What information is available to guide the practice of therapeutic drug monitoring for itraconazole, posaconazole, voriconazole, and isavuconazonium sulfate?

Introduction
Azole antifungal agents are a mainstay of treatment and prophylaxis for invasive fungal infections, but variable pharmacokinetic (PK) properties and numerous drug-drug interactions complicate their use.1,2 Therapeutic drug monitoring (TDM) is the practice of measuring specific drug levels in a patient’s blood at designated time intervals to ensure the drug concentration remains within a target therapeutic or prophylactic range.2 Variability in drug levels may be impacted by the route of administration, drug formulation, severity and location of infection, timing of levels drawn, and patient-specific factors. Therapeutic drug monitoring can be used to optimize efficacy, increase the likelihood of therapeutic success, and reduce risk of breakthrough infections while minimizing risk of toxicity and adverse reactions. Several professional organizations and guidelines support the practice of TDM as standard of care to guide azole antifungal dosing due to their variable PK properties.2-13 This can be especially useful in individuals with altered PK. These guidelines are based on established relationships between drug exposure and clinical response (primarily supported by retrospective studies); a lack of prospective studies over the years has limited the standardization of formal monitoring.

To address the lack of formal monitoring standards, the Society of Infectious Disease Pharmacists (SIDP) provided best practice guidance in 2023 on TDM of azole antifungal agents, with recommendations based on best available evidence and other professional organization recommendations.2 The Table below summarizes the TDM best practice recommendations from SIDP, along with insight from other professional organizations, including Infectious Diseases Society of America, American Society of Transplantation, National Comprehensive Cancer Network, and National Institutes of Health, on the recommendations for TDM in invasive fungal infection prophylaxis and treatment.2-13 In general, guidelines and available evidence support routine TDM in adults receiving voriconazole, itraconazole, and posaconazole. In certain circumstances (described below), TDM may be useful in adults receiving isavuconazonium sulfate; however, TDM is not routinely recommended for this drug. The recommendations within the table are applicable to all relevant fungal infections, including aspergillosis, blastomycosis, histoplasmosis, candidiasis, and mucormycosis. Pharmacokinetic considerations, a summary of best practices from current guidelines, and select supportive literature published outside of guideline systematic reviews for agents of interest are summarized in the paragraphs below.

Voriconazole
Voriconazole exhibits nonlinear, Michaelis-Menten PK properties, leading to intra- and inter-patient PK variability.2 Available literature and guidelines recommend routine TDM of voriconazole for prophylaxis and treatment indications.2,3,5,14 It is available in both intravenous (IV) and oral formulations (tablets, suspension).15 It is a highly bioavailable agent, so dosing is equivalent (1:1) between the IV and oral formulations. However, due to variations in absorption and saturable metabolism based on the nonlinear PK properties, TDM is recommended after switching from IV to oral formulations, or vice versa.2,3,5,16 Voriconazole tablets and oral suspension should be taken without food (either 1 hour before or 1 hour after meals), based on the decrease in bioavailability with food or a full meal.2,15 Voriconazole is metabolized primarily via cytochrome P450 (CYP) enzymes, CYP2C19 (major), CYP2C9 (minor), and CYP3A4 (major). Voriconazole clearance is affected by CYP2C19 polymorphisms, so if available, CYP2C19 genotyping should be considered for patients receiving voriconazole. 17-19 Although not currently the standard of care, some practice guidelines recommend making phenotype-specific dosing adjustments in individuals with certain CYP2C19 phenotypes.

Steady state voriconazole concentrations are typically reached after 5 days, but when a loading dose is given, the target concentration can generally be obtained after 2 days.2,4,5,11 In pharmacodynamic modeling and animal studies, the efficacy measurement is free drug 24-hour area under the curve (AUC)/minimum inhibitory concentration (MIC).2,11 In most patients, trough concentrations (Cmin) of voriconazole are a reasonable surrogate marker for voriconazole exposure (AUC).20,21 Guideline recommendations for TDM are typically based on Cmin.2-5 Across multiple guidelines and for multiple fungal infections, the prophylaxis goal for voriconazole trough concentrations is ≥ 0.5 mg/L and the treatment goal is ≥ 1 to 2 mg/L, although higher targets (up to 4 mg/L) may be necessary in individuals with poor prognosis, immunocompromised patients, or when pathogen MICs are elevated. Generally, for invasive aspergillosis, a trough of ≥ 2 mg/L should be targeted.2-4,22 Many studies in humans have evaluated the association between trough concentration and outcomes for prophylaxis, empiric therapy, or treatment of documented invasive fungal infections, although the target trough concentration for the treatment of uncommon mold infections remains unknown. Toxicity, specifically central nervous system toxicity, has been seen at trough concentrations > 5 to 5.5 mg/L, and some studies have found an increased risk of toxicity with trough concentration thresholds of ≥ 4 mg/L.2,4,23-25 Populations that may require more frequent TDM include patients with cystic fibrosis (due to frequent subtherapeutic concentrations), patients with burn injuries (due to subtherapeutic concentrations with initial dosing), or patients who are obese (due to disproportionate clearance based on body weight).2,25-27

