What is the data for SUBA-itraconazole (Tolsura)?

Comment by InpharmD Researcher

Clinical trials have evaluated SUBA-itraconazole (Tolsura®) in various clinical settings, with most comparing SUBA-itraconazole to conventional itraconazole. Data suggests that SUBA-itraconazole is effective in treating fungal infections with less pharmacokinetic variability and fewer adverse events than conventional itraconazole. Additionally, SUBA-itraconazole as prophylaxis for invasive fungal infections in high-risk patient populations demonstrated more rapid attainment of therapeutic levels with less interpatient variability compared with conventional itraconazole. Due to relatively small sample sizes in trials, larger randomized controlled trials are needed to further validate these findings.
Background

Super-bioavailability-itraconazole (SUBA-itraconazole; Tolsura®) was developed to enhance dissolution and absorption of the active drug by utilizing a pH-dependent polymer matrix. This novel formulation confers more stable bioavailability for patients with elevated gastric pH, consumption of food or acidic substances, or other patient specific factors. Several studies have been conducted investigating its efficacy, as summarized in the below tables. In comparison, conventional itraconazole allows for 55% bioavailability, while the SUBA formulation is noted to be higher during chronic use. Bioavailability with food of conventional formulation is highly variable, whereas the SUBA formulation experiences a 27% reduction in bioavailability. Additionally, intersubject variability is noted to be 21% decreased with the SUBA formulation, as well as 22% increase in total plasma levels when co-administered with omeprazole. Studies have corroborated improved bioavailability, with one trial finding significantly higher mean trough levels accompanied by much less inter-patient variation (60% with conventional vs. 35% with SUBA). However, generalizability of results may be limited by disease states in which SUBA-itraconazole has been studied thus far. [1], [2]

A 2021 open-label trial (N= 89 participants) compared SUBA-itraconazole (n=43) to conventional itraconazole (n= 46) for the treatment of confirmed or suspected endemic mycoses. Patients were randomized to receive either SUBA-itraconazole 130 mg orally twice daily or conventional itraconazole 200 mg orally twice daily for up to 6 months, with regular follow-up to evaluate quality of life, overall drug tolerance, adverse events, and symptoms, as well as to collect pharmacokinetic samples. Pharmacokinetic serum levels of itraconazole and hydroxyl-itraconazole levels, including the combination itraconazole/hydroxyl-itraconazole levels, were not significantly different between trial arms. Additionally, the area under the curve (AUC) for hydroxyl-itraconazole and itraconazole was comparable in both arms. Reported adverse effects were similar between groups, with an overall rate of 74% and 85% of SUBA-itraconazole and conventional itraconazole patients, respectively, experiencing any adverse event; drug-related adverse effects affected 35% and 41% of patients, respectively. Cardiovascular effects (edema and hypertension), nausea, and appetite loss were most frequently reported. The authors concluded that although SUBA-itraconazole is dosed at about 60% of the usual conventional itraconazole dosage (130 mg orally twice daily vs. 200 mg orally twice daily), it exhibits nearly identical blood levels to conventional itraconazole. SUBA-itraconazole and conventional itraconazole demonstrated a similar safety profile, although SUBA-itraconazole is marginally more well tolerated. Of note, this information is derived from the study abstract, as the full trial does not appear to have been published. [3]

A randomized, multicenter, open-label, crossover, bioequivalence study was conducted to assess the pharmacokinetics, safety, efficacy, tolerability, and health economics of oral SUBA-itraconazole compared to conventional itraconazole in patients with proven or probable invasive endemic fungal infection. Patients were administered either SUBA-itraconazole (n= 42) or conventional itraconazole (n= 46) over two stages: an initial 42-day period, followed by continued treatment until Day 180. For SUBA-itraconazole, patients received two 65 mg capsules TID with food for the first three days, then two capsules BID for the remainder of the study. Patients in the conventional itraconazole group received two 100 mg capsules TID with food for the first three days, followed by two capsules BID for the remainder of the study. Findings revealed that a lower percentage of patients achieved therapeutic itraconazole and hydroxy-itraconazole levels with SUBA-itraconazole (60.5%) compared to conventional itraconazole (71%) on Day 14, but this difference was not statistically significant. However, a higher percentage of patients maintained therapeutic plasma trough levels on Day 42 with SUBA-itraconazole (69.3% vs. 58%; p= 0.80). Notably, treatment-related adverse events (15 patients vs. 27 patients) and serious adverse events (4 patients vs. 12 patients) were less frequent with ​​SUBA-itraconazole. One patient receiving SUBA-itraconazole died during the study period, while no deaths occurred in the conventional itraconazole group. [4], [5]

