Voriconazole

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Pharmacokinetics

Oral or intravenous administration
- Solubilising agent added to intravenous preparation to increase aqueous solubility. This agent may accumulate in renal failure and cause nephrotoxicity. As a result IV administration not recommended in patients with GFR<50 ml/min
Bioavailability 96%
- Adsorption reduced by administration with high-fat meals so oral dose administration recommended either 1 hour before or 1 hour after meals
Extensive tissue distribution
- CSF concentrations approximately 50% of plasma
Eliminated by hepatic metabolism via cytochrome P450 enzymes
- Non linear pharmacokinetics – greater than proportional increase in plasma concentration with increase in dose
- Genetic polymorphism in voriaconazole metabolism results in orientals having a greater likelihood of being slow metabolizers

Recommended dose

Loading dose 6 mg/kg IV 12 hourly for two doses followed by 4 mg/kg 12 hourly with option to switch to 400mg PO 12 hourly after 7 days
Reduce dose for patients with Child-Pugh A and B cirrhosis (standard loading dose but halve maintenance dose). Drug has not been studied for patients with more severe cirrhosis. Standard doses recommended for patients with acute hepatic injury due to graft versus host disease, veno-occlusive disease or haemodynamic hepatic injury
Oral therapy recommended in individuals with renal impairment unless benefits of therapy outweigh risks of accumulation of solubulising agent

Spectrum of activity

Multiple Aspergillus spp. Including A. terreus, which is inherently resistant to amphotericin B
Candida albicans and non-albicans Candida including C. krusei which is inherently resistant to fluconazole

Clinical uses

More effective than amphotericin B in the treatment of invasive aspergillosis
Outcome of randomized controlled comparison with amphotericin B for the treatment of candidiasis awaited. Currently licensed in Europe for treatment of C. krusei infections

Drug interactions

Effect of voriconazole on pharmacokinetics of other drugs

due to inhibition of cytochrome P450 enzymes

Drug/class	Effect	Recommendation
Sirolimus	Significantly increased plasma concentration	Contraindicated
Tacrolimus		Reduce dose of tacrolimus to 1/3 on starting voriaconazole. Monitor levels closely. Increase dose, if necessary, on stopping voriaconazole
Cyclosporin		Reduce dose to ½ on starting voriaconazole. Dose may need to be increased on stopping. Monitor levels frequently
Phenytoin		Monitor levels and phenytoin adverse effects frequently
Omeprazole		If patient receiving >40 mg halve dose. Effect may be similar for other proton pump inhibitors that are cytochrome P450 substrates
Rifabutin		Contraindicated
Warfarin	Significantly increased INR	Monitor INR closely
Benzodiazepines	Potential for inhibition of metabolism	Frequent monitoring for adverse effects and depth of sedation. Benzodiazepine dose adjustment may be necessary
Dihydropyridine calcium blockers	Potential for inhibition of metabolism	Frequent monitoring of adverse events and toxicity. Calcium blocker dose adjustment may be necessary

Also affects pharmacokinetics of vinca alkaloids, sulphonylurea oral hypoglycaemics, terfenadine, astemizole, cisapride, pimozide, quinidine, dofetilide, ergot alkaloids, HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and statins

Effect of other drugs on voriconazole pharmacokinetics

induction of cytochrome P450

Drug	Effect on plasma concentration	Recommendation
Rifampacin/rifabutin	Significantly reduced	Contraindicated
Carbamazepine	Likely reduced
Long acting barbiturates	Likely reduced
Phenytoin	Significantly reduced	Increase maintenance dose to 5 mg/kg 12 hourly or to 400mg 12 hourly (200mg in patients <40 kg)

Also affected by HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors

Adverse effects

Generally well tolerate

Visual adverse effects

Approximately 30% of patients or volunteers
Most commonly transient alteration of light perception, photopsia, chromatopsia or photophobia
Usually begin ~30 mins after dose and last ~30 mins
Abnormalities in electroretinograms completely reverse within 2 weeks of discontinuation of therapy

Hepatic enzyme abnormalities

12-20% of patients
Usually transaminases but abnormalities of alkaline phosphatase and bilirubin have been reported. Enzyme abnormalities may normalize even with continued therapy but hepatic failure and death have been reported. Risk of hepatic enzyme abnormalities increases with increased plasma voriaconazole concentrations

Skin rashes

19% of patients
Usually mild
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported

Potential conflict of interest

The Dept of Anaesthesia & Intensive Care, Chinese University of Hong Kong has received educational grants and payment for research from Pfizer Corporation Hong Kong Ltd and educational grants from Merck Sharp & Dohme.

©Charles Gomersall, September, 2008 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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