Itraconazole
Itraconazole exhibits nonlinear PK, accumulates slowly, and has variable bioavailability depending on the formulation.2,28-31 Due to the variability between formulations, dosing between formulations is not equivalent. Itraconazole is available as an oral solution, an oral capsule (Sporanox), and a “super bioavailability” (SUBA) itraconazole oral capsule (Tolsura). The need for TDM generally depends on the formulation of itraconazole that is used.2-4,6,10 For example, itraconazole capsules (Sporanox) exhibit poor bioavailability via the oral route, and absorption is dependent on both food and low gastric pH.2,28 It is recommended that TDM be routinely performed in all patients receiving prophylaxis or treatment doses of Sporanox capsules and generics.2-4 The SUBA-itraconazole capsule has enhanced bioavailability compared to the original capsule, and the need for TDM with this formulation is less well defined. Clinicians may consider routine TDM for treatment indications; this may be particularly beneficial in patients who are immunosuppressed or patients with hematologic malignancies, as they are at higher risk of subtherapeutic concentrations.2,32 Both oral capsule formulations (Sporanox and Tolsura) should be administered with a full meal to ensure maximum absorption.28,29,31 In contrast, the oral suspension is better absorbed on an empty stomach and should be taken without food (either 1 hour before or 1 hour after meals).30 Routine TDM for prophylactic indications is recommended for patients using itraconazole solution.2-5 Itraconazole is metabolized primarily by CYP3A4 enzymes to its active metabolite hydroxyl-itraconazole. Some concentration measurements will measure only the itraconazole concentration, while others will report both itraconazole and hydroxy-itraconazole components, although data is lacking for this practice. The trough concentration recommendations discussed in this review are based on itraconazole alone, measured by chromatographic assays.

Pharmacokinetic studies have demonstrated a relationship between itraconazole dose and/or concentrations and efficacy in prophylaxis and treatment of invasive fungal infections.2-5 Due to its long half-life (34 to 42 hours), concentrations of itraconazole will have minimal variation during a 24-hour dosing interval, so drug concentrations can be measured at any time during the dosing interval, although collection of a trough level is the most common practice. Based on clinical studies, a significantly increased rate of breakthrough infections occurs when itraconazole concentrations are < 0.5 mg/L, compared to higher concentrations.2,33 Based on these studies, most experts recommend a target trough concentration for prophylaxis of ≥ 0.5 mg/L. There are limited data available assessing itraconazole concentrations and treatment efficacy, but animal model studies have established a concentration-effect relationship, specifically for treatment of invasive aspergillosis.2-4 Based on prophylaxis data, chromatographic assay studies, and animal studies, most experts recommend a target trough concentration for treatment of ≥ 1 mg/L for all invasive fungal infections.2-5,11 Trough measurements should generally be measured approximately 5 to 7 days after initial dosing when a loading dose is used, and up to 14 days after initial dosing when no loading dose is used, due to the prolonged half-life and slow drug accumulation. Limited data have found that a trough concentration >3 mg/L (or total itraconazole/hydroxyl-itraconazole concentration of 17.1 mg/L via bioassay) may be associated with increased toxicity, including cardiovascular adverse events; increased mortality was observed with concentrations >5 mg/L. Individuals on continuous renal replacement therapy are at risk of increased clearance of itraconazole and may require increased doses or dosing frequency to achieve target concentrations.34

Posaconazole
Posaconazole is available IV and in various oral formulations, including immediate-release suspension, delayed-release (DR) tablets, and DR powder for oral suspension.2,35-37 Due to differences in bioavailability and absorption, dosing is not equivalent between formulations. The immediate-release suspension requires a high-fat meal with administration for maximum bioavailability, along with a low pH environment. Estimates of bioavailability for the immediate-release suspension range from 8% to 47%. Posaconazole immediate-release oral suspension is not substitutable with posaconazole DR tablets. Posaconazole DR tablets can be administered with or without food and are less impacted by gastric pH due to their pH-sensitive polymer coating. Bioavailability is estimated at approximately 54%. This dosage form is often preferred over oral suspension in individuals unable to eat a full meal, due to higher drug exposure under both fed and fasted conditions, as well as in those with other risk factors for unpredictable absorption. The IV formulation is dosed the same as the DR tablets and switching between these formulations is acceptable, as bioavailability is similar. A DR powder for oral suspension was developed for ease of weight-based dosing in pediatric patients, but will not be discussed further, as it has not been studied for use in adults.

