy (Voriconazole)

CVVH (Continuous venovenous hemofiltration): 1-2g IV q12h

CVVHD (Continuous venovenous hemodialysis): 2g IV q12h

CVVHDF (Continuous venovenous hemodiafiltration) 2g IV q12h

Note: CVVH is mainly for fluid removal alone. Many institutions will employ more

CVVHD or CVVHDF which combine dialysis with fluid removal.

Note: The oral bioavailability of voriconazole is estimated to be 96%.

Consider 2 loading doses of 6mg/kg PO q12h

 

Figure 1. Structural formulas of clotrimazole, miconazole and ketoconazole

Figure 2.  Ergosterol-biosynthesis and the target of the class of antifungal azoles

 

Figure 3.  Structural formulas of itraconazole, fluconazole, voriconazole and two investigational triazoles, posaconazole and ravuconazole