Pharmacology of Voriconazole

Introduction/Overview

Voriconazole represents a cornerstone in the therapeutic armamentarium against invasive fungal infections, a significant cause of morbidity and mortality in immunocompromised patient populations. As a second-generation synthetic triazole antifungal agent, it was developed to address the limitations of earlier azoles, particularly with respect to spectrum of activity and pharmacokinetic properties. Its introduction marked a pivotal advancement in the management of invasive aspergillosis and other serious mycoses. The clinical relevance of voriconazole is underscored by its position as a first-line agent for several life-threatening fungal infections, supported by robust evidence from clinical trials demonstrating superior efficacy to amphotericin B deoxycholate in invasive aspergillosis. A comprehensive understanding of its pharmacology is essential for clinicians and pharmacists to optimize therapeutic outcomes while mitigating the risks associated with its complex pharmacokinetics and potential for significant drug interactions and toxicities.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the molecular mechanism of action of voriconazole and its relationship to its antifungal spectrum.
• Explain the nonlinear pharmacokinetics of voriconazole, including the factors influencing its absorption, distribution, metabolism, and excretion.
• Identify the primary clinical indications for voriconazole therapy and the evidence supporting its use.
• Recognize the major adverse effects, including visual disturbances and hepatotoxicity, and the strategies for their monitoring and management.
• Analyze the complex drug interaction profile of voriconazole, focusing on its metabolism via cytochrome P450 enzymes and the implications for concomitant therapy.

Classification

Voriconazole is classified pharmacotherapeutically as a systemic antifungal agent. Within this broad category, it belongs specifically to the triazole class of antifungals, which is a subgroup of the azole antifungals. The azoles are characterized by the presence of a five-membered azole ring; triazoles contain three nitrogen atoms in this ring, whereas imidazoles contain two. This distinction is pharmacologically significant, as triazoles generally exhibit greater specificity for fungal cytochrome P450 enzymes, contributing to an improved safety profile compared to earlier imidazole agents.

From a chemical perspective, voriconazole is a synthetic derivative of fluconazole. Its chemical name is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol. The key structural modification from fluconazole is the replacement of one triazole ring with a fluoropyrimidine group and the addition of an α-methyl group, which confers enhanced potency and a broader spectrum of activity. This structural alteration reduces its dependence on renal excretion and increases its affinity for fungal cytochrome P450 enzymes. Voriconazole is formulated for intravenous infusion as a sulfobutyl ether β-cyclodextrin sodium (SBECD) complex to enhance water solubility and for oral administration as film-coated tablets or a powder for suspension.

Mechanism of Action

The antifungal activity of voriconazole, like other azoles, is primarily mediated through the inhibition of ergosterol biosynthesis, a critical component of the fungal cell membrane. Ergosterol serves a function in fungi analogous to cholesterol in mammalian cells, providing membrane integrity, fluidity, and the proper function of membrane-bound enzymes.

Molecular and Cellular Mechanisms

The specific molecular target of voriconazole is lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme (encoded by the ERG11 gene in yeasts such as Candida). This enzyme catalyzes the oxidative removal of the 14α-methyl group from lanosterol, a key step in the conversion of lanosterol to ergosterol. Voriconazole binds to the heme iron atom located in the active site of this fungal cytochrome P450 enzyme, acting as a non-competitive inhibitor. This binding prevents the activation of molecular oxygen and the subsequent demethylation reaction.

The inhibition of ergosterol synthesis leads to the accumulation of toxic methylated sterol precursors (e.g., 14α-methylergosta-8,24(28)-dien-3β,6α-diol) within the fungal cell membrane. Concurrently, the depletion of ergosterol disrupts membrane structure and function. The consequences are multifold: increased membrane permeability, inhibition of fungal cell growth and replication, and aberrant activity of membrane-associated enzymes. The fungistatic or fungicidal effect observed may depend on the fungal species and the drug concentration achieved; voriconazole exhibits concentration-dependent fungicidal activity against certain molds like Aspergillus, while its effect against many yeasts is primarily fungistatic.

Spectrum of Activity

The structural modifications of voriconazole confer a significantly broader spectrum of activity compared to fluconazole. Its spectrum encompasses a wide range of yeasts and molds.

