Download Voriconazole therapeutic monitoring Specimen

Voriconazole therapeutic monitoring
Specimen details and interpretation of results
The voriconazole assay is carried out using liquid chromatography- tandem mass
spectrometry and is run twice weekly (usually Monday and Thursday). Samples for the
assay should be plain serum and taken immediately prior to a dose of voriconazole. The
range reported for the assay is for pre-dose/trough specimens and so results do not apply
for samples taken at any time other than immediately before the dose. The recommended
therapeutic range is 2 – 5.5mg/L (see discussion below for more details).
Results will be telephoned through to requesting laboratories as long as a contact
telephone number and name are provided. Please note, results are normally sent out by
post and so lack of contact details on the request form will delay the time for the result to
be received.
Validation of the assay
The assay is carried out by liquid chromatography-tandem mass spectrometry which
allows levels of voriconazole to be determined accurately even in the presence of other
drugs, including other antifungal agents. This method has been shown to be faster and
more selective than other methods of analysis1. The method used at the Mycology
Reference Centre in Leeds has been fully validated according to the guidelines for
“Bioanalytical Method Validation” published by the FDA2. We participate in the European
EQA scheme run by KKGT in Holland.
The need for therapeutic monitoring of voriconazole
Voriconazole is an antifungal drug used in the treatment of various fungal infections and is
the treatment of choice for invasive aspergillosis3. It is available in both oral and IV
formulations, with good oral bioavailability (>90%4). Voriconazole is metabolised by the
cytochrome P450 (CYP) enzymes, particularly CYP2C19 and to a lesser extent CYP 2C9
and CYP 3A4. These enzymes are also involved in the metabolism of a wide range of
other drugs and hence the potential for drug interactions is significant. The result of these
interactions may be either to increase or decrease the metabolism (and hence serum
level) of voriconazole or to increase or decrease the metabolism of the other drug.
Because of this, use of concomitant medications may adversely affect the level of
voriconazole obtained during treatment. Drugs which have the most dramatic effect on
voriconazole levels include rifampicin, carbamazepine, phenobarbital, efavirenz and
ritonavir, all of which are contraindicated for concomitant use with voriconazole5.
In addition to this, the CYP enzymes show genetic polymorphisms6. This is particularly
pronounced for the 2C19 enzyme, for which 26 allelic variants have been described7.
These allelic variants give rise to three main phenotypes: i) homozygous extensive
metabolisers; ii) heterozygous poor metabolisers; and iii) homozygous poor metabolisers.
In Caucasian European populations the poor metaboliser phenotype is mainly associated
with the 2C19*2 allele, whilst in Asian populations, the presence of 2C19*3 can further
contribute to this phenotype. The incidence of poor metabolisers is 2-6% of Caucasian
populations and 15-30% of Asian populations8. Levels of voriconazole in poor
metabolisers can be upto 4 times higher than those in extensive metabolisers9. Recently,
a rapid metaboliser 2C19 phenotype (2C19*17) has been described10 and in patients with
this phenotype, levels of voriconazole are significantly lower than either the extensive
metabolisers or poor metabolisers11. Genetic polymorphisms in CYP2C19 contribute 49%
of the variance in clearance of voriconazole12.
The therapeutic window for voriconazole is relatively narrow. If levels are too low, clinical
efficacy is correspondingly lower and at high levels toxicity is seen. The exact figures for
the lower and upper limit for serum levels are the matter of some discussion and
controversy and the ranges used will vary between laboratories. A study of 52 patients
with invasive fungal disease, demonstrated that lack of clinical response occurred more
frequently in patients with trough levels <1mg/L than those with trough levels > 1mg/L13.
This difference was statistically significant (p=0.02) and when the voriconazole dose was
increased in the patients with low levels, all of them responded. Another study showed
that favourable clinical outcome correlated with trough levels above 2.05mg/L in 28
patients, most of whom had invasive aspergillosis14. Most recently, a study of 25 patients
showed that those with serum trough levels above 2.2 mg/L had significantly better
outcomes and lower fungal infection related mortality than those with lower trough levels
(p=0.003)15.
Voriconazole is associated with a range of toxicities and side effects, including deranged
liver function, visual disturbances and neurotoxicity4. Some studies have demonstrated
that occurrence of toxicity is related to the peak serum trough level. Data shows that there
is a correlation between peak serum trough levels and visual disturbances. The incidence
of visual disturbances at trough levels <3 mg/L is 10-20%, rising to 25% at levels of 3-4
mg/L and upto 40% where levels are 9 mg/L1. Serum trough levels do not appear to
correlate with hepatotoxicity, with similar numbers of patients affected whether their trough
level was above or below 5.5mg/L13.
Currently there is no consensus as to how often, when or in whom voriconazole
therapeutic monitoring should be carried out. Whilst some authors suggest routine
monitoring for all patients as soon as steady state is reached15, others have suggested
monitoring levels only in patients when interacting concomitant medications are introduced
or stopped, when there is any suspicion of toxicity or treatment failure1. Properly
controlled trials are required to address this issue, but until then it may be pertinent to
measure voriconazole trough levels in patients who i) have progressive disease whilst on
therapy, ii) exhibit signs or symptoms of toxicity, iii) receive concomitant medications with
known drug interactions, or iv) where drug compliance is uncertain16.
If you wish to discuss the assay or aspects of voriconazole levels, please contact Dr Ruth
Ashbee in the Mycology Reference Centre on 0113 3926787.
References
1.
A Pasqualotto et al. Voriconazole therapeutic drug monitoring: focus on safety. Expert Opin Drug Saf 2010; 9:125-137
2.
Guidance for Industry. Bioanalytical Method Validation. 2001, Food and Drug Administration.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf
3.
TJ Walsh et al. Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clin
Infect Dis 2008; 46:327-360
4.
LB Johnson and CA Kauffman. Voriconazole: A new triazole antifungal agent. Clin Infect Dis 2003; 36: 630-637.
5.
Voriconazole SPC.
6.
M. Ingelman-Sundberg and SC Sim. Pharmacogenetic biomarkers as tools for improving drug therapy; emphasis on the
cytochrome P450 system. Biochem Biophys Res Commun 2010; 396:90-94
http://www.cypalleles.ki.se/cyp2c19.htm
7.
8.
P.A.H.M. Wijnen et al. Review article: the prevalence and clinical relevance of cytochrome P450 polymorphisms. Aliment
Pharmacol Ther 2007; 26 Suppl 2: 211-219
9.
FDA. Antiviral Drugs Advisory Committee: Briefing document for Voriconazole (Oral and intravenous formulations) 2001
10.
S Sim et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to
proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103-113
11.
G Wang et al. The CYP2C19 ultra-rapid metaboliser genotype influences the pharmacokinetics of voriconazole in healthy
male volunteers. Eur J Clin Pharmacol 2009; 65: 281-285
12.
J Weiss et al. CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin
Pharmacol 2009; 49: 196-204
13.
A. Pascual et al. Voriconazole therapeutic monitoring in patients with invasive mycoses improves efficacy and safety
outcomes. Clin Infect Dis 2008; 46: 201-211
14.
J Smith et al. Voriconazole therapeutic drug monitoring. Antimicro Agents Chemo 2006; 50:1570-1572
15.
S. Miyakis et al. Voriconazole concentrations and outcome of invasive fungal infections. Clin Microbiol Infect 2010; 16:927933
16.
ML Goodwin & RH Drew. Antifungal serum concentration monitoring: an update. J Antimicro Chemo 2008; 61:17-25