SUBA-itraconazole in the treatment of systemic fungal infections

Abstract

Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent proton pump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now US FDA approved in the treatment of blastomycosis, histoplasmosis and aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edema and drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.

Plain Language Summary

Itraconazole is an antifungal agent used in the treatment of a number of mycoses. Prior formulations (versions) of itraconazole required strict dietary requirements and often had poor absorption. A new itraconazole formulation has since been developed – super bioavailable itraconazole (SUBA-itraconazole). This has no food requirements, has superior absorption and maintains effectiveness against a number of fungal infections.

Plain language summary

Article highlights.

Background

• Conventional itraconazole (c-ITZ) suffers from poor absorption and tolerability and new antifungal options are urgently needed.

• A new formulation (SUBA-itraconazole) of itraconazole is now commercially available.

Clinical use: treatment

• SUBA-itraconazole is approved in the treatment of blastomycosis, histoplasmosis and aspergillosis.

• Off-label use is not uncommon in the treatment of other fungal diseases previously treated with c-ITZ and efficacy has been demonstrated in the treatment of dermatophytosis.

• Limited data has been presented in the treatment of pediatric patients, yet SUBA-itraconazole appears effective in this group of patients often excluded from clinical trials.

Clinical use: prophylaxis

• SUBA-itraconazole has been evaluated in several studies for use as antifungal prophylaxis in immunosuppressed populations (hematopoietic stem cell transplant and lung transplant recipients).

In vitro activity

• SUBA-itraconazole has the same spectrum of activity of c-ITZ.

Pharmacokinetics

• (SUBA-itraconazole) of itraconazole is now commercially available with improved pharmacokinetics and has no food or acid requirements for absorption.

Adverse effects & monitoring

• SUBA-itraconazole was compared with the conventional formulation in a head to head study and fewer adverse events were seen in patients treated with SUBA-itraconazole.

1. Background

Conventional itraconazole (c-ITZ) is a triazole, broad-spectrum antifungal that can provide an oral option for the treatment of common fungal infections. Like other azole antifungals, it inhibits fungal growth by inhibition of 14α-demethylase and thereby decreasing production of ergosterol. By limiting the formation of this vital component in the fungal cell membrane and the build-up of toxic precursors, itraconazole can ultimately cause fungal cell death. c-ITZ was approved in the USA in 1992 and is currently approved by the US FDA for the treatment of aspergillosis, blastomycosis, histoplasmosis and onychomycosis. It is available in 100 mg oral capsules and as an oral solution, the latter of which is also FDA approved for esophageal and oropharyngeal candidiasis. However, clinical use of c-ITZ is often complicated by concerns with absorption and adequate bioavailability [1].

Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation of c-ITZ approved in 2018 under the brand name, Tolsura®. It is commercially available in the US as a 65 mg capsule. Similar to c-ITZ, it is currently approved by the FDA for the treatment of blastomycosis, histoplasmosis and aspergillosis. Unlike c-ITZ, it is not FDA approved for the treatment of onychomycosis. SUBA-ITZ is generally considered to be well-tolerated, with the most common adverse effects being gastrointestinal disorders including abdominal pain and diarrhea, peripheral edema and drug-induced hypertension [1]. In this manuscript we summarize the currently available literature on SUBA-itraconazole.

2. Clinical use: treatment

SUBA-ITZ was recently approved to treat blastomycosis, histoplasmosis and aspergillosis in patients intolerant or with infections refractory to amphotericin B, regardless of immune status [2]. It is not currently indicated for the treatment of onychomycosis and is not interchangeable with alternative itraconazole products due to the drastic differences in bioavailability [2,3].

A Phase III multicenter study compared SUBA-ITZ with c-ITZ for the treatment of endemic mycoses. The study determined that SUBA-ITZ could reach similar therapeutic levels as c-ITZ, but at significantly lower doses. The maximum dose utilized in each itraconazole formulations (SUBA-ITZ 130 mg twice daily vs c-ITZ 200 mg twice daily) was given following a 3 day loading period. SUBA-ITZ trended toward fewer adverse events compared with c-ITZ while maintaining similar clinical outcomes such as resolution of clinical symptoms and radiographic abnormalities attributed to infection.