• Yeasts: It is active against most Candida species, including C. albicans, C. tropicalis, C. parapsilosis, and C. krusei (which is intrinsically resistant to fluconazole). Activity against C. glabrata is variable and dose-dependent, and resistance may be observed. It possesses excellent activity against Cryptococcus neoformans.
• Molds: Voriconazole is a first-line agent for infections caused by Aspergillus species, including A. fumigatus, A. flavus, A. terreus, and A. niger. It also demonstrates activity against other hyaline molds such as Fusarium species (notably F. solani) and Scedosporium apiospermum.
• Dimorphic Fungi: It shows in vitro activity against Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis.
• Other Fungi: Activity is observed against certain dematiaceous (pigmented) fungi and the endemic pathogen Penicillium marneffei.

It is important to note that voriconazole lacks clinically useful activity against the agents of mucormycosis (e.g., Rhizopus, Mucor) and against some rare molds.

Pharmacokinetics

The pharmacokinetic profile of voriconazole is characterized by nonlinearity, extensive metabolism, and considerable interpatient variability, necessitating therapeutic drug monitoring in many clinical scenarios to ensure efficacy and avoid toxicity.

Absorption

Oral voriconazole is rapidly and almost completely absorbed, with a bioavailability estimated at approximately 96% under fasting conditions. The presence of food, particularly high-fat meals, reduces bioavailability by up to 20-30% and delays the time to reach maximum plasma concentration (t_max). Therefore, oral administration is recommended at least one hour before or after a meal. The t_max for the oral formulation is typically 1-2 hours. Due to its nonlinear pharmacokinetics, increases in oral dose result in a greater-than-proportional increase in exposure, measured as the area under the concentration-time curve (AUC). This is attributed to the saturation of first-pass metabolism in the liver at higher doses.

Distribution

Voriconazole exhibits extensive tissue distribution, with an apparent volume of distribution (V_d) of approximately 4.6 L/kg, indicating extensive penetration into tissues. It achieves concentrations in cerebrospinal fluid, brain tissue, and ocular fluids that are approximately 50% of corresponding plasma levels, making it a valuable agent for central nervous system and ocular fungal infections. Protein binding is moderate, estimated at 58%. The intravenous formulation contains SBECD, a solubilizing agent, which is renally eliminated. Accumulation of SBECD may occur in patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min), and thus the intravenous formulation is contraindicated in such patients unless the benefit outweighs the risk.

Metabolism

Voriconazole undergoes extensive hepatic metabolism, primarily via the cytochrome P450 enzyme system. The major metabolic pathways involve N-oxidation by CYP2C19, with minor contributions from CYP3A4 and CYP2C9. This metabolic profile is the source of its significant drug interaction potential and pharmacokinetic variability. Genetic polymorphism of the CYP2C19 enzyme is a critical determinant of voriconazole metabolism. Individuals can be classified as poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), or ultrarapid metabolizers (UMs). Poor metabolizers, who carry two non-functional CYP2C19 alleles, may exhibit voriconazole exposure (AUC) up to four times higher than extensive metabolizers when given the same dose. This polymorphism is ethnically linked, with a higher prevalence of poor metabolizers in Asian populations (≈15-20%) compared to Caucasian and African populations (≈2-5%).

Excretion

Less than 2% of an administered dose is excreted unchanged in the urine. Metabolism is the primary route of elimination, with over 80% of the metabolites excreted renally. The primary metabolite, voriconazole N-oxide, possesses minimal antifungal activity. The elimination half-life (t_1/2) is dose-dependent due to nonlinear kinetics, typically ranging from 6 to 24 hours in adults. In children, linear pharmacokinetics are observed, and clearance is more rapid, necessitating higher weight-based dosing regimens compared to adults.

Dosing Considerations

Dosing must account for the nonlinear pharmacokinetics and metabolic variability. A standard loading dose is employed to achieve therapeutic concentrations rapidly. For adults, the recommended intravenous regimen is a loading dose of 6 mg/kg every 12 hours for two doses, followed by a maintenance dose of 4 mg/kg every 12 hours. The oral maintenance dose is typically 200 mg every 12 hours, but may be increased to 300 mg every 12 hours if the patient is not responding and drug levels are subtherapeutic. For patients weighing less than 40 kg, the oral maintenance dose is 100 mg every 12 hours (or 150 mg every 12 hours). Pediatric dosing is based on body weight and is generally higher: a loading dose of 9 mg/kg IV every 12 hours for two doses, followed by 8 mg/kg IV every 12 hours, or 9 mg/kg orally every 12 hours. Therapeutic drug monitoring is strongly recommended to individualize therapy, with a target trough plasma concentration range of 1-5.5 mg/L for most invasive infections. Trough levels below 1 mg/L may be associated with therapeutic failure, while levels above 5.5 mg/L correlate with an increased risk of neurological and hepatic toxicity.