References:

[1] Gintjee TJ, Donnelley MA, Thompson GR 3rd. Aspiring Antifungals: Review of Current Antifungal Pipeline Developments. J Fungi (Basel). 2020;6(1):28. Published 2020 Feb 25. doi:10.3390/jof6010028
[2] Sardana K, Mathachan SR. Super Bioavailable Itraconazole and Its Place and Relevance in Recalcitrant Dermatophytosis: Revisiting Skin Levels of Itraconazole and Minimum Inhibitory Concentration Data. Indian Dermatol Online J. 2021;12(1):1-5. Published 2021 Jan 16. doi:10.4103/idoj.IDOJ_618_20
[3] Peter G Pappas, et al., 120. An open-label comparative trial of SUBA-itraconazole (SUBA) versus conventional itraconazole (c-itra) for treatment of proven and probable endemic mycoses (MSG-15): a pharmacokinetic (PK) and adverse Event (AE) analysis, Open Forum Infectious Diseases, Volume 8, Issue Supplement_1, November 2021, Page S72, https://doi.org/10.1093/ofid/ofab466.120
[4] U.S. National Library of Medicine. Endemic Mycoses Treatment With SUBA-itraconazole vs Itraconazole (MSG15). ClinicalTrials.gov Identifier: NCT03572049. Updated July 7, 2023. Accessed February 14, 2024. https://classic.clinicaltrials.gov/ct2/show/results/NCT03572049
[5] Spec A, Thompson GR, Miceli MH, et al. MSG-15: SUBA-Itraconazole versus Conventional Itraconazole in the Treatment of Endemic Mycoses - a multicenter, open-label, randomized comparative trial. Open Forum Infectious Diseases. Published online January 29, 2024:ofae010. doi:10.1093/ofid/ofae010

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the data for SUBA-itraconazole (Tolsura)?

Please see Tables 1-6 for your response.


 

Efficacy of Super-Bioavailable Itraconazole and Conventional Itraconazole at Different Dosing Regimens in Glabrous Tinea Infection - A Randomized Clinical Trial

Design

Multi-center, open-label, prospective, randomized, three-arm, clinical study

N= 261

Objective

To compare the cure rates with relapse and safety profiles with three commonly prescribed dosing regimens of itraconazole in the management of glabrous tinea

Study Groups

Super-bioavailable itraconazole 130 mg (SB-130; n= 80)

Conventional itraconazole 200 mg (CITZ-200; n= 77)

CITZ-100 (n= 83)

Inclusion Criteria

Aged ≥18 years and ≤ 60 years; with glabrous tinea requiring systemic antifungal therapy, no history of intake of any oral antifungal agent in the preceding four weeks or a topical antifungal/steroid in the preceding two weeks

Exclusion Criteria

Significant medical illnesses, such as metabolic diseases or immunocompromised conditions

Methods

Eligible patients were randomized into three parallel treatment groups (1:1:1) to receive super-bioavailable itraconazole 130 mg once a day, conventional itraconazole 200 mg once a day (2 capsules of 100 mg), or conventional itraconazole 100 mg twice a day, after food.

