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Antifungal Therapeutic Drug Monitoring: Confessions of a Pharmacist

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Adam Cochrane, PharmD, BCPS
Inova Fairfax Hospital
Falls Church, VA, USA

The ability to perform therapeutic drug monitoring (TDM) for antifungal therapy has been available for nearly a decade. Initially, there was not a wealth of data on how to adjust doses based on serum drug levels, or what levels should be targeted to maximize efficacy and minimize toxicity. To be fair, I wasn't quite sure of the role of antifungal TDM in our patient population either. Over time, we have gained significant experience with antifungal TDM, and it is now the standard for all of our patients on voriconazole and posaconazole.

The (U.S.) package insert does not recommend TDM for either of these agents; however, voriconazole's product labeling has the following language:

"If patient response is inadequate, the oral maintenance dose may be increased from 200mg every 12 hours to 300 mg every 12 hours. For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg)."[1]

When examining the product labeling, one can certainly conclude that there must be a more specific way to optimize voriconazole regimens. Titrating doses based on clinical response, or lack thereof, can place patients at risk for therapeutic failure. Conversely, abandoning therapy due to intolerable adverse effects may eliminate therapeutic options in patients that may achieve therapeutic levels with reduced dosing. Voriconazole and posaconazole are both metabolized through our favorite cytochrome P450 pathway, 3A4 (as well as 2C9 and 2C19), and therefore are subject to the same genetic polymorphisms that impact our calcineurin inhibitor levels. Regardless of whether patients are slow or rapid metabolizers, therapeutic drug monitoring will ensure that our patients are getting the correct dose of posaconazole or voriconazole.

A group in Austria examined voriconazole trough levels in a population of the critically ill and hematological malignancy patients. Their results showed that 56% of voriconazole levels were sub-therapeutic (as defined as < 1.5 mg/L) while 8% of levels were found to be supra-therapeutic (> 5.5 mg/L) and associated with hallucinations and encephalopathy. The authors reported that female patients, older patients and patients not on concomitant Proton Pump Inhibitor (PPI) therapy were more likely to have high voriconazole levels. Low body weight, male sex and concomitant PPI therapy were more likely to yield a low voriconazole level [2]. A group in Pittsburgh showed that patients with Cystic Fibrosis had lower voriconazole levels compared to other indications for lung transplant [3].

Posaconazole also has reason to pursue TDM. Patients are instructed to take their posaconazole dose with a high fat meal and acid; the FDA suggests a high fat meal is one in which 500 calories are derived from fat. Many post-transplant diets are limited in calories and fat, making dietary compliance for posaconazole difficult [4]. PPI use is almost ubiquitous in lung transplant, thus nullifying the acidic environment needed for optimal absorption. Posaconazole also has saturable absorption, where absorption of the suspension is better with multiple doses over the course of the day, rather than big doses given less often [5]. Fortunately, there is little variation between peak concentrations and trough concentrations so timing of blood draws (trough versus random) will not have a significant impact in the resultant blood concentration. The goal that we utilize for monitoring posaconazole levels is > 0.8 mg/L.

Based on the limited data, and clinical experience, I have become a believer in voriconazole and posaconazole TDM. Personally, I have been surprised by a few levels I have received in our patients that I would not have anticipated being "out of range." The dose adjustments that occurred enhanced therapy by maximizing benefit and preventing untoward adverse effects. We have also explained adverse events by having a supra-therapeutic level and patients that better tolerated the medication when the dose was decreased. TDM has had an impact on our patients; it might on yours as well. ■

Disclosure Statement: The author has no conflicts of interest to discuss.

1. Vfend® [package insert]. New York, NY: Pfizer Inc.; 2014.
2. Hoenigl M, Duettmann W, Raggam, R, et al. Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies. Antimicrobial Agents and Chemotherapy. 2013; 57(7): 3262-3267.
3. K. Han, B. Capitano, R. Bies, et al. Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients. Antimicrobial Agents and Chemotherapy. 2010; 54(10): 4424-4431.
4. Food and Drug Administration. (2002) Guidance for Industry Food-Effect Bioavailability and Fed Bioequivalence Studies. Rockville, MD.
5. Ezzet F, Wexler D, Courtney R, et al. Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations. Clinical Pharmacokinetics. 2005; 44(2): 211-220.

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