New Antifungal Agents Additions
to the Existing Armamentarium (Part 2)

Volume VI, Number 4 | July/August 2003
Jennifer Long, Pharm.D., BCPS

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Part I is in the available in the previous issue of Pharmacotherapy Update

Introduction

Invasive fungal infections are an important cause of morbidity and mortality, and the number of these cases has been increasing. For example, Candida is now the fourth leading cause of nosocomial infections. This rise may be partially due to medical advances that have enabled the survival of critically ill patients (e.g., intravascular catheters, total parenteral nutrition (TPN), broad spectrum antimicrobials, and dialysis). In addition, the profile of patients at risk for infection with opportunistic fungi, such as Aspergillus, is expanding (e.g., solid organ and bone marrow transplants, acquired immune deficiency syndrome (AIDS), and intensive chemotherapy regimens). It is therefore imperative that the armamentarium of antifungals expands to treat these infections. The ideal antifungal agent would:

1. be fungicidal
2. have a novel mechanism of action
3. have a broad spectrum of activity, including resistant strains, and
4. be well tolerated.

Recently, the Food and Drug Administration (FDA) approved two new antifungals, which may benefit patients with invasive fungal infections. Part I of this article discussed the echinocandins, focusing on caspofungin. Part II of this article will discuss the new azole antifungal, voriconazole.

Voriconazole

In the next few years, several new azole antifungals will be available. These newer agents were developed to expand the spectrum of activity of current azoles and alleviate certain bioavailability issues. The first of the new azole agents approved by the FDA is voriconazole (Vfend®). It is structurally related to fluconazole (Diflucan®); however, an expanded spectrum of activity results from the replacement of one of the triazole rings with a fluorinated pyrimidine as well as the addition of an α-methyl group. Another new azole, posaconazole, is structurally related to itraconazole (Sporanox®). Like voriconazole, several changes to the chemical structure of posaconazole have expanded the spectrum of activity. The new azoles and their current status can be located in Table 2. The remainder of this discussion will focus on voriconazole.

Table 2. New Azole Antifungal Agents

Agent	Status	Manufacturer
Voriconazole (Vfend®)	FDA-approved	Pfizer
Posaconazole (SCH56592; Noxafil™)	Phase III trials	Schering Plough
Ravuconazole (BMS207147)	Phase II trials	Bristol Myers Squibb

 

Mechanism of Action

The azole antifungals inhibit the cytochrome P450 (CYP)-dependent enzyme, 14-α-demethylase. This inhibition disrupts membrane synthesis resulting in depletion of ergosterol and leads to accumulation of toxic sterol precursors. Voriconazole appears to have a stronger affinity for 14-α-demethylase compared to fluconazole. Also, it inhibits the enzyme, 24-methylene dihydrolanasterol demethylase. These two features may explain the increased activity of voriconazole against certain moulds compared to other azole antifungals.

Azole resistance has been documented in several species of Candida. The proposed mechanisms include alteration of 14-α-demethylase and upregulation of genes that encode for efflux pumps. Voriconazole susceptibilities also appear to be influenced by these mechanisms. Certain efflux pumps that affect fluconazole will also affect voriconazole. This explains the increased minimum inhibitory concentrations (MICs) for voriconazole noted in some fluconazole-resistant Candida.

Spectrum of Activity

The National Committee for Clinical Laboratory Standards (NCCLS) has established breakpoints for fluconazole and itraconazole activity for C. albicans. Although NCCLS does not have official breakpoints for non-albicans isolates, the breakpoints for C. albicans are usually adopted for these other species. At this time, the NCCLS has not set breakpoints for voriconazole. Most in-vitro studies demonstrate voriconazole to be fungistatic against yeasts. However, a few in-vitro studies have shown fungicidal activity of voriconazole against certain filamentous fungi.

Yeasts

Voriconazole is active against a majority of Candida species. Voriconazole has activity against C. krusei and C. glabrata which are often times inherently resistant to fluconazole. Fluconazole-resistant C. albicans are usually susceptible to voriconazole, although the MICs are usually higher than those noted for fluconazole-susceptible strains. This may suggest the possibility of cross-resistance. The voriconazole MIC for C. krusei and C. glabrata tend to be higher than C. albicans but are still in the presumed susceptible range. In addition, voriconazole is active against other yeasts such as Cryptococcus, Trichosporon beigelii, and Saccharomyces cerevisiae.

Filamentous fungi

Voriconazole, like itraconazole, has activity against certain filamentous fungi. It is active against Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus.