The need for TDM with posaconazole is based largely on the unpredictable and variable absorption and bioavailability of the immediate release oral suspension.2-5,7,9,13 Guidelines and available literature recommend that routine TDM should be conducted in all patients taking immediate release posaconazole suspension for prophylactic and treatment indications due to the increased potential for subtherapeutic levels. Because the DR tablets, DR powder for oral suspension, and IV formulations have more predictable absorption and bioavailability, TDM is only recommended for prophylactic indications with these formulations; this may decrease the risk of breakthrough fungal infections, although no clear relationship has been identified between posaconazole concentration and the risk of breakthrough infections. Routine TDM for these formulations after initial steady state concentrations are achieved may be unnecessary but can be considered in patients still at risk of subtherapeutic concentrations, including those with poor appetite, relevant concomitant drug interactions, or severe diarrhea. A target trough concentration of ≥ 0.5 to 0.7 mg/L for prophylaxis indications and a target trough concentration of ≥ 1 to 1.5 mg/L for treatment indications are recommended for TDM. Trough concentrations should be measured at steady state, 5 days after initiation when a loading dose is given and 7 days after initiation when no loading dose is given. Higher target concentrations for treatment indications may be warranted based on the pathogen MIC and concerns for resistance. These recommendations are based on TDM studies with the original immediate-release suspension formulation.2,38-40 Increased toxicity, including hepatotoxicity, has been observed at trough levels of > 3 to 3.75 mg/L. Populations that may require more frequent TDM include patients who are obese, who may require increased dosing, and patients with mucositis or altered gastrointestinal function or anatomy (eg, gastric bypass) due to decreased posaconazole absorption.2,41,42

Isavuconazonium sulfate
Isavuconazonium sulfate is the pro-drug of the active isavuconazole and has linear PK properties with low interpatient variability.2,43 Its high bioavailability (approximately 98%) makes dosing equivalent between formulations. It is available as an oral capsule and an IV formulation, both of which can be administered via enteral feeding tube if needed, with comparable plasma concentrations. Clinical data are typically in reference to isavuconazole, as conversion to isavuconazole from the pro-drug is rapid.2,4 Metabolism of isavuconazonium sulfate is primarily through CYP3A4 enzymes.2,43 Routine TDM of isavuconazonium sulfate is not recommended for most patients because of its linear PK properties and the lack of literature establishing an apparent exposure-efficacy or exposure-safety relationship.2,4,12 However, some guidelines state that TDM can be useful in specific situations, particularly when there is a concern for toxicity or lack of response. Optimal drug concentrations for efficacy have not been established, but most patients achieve levels > 1 mg/L with recommended dosing regimens, and this target is recommended by some experts. Similarly, an upper limit associated with toxicity has not been established, but some data exist suggesting that concentrations of 4.6 to 5.1 mg/L may result in increased gastrointestinal toxicity and adverse reactions. Due to isavuconazonium sulfate’s long half-life (130 hours), concentrations of isavuconazonium sulfate will have minimal variation during a 24-hour dosing interval, so drug concentrations can be measured at any time during the dosing interval, although collection of a trough level is most common practice. Trough measurements should generally be measured approximately 5 to 7 days after initial dosing when a loading dose is used, and up to 14 days after initial dosing when no loading dose is used. Populations that may benefit from isavuconazonium sulfate TDM include those receiving isavuconazonium sulfate via alternative methods of administration (eg, via enteral feeding tubes), those with drug interactions of concern, critically ill patients, patients who are extremes of weight (eg, morbidly obese or cachectic), those with refractory infections, or those who have additional factors thought to alter PK properties.2,44-46

Table. Summary of Guideline Recommendations for Azole Antifungal TDM.2-13
Azole agentIndications for TDMTiming of sampleaTarget trough concentrationsCmin Toxicity ceilingPD targetsbRecommendations for dose adjustment
TDM routinely recommended
VoriconazoleProphylaxis or treatment (all patients)Trough

Steady state: about 2 days with LD and 5 days without LD

Once steady state is reached, repeat sampling is warranted every 3 to 5 days if there is uncertainty about concentrations, patient is clinically unstable, or after dose adjustments		Prophylaxis: ≥ 0.5 mg/L

