Azoles Tables and Figures

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

· Opport. yeasts

Increased plasma concentration of azole compounds: