The role of therapeutic drug monitoring in antifungal therapy

September 2006

Therapeutic drug monitoring is commonly employed to aid clinicians in optimizing pharmacologic therapy for a variety of disease states and drug classes. Although the role of this monitoring is well defined for medications such as the anticonvulsant and immunosuppressant drug classes, the utility of therapeutic drug monitoring for antimicrobial therapies remains more controversial.

Therapeutic drug monitoring (TDM) is routine for antibacterial agents such as the aminoglycosides, however debate persists over the appropriate targets to optimize therapy. More recently, the availability of serum concentration monitoring for the protease inhibitors has expanded the practice to HIV management. The ability to monitor drug concentrations also exists for a large number of antifungal therapies. However, many clinicians are struggling to determine the appropriate place in therapy for these tests.

Before deciding whether or not to monitor concentrations of a specific drug, it is important to review the utility of this testing. In other words, will the data you obtain help drive clinical care or is the test being ordered simply because it is available? With a growing number of laboratories offering these services, sometimes the latter is true. Traditionally, drugs are considered candidates for TDM if they possess the following characteristics: narrow therapeutic range, significant interpatient pharmacokinetic variability, and clearly defined toxic and/or therapeutic targets. Monitoring antifungal agents is attractive for some additional reasons including being used for disease states where long treatment courses are required with few clinical markers of efficacy.

Although the practice of antifungal TDM remains in its infancy, data are beginning to emerge that support this practice on a more routine basis for selected agents.

Flucytosine

Arguably, the most clearly defined role for antifungal TDM is with flucytosine. This pyrimidine analog was initially developed for treatment of malignancy, and owes its primary and dose-limiting side effect, marrow suppression, to its similarities with antineoplastic agents. Serum drug concentrations exceeding 100 mcg/mL have been clearly linked with an increased incidence of myelosuppression.

Traditionally, clinicians have dosed flucytosine to this limit of toxicity. The most useful measurement is a peak obtained 2 hours following the oral dose. The target is a concentration of less than 100 mcg/mL to avoid toxicity, but a concentration associated with efficacy has not yet been established.

It has been proposed that lower target flucytosine concentrations may be appropriate. Flucytosine MICs for Cryptococcus and Candida spp are universally less than 10 mcg/mL and therefore, serum concentrations as high as 50-100 mcg/mL may not be required for efficacy. However, there is lack of a strong body of clinical evidence linking efficacy with serum drug concentrations.

Flucytosine concentration monitoring is advocated in the IDSA guidelines for management of cryptococcal disease. Although it is not prescribed routinely, the guidelines do suggest that flucytosine dosing should be monitored and adjusted based on serum drug concentrations where available. Specific clinical scenarios where flucytosine concentration monitoring may be beneficial include patients with renal dysfunction, patients with suspected unreliable drug absorption and patients experiencing toxicity even though dosing appears to be appropriate for the individual’s renal function.

Amphotericin B

Despite significant toxicities, amphotericin B and its lipid formulations remain an important part of antifungal therapy owing to the drug’s broad spectrum of activity. There is much debate about the ability of the parent drug to penetrate sites of infection and the variability among the lipid formulations in drug deposition and release from the lipid vehicle. This may seem like the ideal situation in which to employ drug concentration monitoring, but the routine practice has not been adopted.

Clinical data clearly demonstrate efficacy of this agent without the need to monitor drug concentrations. In fact, despite the inability to detect drugs in certain locations, such as the cerebral spinal fluid, the drug is clearly active in treating disease at these sites. Nor are there data that demonstrate an association with amphotericin B concentration and toxicity. Therefore, monitoring amphotericin B concentrations in serum or other body sites remains largely a research endeavor or reserved for extremely unique clinical situations.

Azole antifungals agents

Each member of the azole antifungal class has unique pharmacokinetic properties. The role of TDM with the various members of the drug class also differs between agents. Fluconazole, with its reliable pharmacokinetic profile in the majority of patients and benign side effect profile, is not a candidate for routine concentration monitoring. Some of the newer agents of this class, however, are subject to significant inter-patient variability in absorption, drug metabolism and drug-drug interactions. Voriconazole (Vfend, Pfizer) and itraconazole are more routinely monitored, although the ideal therapeutic and toxicologic targets remain somewhat controversial. It is unclear whether the newest member of this class, posaconazole, will be subject to routine concentration monitoring. As the drug will initially be limited to an oral dosage form, many clinicians may take comfort in the availability of a method to reliably determine drug concentrations.