In addition to the previously mentioned indications, SUBA-ITZ has also been studied for its role in the treatment of dermatophytosis. Several recent studies directly compared SUBA-ITZ with c-ITZ at variable dosing regimens and determined SUBA-ITZ was well tolerated and may even have more favorable outcomes. Dhoot et al. measured serum and sebum concentrations in response to specific dosing regimens (SUBA-ITZ 100 mg vs. 130 mg once daily and c-ITZ 100 mg twice daily vs. 200 mg once daily) and found SUBA-ITZ 130 mg once daily achieved higher cure rates compared with alternative dosing strategies for either agent (Table 1) [4]. Alternatively, Shah et al. compared a twice daily regimen (50 mg vs. 65 mg) of SUBA-ITZ and determined 65 mg twice daily (total daily dose of 130 mg) achieved a higher cure rate at 6 weeks (62%) compared with the 50 mg regimen (40%) [5].

Table 1.

Treatment dosing strategies for common fungal infections.

Common Indications	c-ITZ	SUBA-ITZ
Blastomycosis	200 mg once daily 400 mg/day maximum	130 mg once daily 260 mg/day maximum
Histoplasmosis	200 mg once daily 400 mg/day maximum	130 mg once daily 260 mg/day maximum
Aspergillosis	200–400 mg daily	130 mg once daily OR 130 mg twice daily
Glabrous tinea†	200 mg once daily	130 mg once daily
Life threatening situations	Loading dose of 200 mg three-times daily (600 mg/day) be given for the first 3 days of treatment, followed by the appropriate recommended dosing based on indication	Loading dose of 130 mg three-times daily (390 mg/day) for the first 3 days, followed by the appropriate recommended dosing based on indication.

^†Dosing derived from Dhoot 2023.

A recent retrospective report of pediatric patients, found a median dose prescribed of 8.5 mg/kg/day and duration of 6 weeks. In this study patients with allergic bronchopulmonary aspergillosis (n = 16), sporotrichosis, cutaneous fungal infection not specified and prophylaxis were indications for therapy. Among patients receiving SUBA-ITZ 10/17 achieved a therapeutic level with poor adherence responsible for the seven patients with low blood levels. Efficacy was high with 13/16 ABPA patients demonstrating a response to therapy [6].

3. Clinical use: prophylaxis

To date, there is no FDA indication for the use of SUBA-ITZ as prophylaxis for fungal infections [2]. However, emerging studies are exploring its role as prophylaxis in immunosuppressed patients. A comparative prospective study assessed 27 patients receiving SUBA-ITZ prophylaxis to 30 patients receiving c-ITZ prophylaxis. Target serum concentrations were more rapidly obtained with SUBA-ITZ group (median 6 days) compared with those receiving c-ITZ (median 14 days) (p <0.0001). The mean serum concentrations of steady-state SUBA-ITZ were higher with less interpatient variability (p <0.001). Treatment failures in the SUBA-ITZ group (n = 2) were attributed to mucositis rather than a failure of prophylaxis, while treatment failures in c-ITZ group were attributed to subtherapeutic levels (n = 5) and gastrointestinal toxicity (n = 1) [7].

A study conducted in Australia investigated the safety and efficacy of SUBA-ITZ for primary antifungal prophylaxis in nearly 200 patients following hematopoietic cell transplantation. The study concluded that SUBA-ITZ was both safe and effective with an average breakthrough in invasive fungal disease of approximately 1% after 180 days. It took around 10 days to achieve therapeutic drug levels (1–2 mg/l) using an aggressive dosing strategy of 200 mg twice daily. Of note, the study utilized a higher dose of SUBA-ITZ than has thus far been recommended in the USA. Approximately 30% of the patient population required dose adjustment to 150 or 100 mg twice daily in order to maintain therapeutic levels [8].

Another study examined SUBA-ITZ prophylaxis in 74 patients receiving allogenic or autologous bone marrow transplant, or hematological malignancies. As in the previously mentioned trial, this study used a high-dose strategy of SUBA-ITZ (200 mg twice daily administered on a full stomach). Therapeutic drug levels (defined as >0.5 mg/l) were achieved at a median of 7 days with most patients (87%) achieving target concentrations by day 14. About 1% of patients had a verified invasive fungal infection while approximately 5% experienced a possible breakthrough infection over the course of the study. Forty-two percent of patients in the study experienced gastrointestinal symptoms, including nausea, vomiting and diarrhea. However, none of the gastrointestinal related symptoms were directly attributed to SUBA-ITZ. A single case of elevated liver function tests resulted in a change in prophylactic therapy from SUBA-ITZ to anidulafungin [9].