The fungicidal activity of voriconazole against Aspergillus does not appear to be as great as amphotericin B but is still better than itraconazole. Voriconazole has also demonstrated in-vitro activity against the following opportunistic dematiaceous and hyaline moulds: Fusarium spp., Penicillium marneffei, Pseudallescheria boydii (Scedosporium apiospermum), and Scedosporium prolifcans. The zygomycetes, including Rhizopus spp. and Mucor spp. are not susceptible to voriconazole.

Dimorphic fungi

Voriconazole has shown in-vitro activity against the endemic fungi, Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis.

Pharmacokinetics

The pharmacokinetic properties of azole antifungals are summarized in Table 3. Voriconazole is well absorbed and has excellent bioavailability. Unlike itraconazole, gastric acid is not needed for absorption of voriconazole. After a loading dose is administered, steady-state concentrations are reached within 1 day, or, if there is no loading dose, steady-state concentrations may not be reached for 5 to 6 days. In adults, voriconazole exhibits non-linear kinetics due to saturable metabolism. The wide intersubject variability noted with voriconazole levels may also be in part to its hepatic metabolism. Voriconazole is metabolized by the CYP450 system including 2C9, 3A4, and 2C19. The CYP2C19 is the major metabolic pathway and is highly subject to genetic polymorphism. Low levels of CYP2C19 may lead to voriconazole levels up to four times higher than those who metabolize voriconazole more extensively. The major metabolite is voriconazole N-oxide, which has minimal antifungal activity. Eight other non-active metabolites have been identified and all are excreted in the urine. Dose adjustments are necessary for patients with mild-to-moderate hepatic impairment (See Indications and Dosage section). No studies have evaluated the use of voriconazole in patients with severe hepatic insufficiency. Renal dose adjustments are not necessary; however, the intravenous formulation is solubilized in sulfobutyl ether ß-cyclodextrin sodium (SBECD) which may accumulate in patients with renal insufficiency. Therefore, intravenous voriconazole should be avoided in patients with a creatinine clearance < 50 mL/min.

Table 3. Pharmacokinetic Parameters of Selected Azoles^a

	Voriconazole (200 mg BID)	Fluconazole (200 mg BID)	Itraconazole (200 mg Q 24 hours)	Posaconazole (200 mg BID)	Ravuconazole (200 mg BID)
Bioavailability (%)	90	93	55b	N/A	N/A
Cmax (mcg/mL)	2.7 — 6	5.6 — 9.6	1.1 — 2b	1.1	3.9
Tmax (hr)	1	3 — 4	1 — 3	N/A	N/A
Volume of Distribution (L)	2 L/kg	40 — 46	796	343	N/A
Protein Binding (%)	51— 67	12	99	N/A	N/A
Half-life (hr)	6	24 ± 9	64	24	113
Primary route of elimination	Hepatic	Renal	Hepatic	Hepatic	Hepatic

^aAdapted from Ann Pharmacother 2000;34:1035 and Pharmacotherapy 2001;21:168S
^b Variability is a function of prandial state and oral formulation
Q = every
BID = twice a day; hr = hrs

Drug Interactions

Voriconazole is a substrate and inhibitor of CYP2C9, 3A4, and 2C19 and has a drug-drug interaction profile similar to itraconazole. Agents metabolized via these pathways are likely to have interactions and require potential dosage adjustments. Tables 4 and 5 summarize select drug interactions with voriconazole. Please note these tables are not all inclusive and other agents metabolized via these pathways may be affected by voriconazole.

Table 4. Effect of Other Drugs on Voriconazole Levels

Drug/Drug Class	Voriconazole Levels	Recommendations for voriconazole dose adjustments
Rifampin/Rifabutin (CYP450 Induction)	Significantly reduced	CONTRAINDICATED
Carbamazepine (Tegretol®) (CYP450 Induction)	Likely to result in significant reduction	CONTRAINDICATED
Long-acting barbiturates (CYP450 Induction)	Likely to result in significant reduction	CONTRAINDICATED
Phenytoin (Dilantin®) (CYP450 Induction)	Significantly reduced	Increase maintenance dose to 5mg/kg IV Q 12 hrs or 400 mg PO Q 12 hrs (If < 40 kg; 200 mg PO Q 12 hrs)
HIV Protease Inhibitors (PIs) (CYP450 Induction)	In-vivo studies showed no effect of indinavir (Crixivan®) on voriconazole; In-vitro studies show potential for interaction	No dose adjustment needed with indinavir. Monitor for adverse effects or toxicity when given with other PIs.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (CYP450 Induction or Inhibition)	Potential for inhibition or induction exists	Monitor for adverse effects and toxicity of voriconazole or monitor for clinical efficacy of voriconazole

