How to Interpret a Voriconazole Drug Level

Voriconazole (VFEND®) is a second-generation azole antifungal that inhibits 14-α-demethylase, causing reduced production of ergosterol, a critical component of the fungal the cell wall.  Voriconazole has a broader spectrum of activity than fluconazole and is often used for the treatment of invasive aspergillosis.  Voriconazole serum concentrations are difficult to predict because of its saturable metabolism, non-linear pharmacokinetics, and poor correlation to weight-based dosing.¹

Pharmacokinetic Profile

Voriconazole undergoes saturable CYP 2C19 metabolism, meaning that an increase in dose may result in a much higher increase in serum concentration.  Of note, the 2C19 metabolic pathway is the same pathway used by clopidogrel (Plavix®), which has been shown to have variable activity in various patient populations.  As an example, 15-20% of Asians are poor 2C19 metabolizers, resulting in a 400% higher AUC of voriconazole than those with normal 2C19 activity.²

Additionally, voriconazole is well known for its drug interaction profile.  In fact, all of the azole antifungals (eg, fluconazole, itraconazole, posaconazole) are all significant CYP 2C9 and 3A4 inhibitors because their therapeutic mechanism of action (14-α-demethylase inhibition) involves the inhibition of a fungal CYP enzyme.

Necessity of Therapeutic Drug Monitoring

Because voriconazole has a high degree of interpatient variability, it is very difficult to select a dose that accurately targets a specific drug level.  Even when dosing based on body weight and correcting for obesity, weight-based dosing is poorly correlated to serum drug concentrations.¹  For this reason, many experts believe that voriconazole therapeutic drug monitoring may improve efficacy and safety.

Timing of a Voriconazole Level

Although the AUC:MIC ratio is the pharmacodynamic parameter most associated with treatment success, voriconazole trough levels are used in clinical practice.  Voriconazole levels should be drawn 12 hours after the most recent dose once the patient is at steady state, which occurs after 5-7 days of consistent voriconazole therapy.

Optimal Trough Level for Efficacy

In vitro, the voriconazole MIC for most fungi is 0.5-1 mg/L.  Because 50% of voriconazole is protein bound (and thus pharmacologically inactive),² it makes intuitive sense that a goal serum trough level should be at least 1-2 mg/L.  In fact, this goal level is supported by the literature.  Although the trials suffer from a number of study design limitations, two of the largest voriconazole drug level trials support a goal trough of at least 1-2.2 mg/L.^3,4  In both trials, patients with levels below goal had a higher incidence of unfavorable clinical outcomes compared to patients above goal.

Optimal Trough Level for Safety

The most common toxicities of voriconazole include transaminitis (increased LFT’s) and visual disturbances.  Although more difficult to define, it appears that a trough level above 5-6 mg/L is associated with a higher incidence of hepatic and neurological toxicities.^2,3  It is important to note that voriconazole-induced transaminitis rarely leads to permanent hepatotoxicity, and that monitoring LFT’s (and other symptoms of toxicity) during therapy will likely provide more patient-specific and timely information to assess for toxicity.

Overall Lack of Data

While there are some trials showing a correlation between voriconazole trough level and efficacy, these are generally poorly designed trials enrolling a small number of a heterogeneous patient population.  Furthermore, due to the small patient population in these trials, it is difficult to provide enough numerical resolution to precisely define an optimal voriconazole trough.  In other words, it is unlikely that current data can differentiate in clinical effect between a trough level of 1, 2, or 3 mg/L.  Of note, although it makes intuitive sense that trough levels should correlate with patient outcome, there are a number of trials, both published and unpublished FDA data, that have failed to show a correlation between voriconazole levels and therapeutic outcomes.²

Summary

• Voriconazole has a high degree of interpatient variability, and some data are suggestive that therapeutic drug monitoring may improve voriconazole efficacy and toxicity
• Voriconazole levels should be drawn 12 hours after the last dose after the patient has received at least 5-7 days of consistent voriconazole therapy.
• Based on relatively weak data, the optimal voriconazole trough level for both efficacy and safety appears to be between 2 and 6 mg/L.

References

1. Pai MP, Lodise TP. Steady-state plasma pharmacokinetics of oral voriconazole in obese adults. Antimicrob Agents Chemother. 2011;55(6):2601-5.  PMID 21422207
2. Howard A, Hoffman J, Sheth A. Clinical application of voriconazole concentrations in the treatment of invasive aspergillosis. Ann Pharmacother. 2008;42(12):1859-64.  PMID 19017830
3. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201-11. PMID 18171251
4. Miyakis S, van Hal SJ, Ray J, et al. Voriconazole concentrations and outcome of invasive fungal infections. Clin Microbiol Infect. 2010;16(7):927-33. PMID 19845698