Whitmore et al. compared various azole prophylaxis regimens in lung transplant patients and utilized a dosing strategy more related to the treatment dosing recommendations for endemic mycoses. The study used SUBA-ITZ 100 mg twice daily for prophylaxis and achieved therapeutic levels of 0.5 mg/l in approximately half of the patients. Two patients had breakthrough fungal infections in the SUBA-ITZ group but did not have therapeutic monitoring data to compare. Overall low attainment of therapeutic levels is thought to be due to the relatively large group of cystic fibrosis patients represented in the study. Patients may have had altered hepatic metabolism or other nonhepatic factors that would have led to reduced levels of itraconazole. Of note, other azole antifungals achieved higher trough levels than SUBA-ITZ, which may require further evaluation for use in patients with cystic fibrosis [10].

In summary, a variety of dosing strategies have been used for SUBA-ITZ prophylaxis in high-risk, immunosuppressed patients. More clinical studies must be conducted in order to determine the most appropriate dosing regimen that can be used for effective fungal prophylaxis. Due to limited evidence and the degree of variation in the reported therapeutic trough levels among current studies, therapeutic drug monitoring will be an important aspect to consider for clinical use.

4. In vitro activity

SUBA-ITZ has the same spectrum of activity to c-ITZ. It displays in vitro activity against most Candida and Aspergillus spp., the endemic mycoses (Blastomyces, Coccidioides, Histoplasma, Sporothrix, Emergomyces and Talaromyces) and Trichophyton spp. No appreciable activity is observed against the Mucorales (Rhizopus spp., Rhizomucor spp., Mucor spp., Absidia spp.), Fusarium, Scedosporium or Scopulariopsis spp [3].

5. Pharmacokinetics

Itraconazole is a major substrate and inhibitor of CYP3A4, and is extensively metabolized into several metabolites, the main one being hydroxy-itraconazole (Table 2) [11]. Plasma concentrations can be characterized by measuring the levels of both itraconazole and hydroxyitraconazole. Itraconazole is highly protein bound and has a half-life elimination ranging between 16 and 42 h.

Table 2.

Comparison of triazole antifungals.

Drug and dosage forms	FDA approved indications	Absorption	Distribution	Metabolism	Elimination
c-ITZ Oral capsule, oral solution	Aspergillosis Blastomycosis Histoplasmosis Onychomycosis	BA: ∼55%, variable TTP: 2–5 h	Highly protein bound (99.8%) Vd: >700 L	Hepatic (CYP3A4)	Urine (35%), feces (54%) t1/2: 16–42 h
SUBA-ITZ Oral capsule	Aspergillosis Blastomycosis Histoplasmosis	BA: -- TTP: 3.5–4 h	Highly protein bound (99.8%) Vd: >700 L	Hepatic (CYP3A4)	Urine (35%), feces (54%) t1/2: 34–42 h (fed state)
Fluconazole IV solution, oral suspension, oral tablet	Candidiasis Cryptococcosis	BA: >90% TTP: 1–2 h	Minimally protein bound (11–12%) Vd: ∼0.6 L/kg	Not significantly metabolized	Urine (80%) t1/2: 20–50 h
Posaconazole IV solution, oral suspension, oral DR tablet, oral packet	Invasive aspergillosis Oropharyngeal candidiasis	BA: ∼70–80% (oral suspension), variable (IR suspension, oral DR tablet) TTP: ∼3–5 h (oral suspension), ∼4–5 h (tablets)	Highly protein bound (>98%) Vd: 287 L	Not significantly metabolized	Feces (71%), urine (13%) t1/2: 35 h (oral suspension), 26–31 h (tablet)
Voriconazole IV solution, oral suspension, oral tablet	Aspergillosis Candidiasis	BA: 96% TTP: 1–2 h	Moderately protein bound (58%) Vd: 4.6 L/kg	Hepatic (CYP2C19 [major], CYP2C9, CYP3A4)	Urine t1/2: variable, dose-dependent
Isavuconazonium sulfate Oral capsule (isavuconazole available as IV solution)	Aspergillosis Mucormycosis	BA: 98% TTP: 2–3 h	Highly protein bound (>99%) Vd: ∼450 L (IV solution)	Prodrug, hydrolyzed in the blood to isavuconazole Hepatic (CYP3A4, CYP3A5)	Feces (46.1%), urine (45.5%) t1/2: 130 h (IV solution)

Pharmacokinetic parameters are only listed for oral formulations unless otherwise noted.