 

Table 5. Effect of Voriconazole on Levels of Other Drugs

Drug/Drug Class	Drug Level	Drug Dosage Adjustment
Sirolimus (Rapamune®) (CYP3A4 Inhibition)	Significantly increased	CONTRAINDICATED
Terfenadine, astemizole, cisapride, pimozide, quinidine (CYP450 Inhibition)	Drug levels likely increased	CONTRAINDICATED
Ergot alkaloids (CYP450 Inhibition)	Drug levels likely increased	CONTRAINDICATED
Cyclosporine (CYP3A4 Inhibition)	AUC significantly increased	Decrease cyclosporine dose by one-half and follow levels
Tacrolimus (Prograf®) (CYP3A4 Inhibition)	Significantly increased	Decrease tacrolimus dose by one-third and follow levels
Phenytoin (Dilantin®) (CYP2C9 Inhibition)	Significantly increased	Frequently monitor phenytoin levels and monitor for adverse effects
Warfarin (Coumadin®) (CYP2C9 Inhibition)	Increased INR/PT	Monitor INR/PT; may require dose adjustment of warfarin
Omeprazole (Prilosec®) (CYP2C19/3A4 Inhibition)	Significantly increased	If omeprazole dose > 40 mg/day decrease dose by one-half; other PPIs may require dose adjustment
HIV Protease Inhibitors (PIs) (CYP3A4 Inhibition)	No effects on indinavir; In-vitro studies show potential for interaction	Monitor for adverse effects and toxicity of PIs
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (CYP3A4 Inhibition)	Potential for increased levels	Monitor for adverse effects and toxicity of NNRTIs
HMG-CoA Reductase Inhibitors (CYP3A4 Inhibition)	Potential for increased levels	Monitor for adverse effects; may require dose adjustment of the HMG - CoA Reductase Inhibitor
Dihydropyridine calcium channel blockers (CCBs) (CYP2C9 Inhibition)	Potential for increased levels	Monitor for adverse effects; may require dose adjustment of CCB
Sulfonylurea (CYP2C9 Inhibition)	Potential for increased levels	Monitor for hypoglycemia; may require dose adjustment
Vinka alkaloids (CYP3A4 Inhibition)	Potential for increased levels	Monitor for adverse events and neurotoxicity; may require dose adjustment of vinka alkaloids
Cyclophosphamide (CYP3A4 Inhibition)	May prevent conversion to active metabolite	Unknown

AUC = area-under-the-curve
INR = international normalized ratio
PT = prothrombin time
PPI = proton pump inhibitor

Adverse Effects

Voriconazole is associated with similar adverse effects when compared to other azole antifungals (e.g., hepatotoxicity). In addition, there are other effects not previously noted with the class. The potential adverse effects associated with voriconazole are summarized in this section, although the true incidence in clinical practice is unknown. Voriconazole is teratogenic in animals and may cause harm when administered during pregnancy. It is listed as a pregnancy-risk category D and patients should be informed of the potential hazards to the fetus.

Ocular

The most common side effect with voriconazole is a reversible disturbance of vision. The reaction has been reported as increased brightness, blurred vision, altered visual perception, photophobia, altered color perception, and ocular discomfort. The incidence in healthy volunteers and in clinical studies was approximately 30%, with only 1% of volunteers discontinuing therapy secondary to visual effects. The reaction usually occurred approximately 30 minutes after a dose, persisted for 30 minutes, and was most common during the first week of therapy. The exact mechanism is unknown; however, the abnormalities were consistent with drug effect on the rods and cones. The effects on ocular function are not known when voriconazole therapy extends beyond 28 days or when patients require retreatment.

Skin Effects

Skin rashes appear to be the second most common adverse effect of voriconazole. In some clinical trials, the incidence has been reported as high as 18%. Most rashes were mild-to-moderate but severe rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported. Photosensitivity reactions are also common and patients should avoid direct sunlight.

Hepatic Effects

Increased AST, ALT, and alkaline phosphatase levels have been reported in clinical trials in-volving voriconazole. Patients at risk for abnormal liver function tests (LFTs) appear to have high voriconazole plasma concentrations and receive a longer duration of therapy (i.e., e" 7 days). The majority of these patients remain asymptomatic, although severe life-threatening hepatitis has been described. Other effects include increased liver weight, centrilobular hypertrophy, hepatocellular fatty change, single cell necrosis, and subcapsular necrosis. According to the product labeling, LFTs should be performed prior to therapy, within the first 2 weeks of initiation, and every 2 to 4 weeks during therapy.