Therapeutic Uses/Clinical Applications

Voriconazole is indicated for the treatment of serious, invasive fungal infections. Its use is typically reserved for situations where the benefits outweigh the risks associated with its side effect and interaction profile.

Approved Indications

• Invasive Aspergillosis: Voriconazole is the drug of choice for primary therapy of invasive aspergillosis in most patient populations. This recommendation is based on a landmark randomized clinical trial which demonstrated significantly superior efficacy (successful outcomes in 53% vs. 32% of patients) and improved survival with voriconazole compared to conventional amphotericin B, along with a better safety profile.
• Candidemia in Non-neutropenic Patients: It is approved for the treatment of candidemia in non-neutropenic patients and for disseminated candidal infections involving the abdomen, kidney, bladder wall, and wounds.
• Esophageal Candidiasis: Voriconazole is effective for the treatment of esophageal candidiasis, including cases refractory to fluconazole and/or itraconazole therapy.
• Serious Infections due to Fusarium spp. and Scedosporium apiospermum: It is indicated for these infections, which are often resistant to other antifungal agents. Voriconazole is often considered a primary therapeutic option for these challenging molds.

Off-Label Uses

Several off-label applications are supported by clinical guidelines and evidence from case series or comparative studies.

• Empirical Antifungal Therapy in Febrile Neutropenia: While not a first-line empirical agent, it may be considered in specific high-risk settings, particularly when there is a high pre-test probability of invasive aspergillosis or other mold infections.
• Antifungal Prophylaxis: In high-risk hematopoietic stem cell transplant recipients with graft-versus-host disease, voriconazole is an option for prophylaxis against invasive fungal infections, though posaconazole is often preferred based on trial data.
• Central Nervous System Fungal Infections: Due to its excellent CNS penetration, it is frequently used for the treatment of fungal meningitis and brain abscesses caused by susceptible organisms, such as Aspergillus, Seedosporium, and Cryptococcus.
• Ocular Fungal Infections: Its good intraocular penetration supports its use in the treatment of fungal endophthalmitis and keratitis.
• Chronic Pulmonary Aspergillosis: It is a mainstay of long-term oral therapy for this condition.

Adverse Effects

The use of voriconazole is associated with a range of adverse effects, from common, transient disturbances to serious, potentially life-threatening reactions.

Common Side Effects

• Visual Disturbances: Up to 30% of patients may experience transient, reversible visual changes. These include photopsia (perceived flashes of light), photophobia, blurred vision, altered color perception, and increased brightness of images. The mechanism is thought to involve reversible effects on retinal photoreceptors. These symptoms typically occur within 30 minutes of dosing, last for approximately 30 minutes, and often diminish with continued therapy. Patients should be advised to avoid driving or operating hazardous machinery at night during treatment.
• Gastrointestinal Effects: Nausea, vomiting, diarrhea, and abdominal pain are relatively common.
• Skin Reactions: Rash is frequently reported. Most rashes are mild to moderate, but severe cutaneous adverse reactions (SCARs) like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported.
• Elevated Liver Enzymes: Asymptomatic increases in serum transaminases (ALT, AST) and alkaline phosphatase are common, occurring in up to 15-20% of patients.

Serious/Rare Adverse Reactions

• Hepatotoxicity: Serious hepatic reactions, including clinical hepatitis, cholestasis, and fulminant hepatic failure, can occur. Risk factors may include pre-existing liver disease, high plasma concentrations, and concomitant hepatotoxic drugs. Liver function tests should be monitored at initiation and regularly during therapy.
• Severe Cutaneous Adverse Reactions: As noted, SJS and TEN, while rare, are potentially fatal and require immediate drug discontinuation.
• Prolonged QT Interval: Voriconazole has been associated with QT interval prolongation on the electrocardiogram, which may predispose to ventricular tachyarrhythmias, including torsades de pointes. Caution is warranted in patients with congenital or acquired QT prolongation, electrolyte imbalances, or concomitant use of other QT-prolonging drugs.
• Peripheral Neuropathy: Cases of peripheral neuropathy, including paresthesias, have been reported, often associated with long-term therapy.
• Skeletal Toxicity: Long-term use (often >12 months) has been linked to periostitis, arthralgias, and elevated serum fluoride and alkaline phosphatase levels, likely due to the fluoride moiety in its chemical structure.
• Photosensitivity and Photocarcinogenesis: Chronic use is associated with pronounced photosensitivity reactions and an increased risk of developing skin malignancies, particularly squamous cell carcinoma. Patients on long-term therapy require rigorous sun protection and regular dermatological evaluation.