Duration

Enrolment: December-2021 through August-2022

Entire study duration: 10 weeks

Treatment period: 6 weeks

Observation period: 4 weeks

Outcome Measures

Primary: Complete cure in different dermatophytosis groups at week 6

Secondary: safety; mycological cure rates

Baseline Characteristics

 

SB-130 (n= 80)

CITZ-200 (n= 77)

CITZ-100 (n= 83)  

Age, years

37.40 ± 12.44 37.46 ± 12.48 37.40 ± 12.48  

Female

52%  52% 49%   

Body mass index, kg/m2

24.48 ± 4.21 25.27 ± 4.89 25.08 ± 4.63  

No. of lesions

<3 Lesions 

≥3 Lesions

 

15%

85%

 

6%

94%

 

7%

93% 

 

Duration of disease

<6 months 

≥6 Months

 

24%

76%

 

26%

74%

 

27%

73%

 

Mean scores

LSS 

ASS

DLQI

 

9.43 ± 1.97

2.41 ± 0.60

17.22 ± 5.65

 

9.32 ± 2.07

2.42 ± 0.62

17.17 ± 6.64

 

9.79 ± 1.19

2.40 ± 0.56

17.45 ± 5.99

 

LSS, Lesion Severity Score; ASS, Area Severity Score; DLQI, Dermatology Life Quality Index

Results

Endpoint

SB-130 (n= 80)

CITZ-200 (n= 77)

CITZ-100 (n= 83)

p-value

Completely cured 

Clinical improvement 

Clinical Failure

69%

18%

13%

61%

31%

8%

46%

37%

17%

0.05#

-

-

Chronic dermatophytosis (≥6 months) group

SB-130 (n= 61) CITZ-200 (n= 57) CITZ-100 (n= 61)  

Completely cured 

Clinical improvement 

Clinical Failure

67%

18%

15%

58%

35%

7%

44%

36%

20% 

<0.05#

-

Obese patients (BMI ≥25) with dermatophytosis group

SB-130 (n= 35) CITZ-200 (n= 39) CITZ-100 (n= 37)  

Completely cured 

Clinical improvement 

Clinical Failure

63%

23%

14%

59%

33%

8% 

32%

46%

22% 

<0.05*

-

-

*Statistically significant (SB-130 and CITZ-200 versus CITZ-100)

#Statistically significant (SB-130 versus CITZ-100)

There was no statistical difference between any of the groups in achieving mycological cure (p= 0.14).

Adverse Events

Common Adverse Events: In the SB-130 group, only one patient had pruritus vs. three patients in the CITZ-200 group reported adverse events (pruritus, erythema, and burning in one patient each), and none of the patients had any adverse events in CITZ-100 group.

Serious Adverse Events: None

Percentage that Discontinued due to Adverse Events: None

Study Author Conclusions

In this clinical study, moderate efficacy with all doses of ITZ was reported but was better with OD dosing. Although there was no statistical difference between SB-130 and CITZ-200, SB-130 may be preferred over CITZ-200 owing to the advantage of SB over the conventional ITZ.

InpharmD Researcher Critique

The results are limited by a short duration of follow-up for relapses. Additionally, open-label design may introduce biases to analysis.



References:

Shenoy MM, De A, Shah B, et al. Efficacy of Super-Bioavailable Itraconazole and Conventional Itraconazole at Different Dosing Regimens in Glabrous Tinea Infection - A Randomized Clinical Trial [published correction appears in Drug Des Devel Ther. 2023 Sep 28;17:3033-3034]. Drug Des Devel Ther. 2023;17:2899-2908. Published 2023 Sep 21. doi:10.2147/DDDT.S421583

 

SUBA-Itraconazole versus Conventional Itraconazole in the Treatment of Endemic Mycoses: a multicenter, open-label, randomized comparative trial

Design

Multicenter, prospective, open-label, randomized, comparative, parallel-arm trial

N= 88

Objective

To evaluate SUBA-itraconazole's (SUBA-itra) efficacy, safety, and pharmacokinetics compared to conventional itraconazole (c-itra) treatment for endemic fungal infections

Study Groups

SUBA-Itra (n= 42)

c-Itra (n= 46)

Inclusion Criteria

Adults; proven or probable infection with endemic mycosis (Histoplasma, Coccidioides, Paracoccidioides, Blastomyces, Sporothrix, Talaromyces marneffei; discontinued fluconazole for seven days before enrollment

Exclusion Criteria

Use of alternative antifungal therapy for more than 14 days; significant liver dysfunction; evidence of central nervous system infection; inability to take oral medications; history of congestive cardiac failure or ventricular dysfunction; lactating or pregnant