It is too early to determine if the risk of hepatotoxicity is greater with voriconazole when compared to other azole antifungals.

Infusion-Related Reactions

In healthy subjects, the product labeling states that during infusion anaphylactoid-type reactions (e.g., flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, and rash) have occurred immediately upon initiation.

Cardiac Effects

In animal models, high doses of voriconazole have been associated with arrhythmias, in-cluding prolongation of the QTc interval. The plasma concentrations of voriconazole ranged from 24 to 56 mcg/mL in these studies. The product labeling states that during clinical development and post-marketing surveillance, rare cases of torsade de pointes have been reported. All patients had confounding factors that made it difficult to assess the contribution of voriconazole. Therefore, in patients receiving voriconazole, it is recommended to maintain normal levels of potassium, mag-nesium, and calcium.

Clinical Trials

The major trials involving voriconazole are summarized below. Please note that there are major caveats and questions regarding design and statistical methods for these trials that are beyond the scope of this article. The highlights of the trials are mentioned.

Aspergillosis

Voriconazole was approved for this indication based upon a noncomparative trial and a randomized trial comparing voriconazole to conventional amphotericin B (CAB).

The noncomparative trial had 116 evaluable patients, 70% of which had pulmonary invasive aspergillosis (IA). Patients could receive voriconazole as primary therapy or salvage therapy. Fourteen percent (16/116) had a complete response, however, 2 of these patients died. Thirty-four percent (40/116) had a partial response but 16 of these patients died. Response rates were better in patients receiving voriconazole as primary therapy than salvage therapy. Twenty patients in this trial were noted to have increased liver function tests and one case of liver failure is mentioned. Overall it is difficult to ascertain the role of voriconazole from this trial due to the uncontrolled design.

The subsequent large randomized trial compared voriconazole to CAB for primary IA. The primary objective of the study was non-inferiority at week 12. An expert panel blinded to therapy determined outcomes of patients. Overall, 144 patients were randomized to receive voriconazole and 133 patients were randomized to CAB. Complete or partial responses at week 12 were found in 53% of voriconazole patients compared to 32% of CAB patients (difference 21%; 95% CI, 10.4%-32.9%). While results point to the fact that voriconazole may be more effective than CAB there are several points to keep in mind. First, physicians were permitted to switch patients' therapy to another drug if they were failing to respond or experiencing side effects, and these were not classified as failures. Approximately 25% of patients in the CAB group were changed to itraconazole and approximately 25% in the voriconazole group were changed to an amphotericin product. In addition, the median duration of therapy was much longer for voriconazole than CAB (median of 77 days for voriconazole compared to 10 days for CAB). This trial demonstrates voriconazole can be an effective therapy but some debate exists regarding if it is truly superior to amphotericin from the design of this trial.

Pseudoallescheria/Scedoporium/Fusarium

These fungi have emerged as significant pathogens in immunocompromised hosts. In-vitro data shows voriconazole to be active against these difficult to treat pathogens. In addition, small case series have shown voriconazole to be promising in the treatment of these infections in both adults and children.

Candidiasis

Voriconazole is not approved for the treatment of candidal infections. A randomized, double-dummy trial to compare the efficacy and safety of voriconazole versus fluconazole in 391 immuno-compromised patients with esophageal candidias was performed. Patients received either fluconazole 200 mg/day or voriconazole 200 mg BID for at least seven days. There was no difference between the groups in respect to cure, determined by esophagoscopy. A trial comparing voriconazole to CAB followed by fluconazole is currently ongoing.

Febrile Neutropenia

Voriconazole was compared to liposomal amphotericin B (LAMB) for empiric therapy of febrile neutropenia in an open-label prospective trial. The results of this trial which enrolled 412 patients in the voriconazole group and 422 patients in the LAMB group have been controversial. The voriconazole group did not meet the predefined primary endpoint for non-inferiority compared to LAMB. The trial did show a trend towards less breakthrough fungal infections in the voriconazole group. However, based upon this trial the FDA voted voriconazole would not be indicated for the empiric treatment of febrile neutropenia.

Indications and Dosage

Voriconazole is FDA-approved for the following indications:
Treatment of invasive aspergillosis (both primary and salvage therapy)
Treatment of serious fungal infections due to Fusarium and Scedosporium spp in patients refractory or intolerant to other therapy

The recommended dosing per Cleveland Clinic Foundation Antimicrobial Guidelines differs from the package insert (See Tables 6a and 6b). The rationale is based on clinical trials using this dosing scheme and the excellent bioavailability of oral voriconazole.