BA: Bioavailability; TTP: Time to peak; Vd: Volume of distribution.

c-ITZ formulations have a reported bioavailability of approximately 55%, however this is confounded by poor or variable inter- and intra-patient bioavailability. SUBA-ITZ utilizes a novel pH-dependent polymer technology to increase bioavailability and reduce interpatient variability. One study comparing SUBA-ITZ 130 mg twice daily to c-ITZ 200 mg twice daily demonstrated that SUBA-ITZ had a 173% higher bioavailability compared with c-ITZ, as well as 21% less variability in bioavailability between subjects [2,12]. This finding is supported by numerous other pharmacokinetic studies. Steady state was achieved in both fasting and fed states with a dosing regimen of SUBA-ITZ 65 mg twice daily. However, healthy adults exhibited similar trough levels but decreased peaks in the fed states, which may be explained by a more prolonged absorption with feeding [13].

Unlike c-ITZ which must be administered with a meal, SUBA-ITZ can be taken with or without food. Absorption of SUBA-ITZ is not dependent on the acidic environment within the stomach, which allows for more flexibility in drug administration [14]. Several studies have found that minimum SUBA-ITZ levels measured in the fed and unfed states are within 10% of each other. In addition, SUBA-ITZ is not affected by co-administration with a proton pump inhibitor. One study characterized the pharmacokinetics of SUBA-ITZ 130 mg twice daily with and without co-administration of a proton pump inhibitor. Co-administration with omeprazole resulted in a 22% increase in total plasma exposure and a 31% increase in peak plasma exposure for SUBA-ITZ [13]. An overview of key pharmacokinetic studies is outlined in Supplementary Table S1.

6. Adverse effects & monitoring

SUBA-ITZ is generally well tolerated, but common adverse effects include gastrointestinal symptoms such as nausea (11%), vomiting (5%), diarrhea (3%) and abdominal pain (2%). Other key adverse effects include rash (9%), edema (4%), hypertension (3%), QTc prolongation and hepatotoxicity (3%). Thus, all patients on SUBA-ITZ should be monitored for changes in liver and renal function, and electrocardiogram evaluation if risk factors co-exist and signs/symptoms of heart failure. Of note, rash was more common in patients receiving immunosuppressive therapy.

Serum trough itraconazole and hydroxyitraconazole levels are recommended in patients on SUBA-ITZ for the treatment or prolonged prophylaxis of invasive aspergillosis, or in those with a concern for variable pharmacokinetics. It is recommended that the serum trough level be collected after the patient has been on a stable dose of SUBA-ITZ for at least 7 days. The minimum goal trough level is 0.5 mg/l for prophylaxis and 1 mg/l for treatment. It is common for therapeutic drug monitoring laboratory results to provide both itraconazole and the active metabolite hydroxy-itraconazole serum drug concentrations [11]. The maximum threshold for toxicity is 10 mg/l although toxicity can be observed at levels considerably lower.

In summary SUBA-ITZ offers several pharmacokinetic benefits compared with the c-ITZ formulation. The lack of food effect and ability to take with acid suppressants are welcome advancements easing patient compliance. Similar serum drug concentrations with lower dosing regimens and a potentially reduced toxicity profile are additional advantages. Additional studies will further refine our understanding of this novel formulation and aid in the development of prophylaxis and treatment regimens for patients.

7. Conclusion

Currently available antifungal agents have been a welcome advance in the treatment and prophylaxis of fungal diseases. However, efficacy concerns, drug–drug interactions, subtherapeutic drug levels, food requirements and intolerance require ongoing investigation for novel agents. SUBA-itraconazole solves many of the issues previously observed with c-ITZ and may be an appropriate option in the treatment or prophylaxis of fungal diseases.

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17460913.2024.2362128

Financial disclosure

Existing Department of Pharmacy Departmental funds from the University of California Davis Medical Center were used for the creation of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

GR Thompson has received research support and consulting fees from Astellas, Basilea, Cidara, F2G, Mayne, Melinta, Mundipharma, Scynexis and Pfizer. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.