Black Box Warnings

Voriconazole carries a boxed warning from regulatory agencies concerning several serious risks:

1. Hepatotoxicity: The warning emphasizes that severe hepatic reactions, including hepatic failure and death, have occurred. Liver function must be monitored.
2. Visual Disturbances: It highlights the occurrence of transient visual changes and advises monitoring and patient counseling.
3. Cardiovascular Risks: The warning notes that voriconazole has been associated with QT interval prolongation and rare cases of torsades de pointes, particularly in patients with proarrhythmic conditions.
4. Dermatological Reactions: It includes the risk of photosensitivity, phototoxicity, and skin cancer with long-term use.

Drug Interactions

The drug interaction profile of voriconazole is extensive and complex, stemming primarily from its metabolism by and its potent inhibition of key cytochrome P450 enzymes. Careful review of concomitant medications is mandatory prior to initiation of therapy.

Major Drug-Drug Interactions

Interactions can be categorized based on whether voriconazole affects other drugs or is affected by them.

Drugs that Increase Voriconazole Concentrations: Strong CYP2C19 inhibitors (e.g., omeprazole, esomeprazole) can increase voriconazole levels. While proton pump inhibitors are often used together, high doses may necessitate monitoring.

Drugs that Decrease Voriconazole Concentrations: Inducers of CYP450 enzymes significantly reduce voriconazole efficacy.

• Rifampin, Rifabutin, Carbamazepine, Phenytoin, Long-acting Barbiturates: These potent enzyme inducers can reduce voriconazole AUC by over 90%. Concomitant use is generally contraindicated. Rifabutin also increases the risk of uveitis when combined with voriconazole.
• St. John’s Wort: This herbal supplement induces CYP3A4 and can markedly reduce voriconazole concentrations.

Drugs Whose Concentrations are Increased by Voriconazole: As a potent inhibitor of CYP2C19, CYP3A4, and to a lesser extent CYP2C9, voriconazole can increase levels of many co-administered drugs, potentially leading to toxicity.

• Sirolimus: Contraindicated. Voriconazole increases sirolimus AUC by approximately 11-fold.
• Ergot Alkaloids (ergotamine, dihydroergotamine): Contraindicated due to risk of severe ergotism.
• CYP3A4 Substrates: Dose reduction and close monitoring are required for drugs with a narrow therapeutic index:
  • Cyclosporine, Tacrolimus: Voriconazole can increase their levels by 2-3 fold. Doses of these calcineurin inhibitors should be reduced (e.g., by 50%) upon voriconazole initiation and levels monitored closely.
  • Benzodiazepines (midazolam, triazolam): Increased sedation and prolonged effect.
  • Statins (simvastatin, lovastatin, atorvastatin): Increased risk of myopathy/rhabdomyolysis.
  • Fentanyl, Alfentanil, Oxycodone: Risk of prolonged respiratory depression.
  • Warfarin: Increased anticoagulant effect; INR must be monitored closely.
  • Sulfonylureas (e.g., glipizide): Increased risk of hypoglycemia.
  • Vinca Alkaloids (vinblastine, vincristine): Increased risk of neurotoxicity.
• QT-Prolonging Agents: Concomitant use with other QT-prolonging drugs (e.g., Class IA/III antiarrhythmics, certain antipsychotics, macrolide antibiotics) may have additive effects and increase arrhythmia risk.

Contraindications

Absolute contraindications to voriconazole therapy include:

• Hypersensitivity to voriconazole or any component of its formulation.
• Concomitant administration with the following drugs due to severe interaction risks: sirolimus, rifampin, rifabutin, carbamazepine, long-acting barbiturates, ergot alkaloids, and the CYP3A4 substrate quinidine (due to QT prolongation risk).
• Use of the intravenous formulation in patients with moderate to severe renal impairment (CrCl < 50 mL/min) due to SBECD accumulation, unless the benefit justifies the risk.

Special Considerations

Pregnancy and Lactation

Voriconazole is classified as Pregnancy Category D. Animal studies have demonstrated evidence of fetal harm, including teratogenicity (cleft palate, hydroureter, hydronephrosis) at doses close to the human therapeutic dose. There are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether voriconazole is excreted in human milk. Given the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug.