Itraconazole

Itraconazole was the first oral antifungal agent available to treat mold infections. It is limited, however, by issues related to bioavailability. The intravenous preparation is difficult to use in patients with decreased renal function so clinicians are often forced to rely on the oral preparations of this drug. The oral capsules are poorly bioavailable and require acid for absorption. This makes the formulation difficult to administer in patients requiring acid suppression therapy and in those with altered gastrointestinal absorption, which are two common occurrences in patients at risk for invasive fungal infections. Some of these concerns were addressed by the release of an oral itraconazole solution, which has largely replaced the capsules in clinical use. The new formulation results in a 30% increase in drug exposure, but significant variability between patients remains a problem.

The inability to reliably predict serum drug exposure from either oral product has led to the practice of routine drug concentration monitoring at many institutions. The purpose of this testing is to confirm drug absorption. Further ideal targets for therapeutic efficacy have not yet been clearly defined, but some early attempts at identifying these parameters are discussed below.

When monitoring itraconazole concentrations, it is important to know the testing method used. Bioassay does not differentiate between itraconazole and its active metabolite, hydroxyitraconazole. The latter is present at concentrations two to three fold the parent drug and is the cause of higher reported itraconazole concentrations when this method is used. High performance liquid chromatography (HPLC), used by most commercial laboratories, differentiates between the two compounds and therefore, reports concentrations of parent drug in addition to the hydroxyitraconazole concentration. Currently, most interpretive criteria are based on concentrations of the parent drug, itraconazole, but at some centers it is common practice to use the sum of parent drug and metabolite concentrations when analyzing TDM results.

Sample timing is another factor in itraconazole monitoring that is not standardized. Some practitioners continue to monitor peak drug concentrations, obtained two to six hours after an oral dose, as this was the practice in many early clinical trials. Many centers have converted to trough concentration monitoring. The leading principle behind this approach is to ensure that adequate drug concentrations are maintained for the entire dosing period, thus potentially optimizing the pharmacodynamic properties of the azole class.

Many clinicians would argue that a single random or trough concentration of more than 0.5 mcg/mL sufficiently documents drug absorption. It is likely that different targets are needed depending on the indication for using the drug. Some have suggested that concentrations of drug should exceed 1.0 mcg/mL or 1.5 mcg/mL to adequately treat documented Aspergillus or central nervous system infections. Toxicity may also be related to serum concentration and there are reports that suggest serum itraconazole concentrations exceeding 5 mcg/mL may be associated with increased risk of side effects such as adrenal insufficiency.

Voriconazole

Since its introduction in 2002, voriconazole has become the drug of choice for treatment of aspergillosis. Administration of this azole is complicated by high inter-patient variability in metabolism resulting in different drug concentrations and effect from drug-drug interactions. This is further complicated by non-linear pharmacokinetics that make empiric dose escalation unpredictable.

TDM of voriconazole has an increasingly important role in administration of this therapy. Side effects including visual disturbances and hepatic function abnormalities have been linked to elevated serum drug concentrations greater than 6 mcg/mL. More recently, investigators have also correlated clinical outcome with a serum drug concentration threshold of 2.05 mcg/mL.

Based on these limited clinical data, the accepted target concentrations are a peak of less than 6 mcg/mL and a trough of more than 2 mcg/mL to limit toxicity and ensure efficacy, respectively. Although not substantiated in clinical trials, slightly lower target troughs may be appropriate in patients receiving voriconazole as prophylaxis. Patients who are experiencing adverse events, who are on multiple medications with activity at the cytochrome P450 enzyme system, have questionable GI absorption and those not responding to therapy are all ideal candidates in which to consider voriconazole TDM.

Echinocandins

TDM has not yet found an established role in echinocandin therapy. Early in vitro reports suggest that efficacy may be associated with drug concentrations. There may also be a concentration threshold at which no additional and or even a decrease in antifungal activity is seen. At this time, there are no sufficient data to justify routine monitoring and certainly, no target concentrations have been proposed for any member of this class.

Summary

Antifungal TDM is becoming a more established practice in the management of fungal disease. Several questions remain about the optimal use of this monitoring including the most appropriate concentrations for each agent and the precise patient populations this will benefit the most. Although there are clearly scenarios where routine monitoring will one day become standardized, the availability of testing for the majority of agents will, in the mean time, aid clinicians in the management of selected, difficult to manage cases. Wise use of these tests will allow clinicians to more judiciously use the limited number of available antifungal therapies.

For more information:

• Smith J, Safdar N, Knasinski V. Voriconazole therapeutic drug monitoring. Antimicrob Agent Chemother. 2006;50:1570-2.
• Summers KK, Hardin TC, Gore SJ, Graybill JR. Therapeutic drug monitoring of systemic antifungal therapy. J Antimicrob Agent Chemother. 1997;40:753-64.