Table 6a. CCF-Specific Dosing Guidelines

	Loading Dose (IV/PO)	Maintenance Dose (IV/PO)
< 100 kg	400 mg IV Q 12 hrs x 2 doses	200 mg IV Q 12 hrs
> 100 kg	600 mg IV Q 12 hrs x 2 doses	200 mg IV Q 12 hrs

 

Table 6b. Product Labeling Dose and Administration

	Intravenous	Oral
		> 40 kg	< 40 kg
Loading Dose	2 doses of 6 mg/kg Q 12 hrs x 24 hrs	2 doses of 400 mg Q 12 hrs x 24 hrs	2 doses of 200 mg Q 12 hrs x 24 hrs
Maintenance Dosea,b,c
Serious Candida Infectionsd	3 mg/kg Q 12 hrs	200 mg Q 12 hrs	100 mg Q 12 hrs
Aspergillosis, Scedosporium and Fusarium, other moulds	4 mg/kg Q 12 hrs	200 mg Q 12 hrs	100 mg Q 12 hrs

^aInitial oral maintenance dose of 200 mg Q 12 hrs is recommended rather than 300 mg Q 12 hrs for considerations of hepatic safety
^bProvision is made for dose increase if inadequate response; 300 mg PO BID (if < 40 kg: 150 mg PO BID); if not tolerating therapy IV dose may be decreased to 3 mg/kg IV Q 12 hrs
^cMaintenance dose may need to be decreased by 50% for patients with mild-to-moderate hepatic impairment (Child-Pugh class A or B), not enough data to recommend in patients with severe hepatic impairment (Child-Pugh class C)
^dNot a FDA-approved indication

Restrictions

Voriconazole is restricted at CCF to the Department of Infectious Diseases for the following:

1. Treatment of presumed or documented invasive fungal infections; or
2. Monotherapy or combination therapy with amphotericin/caspofungin for presumed or documented invasive mould infections; or
3. Second-line therapy for Candida infections in patients intolerant or failed amphotericin/azole therapy; and
4. The intravenous formulation is restricted to patients who are unable to take oral medications.

Cost Comparison

Table 7. Daily Cost of Antifungal Therapy

	Dosage	Cost
Caspofungin (Cancidas®) [FR]	70 mg IV x 1 dose	$473.88
	50 mg IV Q 24 hrs	$367.87
Voriconazole (Vfend®) [FR]	400 mg IV Q 12 hrs	$425
	400 mg PO Q 12 hrs	$125
	200 mg IV Q 12 hrs	$212.50
	200 mg PO Q 12 hrs	$62.50
Itraconazole (Sporanox®) [F] - The intravenous formulation is non-formulary	200 mg capsule Q 24 hrs	$17.00
	200 mg solution Q 24 hrs	$17.00
Amphotericin B [F]	50 mg vial	$10
Amphotericin B Lipid Complex (ABLC; Abelcet®) [FR]	100 mg vial	$230.00
	3 mg/kg for a 70 kg person	$420.00
	5 mg/kg for a 70 kg person	$805.00
Fluconazole (Diflucan®) [F]	400 mg IV Q 24 hrs	$147.50
	400 mg PO Q 24 hrs	$28.00
	200 mg IV Q 24 hrs	$100.00
	200 mg PO Q 24 hrs	$14.00

¹Cost based on average wholesale price (AWP)
²At CCF, with contract pricing, the cost of itraconazole PO < voriconazole PO < voriconazole IV ≈ ABLC < caspofungin IV
F = Formulary
FR = Formulary Restricted

Conclusion

As the rates of invasive fungal infections increase, it is important to have new agents effective against these pathogens. Caspofungin appears to be very good for Candida infections and effective in salvage therapy for aspergillosis. It appears to be well tolerated and has limited drug interactions. Voriconazole, while having many drug interactions and some potential concerning side effects, has added greatly to the armamentarium of agents active against Aspergillus and emerging moulds. The role of combination therapy with azoles, amphotericin, and echinocandins is being investigated in in-vitro models and a few case reports have been published. While this practice needs further study before definitive recommendations can be made, it may hold promise for the treatment of serious and life-threatening invasive fungal infections.

References Available Upon Request

Part I is in the available in the previous issue of Pharmacotherapy Update

Return to Pharmacotherapy Update Index