Methods

Eligible patients were randomized (1:1) to c-itra or SUBA-itra. Patients randomized to SUBA-itra received 130 mg TID for three days, followed by 130 mg BID for days 4-42 (Stage 1– Open Label Parallel Group). Subsequently, they received 130 mg twice daily for days 43-180 (Stage 2– Open-Label Extension). Patients randomized to c-itra capsule received 200 mg TID for three days, 200 mg BID for days 4-42 (Stage 1), and 200 mg BID for days 43-180 (Stage 2). Dose modification was permitted at the discretion of site investigators. Patients were stratified for HIV status.

Clinical success was defined as the partial or complete resolution of attributable clinical symptoms, physical findings, and radiographic abnormalities attributed to infection. Failure was defined as the lack of improvement or worsening of attributable clinical signs, physical findings, or radiologic imaging. Mycologic outcomes were categorized as success (eradication or presumed eradication) or failure (persistence or presumed persistence).

Duration

June 28, 2018 through January 15, 2021

Outcome Measures

Clinical success (partial or complete resolution of attributable clinical symptoms, physical findings, and radiographic abnormalities attributed to infection); mycologic success (eradication or presumed eradication) at days 42 and 180; comparative pharmacokinetic (PK; drug levels)

Baseline Characteristics*

 

SUBA-Itra (n= 42)

c-Itra (n= 46)

 

Age, years

52.9 ± 18.2 48.1 ± 17.4  

Male

62% 57%  

White

64% 70%  

Body mass index, kg/m2

38.8 ± 12 26.6 ± 6.2  

Diagnosis

Blastomycosis

Coccidioidomycosis

Histoplasmosis

Sporotrichosis

 

9 (21.4%)

9 (21.4%)

23 (54.8%)

1 (2.4%)

 

9 (19.6%)

4 (8.7%)

28 (60.9%)

5 (10.9%)

 

Medication history

Corticosteroids

Immunosuppressive Therapy

 

14 (33%)

14 (33%)

 

9 (20%)

15 (33%)

 

Treatment groups were well balanced with no significant difference at baseline.

Results

Endpoint

SUBA-Itra (n= 42)

c-Itra (n= 46)

 

Clinical success

Day 42

Day 180

 

29 (69%)

25 (60%)

 

31 (67%)

30 (65%)

 

Mycologic success

Day 42

Day 180

 

19 (45%)

17 (40%)

 

22 (48%)

22 (48%)

 

There was no difference between the area under the curve (AUC) of SUBA-itra and c-itra in both the itraconazole component (1,963 vs. 1,897, p= 0.80) and the hydroxyitraconazole component (1,015 vs. 1,058, p= 0.77).

Less variability in drug levels was observed on days 7 (p=0.03) and 14 (p=0.06) in the SUBA-itra group. Once dose adjustments were made, drug level variability on day 42 was comparable between the two groups (p=0.41).

Adverse Events

Common Adverse Events SUBA- itra vs. c-itra: cardiovascular (33% vs. 41%); gastrointestinal (7% vs. 20%)

Serious Treatment Adverse Events SUBA-itra vs. c-itra: 12% (2 cardiovascular, one integumentary, one metabolic, and one respiratory) vs. 50% (four cardiovascular, eight gastrointestinal, two general, two hepatobiliary, three infectious, and one each of musculoskeletal, neurologic, reproductive, and respiratory); p= 0.0002

Percentage that Discontinued due to Adverse Events: Three patients in the c-itra arm

Study Author Conclusions

SUBA-itra, compared to c-itra, effectively treated selected dimorphic fungal infections and appeared to have less PK variability and fewer adverse events. The observed outcomes suggest it is a welcome addition to the antifungal armamentarium.

InpharmD Researcher Critique

This study is mainly limited by its small sample size and open-label design. The exclusion of patients with meningitis, paracoccidioidomycosis, and talaromycosis may limit the generalizability of the results.



