Voriconazole

Atul K Patel MD, FIDSA
Infectious Diseases Clinic, Vedanta Institute of Medical Sciences, Ahmedabad, India

Voriconazole (VCZ) is a second-generation, broad-spectrum triazole antifungal agent. Its spectrum of activity includes Aspergillus, Candida, Fusarium and Scedosporium species. It has no activity against Mucorales and reports suggest that VCZ exposure could be a potential risk factor for infection with Mucorales. VCZ is also not effective for urinary candidiasis as it does not achieve sufficient urinary concentration.

Approved indications of VCZ include treatment of invasive aspergillosis, candidemia, disseminated candidiasis (skin, abdomen, kidney, bladder wall, wounds), esophageal candidiasis, and other serious infections caused by Scedosporium apiospermum and Fusarium spp. in patients intolerant or refractory to other therapy.

Pharmacokinetic parameters

VCZ has high (96%) oral bioavailability.¹ When administered with food, its absorption is reduced and this results in a 22% reduction in exposure at steady state level. It exhibits saturable metabolism and demonstrates nonlinear kinetics, irrespective of the route of administration, with increasing doses resulting in supra-proportional increases in drug exposure. A dosage increase from 3 to 4 mg/kg intravenously every 12 hours results in a 2.3-fold increase in the area under the curve (AUC).^2,3

In pediatric patients, VCZ oral bioavailability is 44.6-66% and its elimination appears to be faster compared with adults, requiring higher weight-based doses. Higher VCZ concentrations have been reported in patients aged ≥65 years with standard dosage.

VCZ is extensively metabolized by CYP2C19 and, to a lesser degree, by CYP2C9 and CYP3A4. CYP2C19 exhibits genetic polymorphisms among various ethnic populations. Approximately 15-20% of Asians are poor CYP2C19 metabolizers, which may result in four times the exposure to VCZ compared with extensive metabolizers.^2,4 VCZ pharmacokinetics has high interpatient variability due to CYP2C19 genetic polymorphism and drug-drug interactions.

Dosage recommendations

Adult patients:

Two loading doses of VCZ 6 mg/kg given 12 hours apart, followed by 4 mg/kg every 12 hours, is the recommended dosage.

Pediatric patients:

Aged 2 to <12 years and 12-14 years with a body weight <50 kg: two loading doses of 9 mg/kg given 12 hours apart, followed by 8mg/kg every 12 hours.

Obese patients:

Standard VCZ dosing using actual body weight in obese and overweight patients resulted in higher associated serum concentrations. Dosing using adjusted body weight may be necessary in this population in order to achieve optimal concentrations while preventing the potential for increased toxicity.⁵

Patients with renal insufficiency:

Oral VCZ can be used as standard recommendation. Intravenous VCZ is not recommended due to potential nephrotoxicity of sulfobutylether-beta-cyclodextrin (SBECD), which is a solubilizing excipient used for intravenous VCZ formulation. However, a recent study showed that SBECD, does not increase risk of renal damage in patients with compromised renal functions.⁶

Drug-drug interactions

VCZ is metabolized extensively by the liver microsomal enzyme system and at the same time, it is also a potent inhibitor of CYP3A4, CYP2C19, CYP2C9 and CYP2B6 enzymes.

Co-administration of VCZ with enzyme inducers (eg, efavirenz, rifampicin, phenytoin, St John’s wort) reduces VCZ exposure while VCZ increases the exposure of substrates for cytochrome enzymes such as midazolam, tacrolimus, phenytoin, sirolimus, omeprazole and rifabutin by inhibiting substrate metabolism. Similarly, concomitant use of enzyme inhibitors, such as fluconazole and erythromycin, increases the VCZ AUC by 150% and 67%, respectively. Concomitant use of enzyme inducers, inhibitors or substrates for hepatic microsomal enzymes requires close monitoring with therapeutic drug monitoring.

Therapeutic drug monitoring

Current literature suggests that trough concentrations at steady-state should be used to evaluate plasma VCZ concentrations.³ Initial trough concentrations should be obtained 5 days after the start of therapy to ensure steady-state concentrations are measured. Target VCZ trough therapeutic range is 1-5.5 μg/mL.

Adverse drug reactions

Common adverse drug reactions are transient visual disturbances, typically occur within 30 minutes after dosing. Other less common adverse drug reactions include increase transaminases, rash, photosensitivity, hallucinations, jaundice and encephalopathy. Higher VCZ level is associated with higher incidence of visual disturbances, hepatotoxicity and neurologic toxicity (eg, confusion, hallucinations, extrapyramidal effects).^3,7

As VCZ is a trifluorinated antifungal, long-term use of VCZ is a risk factor for the development of fluoride excess and subsequent painful periostitis and exostoses in post-transplant patients.⁸ A trough concentration of >3.0 μg/mL is associated with increased hepatotoxicity, particularly for the Asian population, and >4.0 μg/mL is associated with increased neurotoxicity.⁹

Routine therapeutic drug monitoring of VCZ may reduce drug discontinuation due to adverse events and improve the treatment response in patients with invasive fungal infections.¹⁰

VCZ: Clinical pearls

• VCZ has high oral bioavailability in adults.
• Pediatric patients require higher weight-based dosage.
• VCZ therapeutic drug monitoring is recommended due to CYP2C19 genetic polymorphism and drug-drug interactions.
• Trough level should be obtained 5 days after initiation of therapy.
• Clinicians should be careful for significant drug interactions associated with VCZ usage.
• Visual disturbances are transient and typically seen within 30 minutes after starting therapy.

References:

1. Scott LR, Simpson D. Clin Infect Dis 2003;36:630-637.
2. Smith J, et al. Antimicrob Agents Chemother 2006;50:1570-1572.
3. Pascual A, et al. Clin Infect Dis 2008;46:201-211.
4. Goodwin ML, Drew RH. J Antimicrob Chemother 2008;61:17-25.
5. Davies-Vorbrodt S, et al. Pharmacotherapy. 2013;33:22-30.
6. Lilly CM, et al. BMC Infect Dis 2013;13:14.
7. Tan K, et al. J Clin Pharmacol 2006;46:235-243.
8. Wermers RA, et al. Clin Infect Dis 2011;52:604-611.
9. Jin H, et al. J Antimicrob Chemother 2016 Mar 10. pii: dkw045. [Epub ahead of print]
10. Park WB, et al. Clin Infect Dis 2012;55:1080-1087.