Pediatric Considerations

Pharmacokinetics in children are linear, unlike in adults. Children have a higher capacity for voriconazole clearance, necessitating higher weight-based doses to achieve therapeutic exposures similar to adults. The recommended intravenous maintenance dose is 8 mg/kg every 12 hours, and the oral dose is 9 mg/kg every 12 hours (maximum 350 mg). Therapeutic drug monitoring is particularly important in this population due to high variability. The safety profile in children is generally similar to adults, though the incidence of phototoxicity may be lower. The intravenous formulation’s SBECD vehicle requires caution in pediatric patients with renal impairment.

Geriatric Considerations

No major dose adjustments are recommended solely based on age. However, elderly patients are more likely to have decreased hepatic, renal, or cardiac function, and to be on multiple concomitant medications. These factors increase the risk of adverse effects and drug interactions. Careful monitoring of hepatic function, renal function, and drug levels, along with a thorough review of the medication regimen, is essential.

Hepatic Impairment

Voriconazole is extensively metabolized in the liver. In patients with mild to moderate hepatic impairment (Child-Pugh Class A and B), the standard loading dose is recommended, but the maintenance dose should be halved. For example, the intravenous maintenance dose should be reduced from 4 mg/kg to 2 mg/kg every 12 hours, and the oral dose from 200 mg to 100 mg every 12 hours (or from 100 mg to 50 mg every 12 hours for patients < 40 kg). Voriconazole is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) unless the benefit outweighs the risk. Liver function tests must be monitored closely in all patients with hepatic impairment.

Renal Impairment

Renal excretion of unchanged voriconazole is negligible. However, the intravenous vehicle, SBECD, accumulates in patients with moderate to severe renal impairment (CrCl < 50 mL/min). This accumulation has been associated with renal tubular toxicity in preclinical models. Therefore, the intravenous formulation is contraindicated in such patients. Oral voriconazole may be used, as SBECD is not absorbed from the gastrointestinal tract. In patients with end-stage renal disease undergoing hemodialysis, the oral route is preferred, as voriconazole and SBECD are not significantly removed by dialysis.

Summary/Key Points

• Voriconazole is a broad-spectrum triazole antifungal agent and a first-line therapy for invasive aspergillosis and serious infections caused by Fusarium and Scedosporium apiospermum.
• Its mechanism involves inhibition of fungal lanosterol 14α-demethylase, disrupting ergosterol synthesis in the fungal cell membrane.
• Pharmacokinetics are nonlinear in adults, characterized by extensive hepatic metabolism via CYP2C19 (subject to genetic polymorphism), high oral bioavailability, and excellent tissue penetration, including into the CNS.
• Therapeutic drug monitoring (target trough: 1-5.5 mg/L) is recommended to optimize efficacy and minimize toxicity due to high interpatient variability.
• Common adverse effects include transient, reversible visual disturbances, rash, and elevated liver enzymes. Serious risks include hepatotoxicity, QT prolongation, severe skin reactions, and, with long-term use, photosensitivity and skeletal toxicity.
• It has an extensive and potentially hazardous drug interaction profile, primarily due to its inhibition of CYP2C19, CYP3A4, and CYP2C9. Concomitant use with potent enzyme inducers (e.g., rifampin) is contraindicated, and doses of narrow-therapeutic-index drugs like calcineurin inhibitors must be adjusted.
• Special considerations include dose reduction in hepatic impairment, avoidance of the IV formulation in moderate-severe renal impairment, higher weight-based dosing in children, and careful assessment of risks in pregnancy and the elderly.

Clinical Pearls

• Always check for drug interactions before initiating voriconazole, paying particular attention to immunosuppressants, anticonvulsants, and antiarrhythmics.
• Counsel patients about the high likelihood of transient visual disturbances and advise against hazardous activities (like night driving) during the initial phase of therapy.
• Implement rigorous sun protection measures (sunscreen, protective clothing) for any patient on voriconazole, especially those on long-term therapy, due to the risk of phototoxicity and skin cancer.
• In patients failing therapy or experiencing toxicity, a voriconazole trough level is often more informative than dose alone due to the drug’s nonlinear and variable pharmacokinetics.
• Consider CYP2C19 genotyping in patients who have difficulty achieving therapeutic levels or who experience toxicity at standard doses, particularly those of Asian ancestry.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.