References:

Andrej Spec,et al., MSG-15: SUBA-Itraconazole versus Conventional Itraconazole in the Treatment of Endemic Mycoses - a multicenter, open-label, randomized comparative trial, Open Forum Infectious Diseases, 2024;, ofae010, https://doi.org/10.1093/ofid/ofae010

 

Comparative Efficacy of Super Bioavailable Itraconazole Capsules 50 mg vs. 65 mg Twice Daily in the Management of Glabrous Tinea

Design

Single-center, open-label, prospective, randomized, clinical study

N= 98

Objective

To compare the efficacy of super bioavailable itraconazole (SBITZ) 50 mg vs 65 mg BID in the treatment of glabrous tinea

Study Groups

SBITZ-50 mg (n= 50)

SBITZ-65 mg (n= 48)

Inclusion Criteria

Adults ≤60 years; diagnosed with glabrous tinea; requiring systemic antifungal medication; no prior history of using an oral antifungal in the previous four weeks or a topical antifungal/steroid in the prior two weeks

Exclusion Criteria

Serious medical disorders that would have affected clinical outcomes (metabolic diseases or immunocompromised conditions)

Methods

Eligible patients were randomized to SBITZ 50 mg or SBITZ 65 mg BID, after food, for 6 weeks. Patients were not permitted to use any other antifungal medications but were prescribed a topical emollient combining white soft paraffin and light liquid paraffin. Efficacy and safety assessments were done at week-3 and 6 with a follow-up at week-10 for relapse.

Duration

May 2022 through September 2022

follow-up: 10 weeks

Outcome Measures

Primary: Complete cure at week 6

Secondary: Clinical response and efficacy scores at week 6

Baseline Characteristics

 

SBITZ-50 mg (n= 50)

SBITZ-65 mg (n= 48)

 

Age, years

36.72 ± 12.16 35.26 ± 11.14  

Female, n

22 23  

Body mass index, kg/m2

24.52 ± 2.95 24.68 ± 3.14  

Duration of disease, n

<6 months

>6 months

 

14

36 

 

12

36

 

Mean score

LSS 

ASS 

DLQI

 

7.21 ± 2.04

2.81 ± 0.42

13.43 ± 2.54

 

7.50 ± 1.90

2.92 ± 0.34

13.64 ± 2.12

 

LSS, Lesion Severity Score; ASS, Area Severity Score; DLQI, Dermatology Life Quality Index

Results

Endpoint

SBITZ-50 mg (n= 50)

SBITZ-65 mg (n= 48)

p-value

Clinical response

Completely cured

Relapse

 

20 (40%) 

3 (15%)

 

30 (62%)

5 (17%)

 

<0.05

1

Efficacy Scores at week 6

LSS 

ASS 

DLQI

 

1.57 ± 1.22

0.76 ± 0.59

2.91 ± 2.06  

 

0.78 ± 0.82

0.46 ± 0.50

1.67 ± 1.28

 

0.003

0.008

0.0006

Recalcitrant dermatophytosis subgroup

SBITZ-50 mg (n= 36) SBITZ-65 mg (n= 36) p-value

Clinical response 

Completely cured

Relapse

 

13 (36%)

2 (15%)

 

23 (64%)

4 (17%)


<0.05

1

Efficacy Scores at week 6

LSS 

ASS 

DLQI

 

2.33 ± 1.17

1.11 ± 0.52

4.03 ± 1.89

 

0.76 ± 0.91

0.42 ± 0.50

1.78 ± 1.35

 

0.0001

0.0001

0.0001

Adverse Events

Common Adverse Events: No derangements in liver enzymes were noted at the end of treatment in both the groups.

Serious Adverse Events: None

Percentage that Discontinued due to Adverse Events: None

Study Author Conclusions

Patients treated with super bioavailable itraconazole 65 mg demonstrated significant results over 50mg in terms of achieving complete cure rates in dermatophytosis. Additionally, significant improvement in the clearance of lesions and cure rate in subgroup of patients like recalcitrant dermatophytosis was also noticed for super bioavailable itraconazole 65 mg capsules. All these findings may lead super bioavailable itraconazole 65 mg to be placed in the armamentarium of dermatophytosis management.