Treatment: ≥ 1 to 2 mg/L

Higher targets (up to 4 mg/L) may be needed for individuals with poor prognosis, immunocompromised patients, or elevated pathogen MICs to reduce incidence of breakthrough infection		4 to 5.5 mg/LAspergillosis: AUC0-24/MIC >25

Cmin/MIC 2 to 5 mg/L		50 to 100 mg dosing increments due to tablet size

If concentrations are subtherapeutic, consider increasing dosing frequency (more than every 12 hours), adding CYP2C19 inhibitors (eg, omeprazole), or discontinuing CYP450 inducers (eg, rifampin, phenytoin)
ItraconazoleSporanox capsules and generics: prophylaxis or treatment (all patients recommended)

Sporanox solution and generics: prophylaxis indications recommended

SUBA-itraconazole capsules (Tolsura): may consider routine TDM for treatment indications		Any point in dosing interval, although troughs are most common in practice

Steady state: about 5 to 7 days with LD and 10 to 14 days without LD		Prophylaxis: ≥ 0.5 mg/L

Treatment: ≥ 1 mg/L		17.1 mg/L via bioassay, or 3 to 4 mg/L via HPLC or LC/MSNot establishedSporanox capsules: 100 mg dosing increment

Solution: 10 mg/mL; 50 to 100 mg dosing increments

Tolsura capsules: 65 mg dosing increments
PosaconazoleImmediate-release suspension: prophylaxis or treatment (all patients)

DR tablet, DR suspension, or IV: prophylaxis indications recommended; may consider routine TDM for treatment		Trough

Steady state: 5 days with LD and 7 days without LD		Prophylaxis: ≥ 0.5 to 0.7 mg/L

Treatment: ≥ 1 to 1.5 mg/L (higher targets may be warranted based on the pathogen MIC and concerns for resistance)		>3 to 3.75 mg/LAUC0-24/MIC >25 to 50DR tablets: 100 mg dosing increments; doses up to 300 mg twice daily have been used
TDM recommended only in specific situations
Isavuconazonium sulfateRecommended for:

Alternative methods of administration, such as opened capsules via enteral feeding tubes

When DDIs are of concern

Critical illness

Extremes of weight

Refractory or resistant infections

Pediatric patients

Additional factors thought to alter PK		Any point in dosing interval (troughs are most common)

Steady state: about 5 to 7 days with LD and 10 to 14 days without LD		No target established for prophylaxis and not routinely used

No target established for treatment; some expert opinion considers ≥ 1 to 3 mg/L		> 4.6 to 5.1 mg/LAUC0-24/MIC >25 to 50IV, oral: 186 mgc increments; doses up to 372 mg twice daily or 744 mg daily have been reported
Abbreviations: AUC0-24=24-hour area under the curve; Cmin=minimum (trough) concentration; CYP=cytochrome P-450; DDI=drug-drug interaction; DR=delayed release; HPLC=high-performance liquid chromatography; IV=intravenous; LC/MS=liquid chromatography/mass spectrometry; LD=loading dose; MIC=minimum inhibitory concentration; PD=pharmacodynamic; PK=pharmacokinetic; SUBA=super bioavailability; TDM=therapeutic drug monitoring.
aIn relation to drug initiation or change in steady-state concentrations
bPreclinical PK/PD efficacy target for all azoles is AUC0-24/MIC
c186 mg isavuconazonium sulfate = 100 mg isavuconazole

Conclusion
Therapeutic drug monitoring of azole agents in invasive fungal infections can be used to optimize efficacy, increase likelihood of therapeutic success, and reduce risk of breakthrough infections while minimizing risk of toxicity and adverse reactions. Variability of drug levels may be impacted by the route of administration, drug formulations, severity and location of infection, timing of levels drawn, and patient considerations. Guidelines and available evidence support routine TDM in adults receiving any formulation of voriconazole for all prophylactic and treatment indications, itraconazole oral capsules (Sporanox) for all prophylactic and treatment indications, itraconazole oral solution for prophylactic indications, and posaconazole immediate-release suspension for all prophylactic and treatment indications. Routine TDM for treatment indications may be considered with SUBA-itraconazole (Tolsura) and posaconazole DR and IV formulations but may not be necessary in all patients. In certain circumstances and patient populations, TDM may be useful in adults receiving isavuconazonium sulfate, but TDM is not routinely recommended for this drug.

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Prepared by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois Chicago Retzky College of Pharmacy

November 2024

The information presented is current as of October 20, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.