InpharmD Researcher Critique

This was a relatively small study performed in India and inherently limited by its single-center, open-label design. Randomized, double-blind, comparative studies are needed to determine the super bioavailable itraconazole dosing strategy and place in therapy. 



References:

Shah B, Mistry D, Jairam D, et al. Comparative Efficacy of Super Bioavailable Itraconazole Capsules 50 mg vs 65 mg Twice Daily in the Management of Glabrous Tinea. Infect Drug Resist. 2023;16:2409-2416. Published 2023 Apr 24. doi:10.2147/IDR.S407946

 

Serum Levels, Safety and Tolerability of New Formulation SUBA-itraconazole Prophylaxis in Patients with Hematological Malignancy or Undergoing Allogeneic Stem Cell Transplantation

Design

Single-center, prospective, investigator-initiated, comparative, cohort study

N= 57

Objective

To assess therapeutic levels, safety, and tolerability of a novel formulation SUBA-itraconazole (where SUBA stands for SUper BioAvailability) when compared with conventional itraconazole liquid when used as anti-fungal prophylaxis in patients undergoing allogeneic allogeneic stem cell transplantation (HSCT) or in hematological malignancy patients with an intermediate/high risk of invasive fungal infection (IFI)

Study Groups

SUBA-itraconazole (n= 27)

Itraconazole liquid (n= 30)

Inclusion Criteria

Underwent an allogeneic HSCT; had a hematological malignancy; considered to have an intermediate or high risk of IFI 

Exclusion Criteria

Acute myelogenous leukemia (AML); myelodysplastic syndrome (MDS); acute or chronic graft vs. host disease (GVHD)

Methods

All consecutive patients who underwent an allogeneic HSCT from a single tertiary referral hospital in Sydney, Australia were evaluated for therapeutic concentrations. Plasma itraconazole concentrations were measured twice weekly from initiation of therapy and target trough concentrations for prophylactic efficacy were defined as > 500 ng/mL.

Regular liver function tests (LFTs) were performed to assess drug-attributable hepatotoxicity; if moderate to severe toxicity was seen [defined as Drug-Induced Liver Injury Network (DILIN) grade 3+ liver injury with raised serum aminotransferase or alkaline phosphatase levels and total serum bilirubin level >2.5mg/dL]. SUBA-itraconazole patients and the historical control group were well-matched concerning age, sex, and indication for antifungal administration.

Duration

February 2014 through August 2016

Outcome Measures

Time to therapeutic concentrations; therapeutic concentrations at day 10; treatment failure

Baseline Characteristics

 

SUBA-itraconazole (n= 27)

Itraconazole liquid (n= 30)

 

Mean age (range), years

50.2 (18 to 76) 53.2 (25 to 71)  

Female, n

11 10  

Mean weight (range), kg

74.8 (45 to 98) 71.3 (49 to 118)  

Hematological malignancy, n

Grade 4 mucositis, n

5

1

5

1

 

HSCT, n

Reduced-intensity conditioning

Myeloablative conditioning

Sibling donor

Matched unrelated donor

Haploidentical donor

22

16

6

10

12

25

22

3

10

14 

 

Time to engraftment, day

Duration of neutropenia, day

17.7 (12 to 28)

8.8 (0 to 17)

17.4 (9 to 26)

12.2 (0 to 27)

 

Overall survival at day +100

88.9% 90%  

Overall survival for liquid itraconazole versus SUBA-itraconazole was not significantly different (90.0% vs 88.9%) (p= 0.29).

The 3-year overall survival estimate for the entire cohort was 75.4%. Over the study period, a total of 336 serum itraconazole levels were taken (173 for SUBA-itraconazole vs. 163 for liquid itraconazole).

Results

Endpoint

SUBA-itraconazole (n= 27)

Itraconazole liquid (n= 30)

p-value

Mean time to therapeutic concentrations (95% confidence interval [CI]), days

6 (5 to 11) 14 (12 to 21) <0.0001 

Therapeutic concentrations at day 10 (95% CI)

69% (44% to 81%) 21% (7% to 33%) <0.0001

There were two (7.4%) treatment failures in the SUBA-itraconazole group, both due to cessation of therapy for mucositis, compared with seven (23.3%) treatment failures in the liquid itraconazole group, due to subtherapeutic levels (n= 5), mucositis (n= 1) and gastrointestinal intolerance (n= 1) (p= 0.096).

Three patients in the SUBA-itraconazole and eight patients in the liquid itraconazole group developed mild Liver function test (LFT) derangement (DILIN grade 1+), while two patients in the liquid itraconazole group developed moderate raised bilirubin (>2.5 mg/dL, DILIN grade 2+).

Adverse Events

Common Adverse Events: See results

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: See results

Study Author Conclusions

The use of the SUBA-itraconazole formulation was associated with more rapid attainment of therapeutic levels with less interpatient variability compared with conventional liquid itraconazole when used as IFI prophylaxis in allogeneic HSCT or intermediate-/high-IFI risk hematological malignancy patients.

InpharmD Researcher Critique

Given the inclusion of a historical control group, the results may be subject to selection biases. Moreover, this was a small study, performed in a single medical center in Australia, potentially limiting the generalizability of the results.



References:

Lindsay J, Sandaradura I, Wong K, et al. Serum levels, safety and tolerability of new formulation SUBA-itraconazole prophylaxis in patients with hematological malignancy or undergoing allogeneic stem cell transplantation. J Antimicrob Chemother. 2017;72(12):3414-3419. doi:10.1093/jac/dkx295

 

Bioavailability of Single-Dose SUBA-Itraconazole Compared to Conventional Itraconazole under Fasted and Fed Conditions

Design

Open-label, single-dose, randomized, four-period, four-treatment, four-sequence, crossover bioequivalence study

N= 52

Objective

To evaluate the relative bioavailability of a single oral dose of SUBA-itraconazole (S-ITZ) compared to conventional itraconazole (C-ITZ) capsules when administered under fasted and fed conditions

Study Groups

All patients (N= 52)

S-ITZ: Fasted (n= 51)

S-ITZ: Fed (n= 50)

C-ITZ: Fasted (n= 52)

C-ITZ: Fed (n= 51)

Inclusion Criteria

Age 18 to 65 years; BMI from 18 to 30 kg/m²; considered health based upon medical history, electrocardiogram (ECG), laboratory evaluation, and physical examination and vital signs measurements

Exclusion Criteria

History or current evidence of chronic infection or other comorbidities; female subjects of childbearing age not willing to abstain from intercourse or use appropriate contraception for 30 days before and 3 months after the study; use of medications known to significantly induce or inhibit CYP3A4 or CYP2D6  

Methods

S-ITZ 65-mg or C-ITZ 100-mg capsules were given to subjects in a fed or fasted state throughout each research period in compliance with the randomization sequence. Comparing PK parameters within the same participant was made possible by the crossover research design. Dosage blinding was not done. Blood samples were taken between one and twelve hours after the dose was administered, 60 minutes before the dose, and before breakfast for those on the fed regimen. The amounts of ITZ and hydroxyitraconazole (OH-ITZ) plasma were determined using tandem mass spectrometry in liquid chromatography.

Outcome Measures

Pharmacokinetic results of itraconazole and hydroxyitraconazole levels comparing SUBA-itraconazole and conventional itraconazole under fasted and fed states

Baseline Characteristics

  Study group (N=52)        

 

 

 

Age, years (range)

39 (19 - 54)              

Female

51.9%              

White

Asian

African American 

50%

28.8%

21.2%

             

Participants were healthy, male or female, nonsmokers, with body mass indices of 18 to 30, and without drug allergies who gave informed consent.

Results

Pharmacokinetic results of itraconazole and hydroxyitraconazole levels comparing SUBA-itraconazole and conventional itraconazole under fasted and fed states

Parameter

 

Itraconazole

Hydroxyitraconazole
S-ITZ: fasted (65 mg ITZ) S-ITZ: fed (65 mg ITZ)

C-ITZ: fasted (100 mg ITZ)

C-ITZ: fed (100 mg ITZ) S-ITZ: fasted (65 mg ITZ) S-ITZ: fed (65 mg ITZ) C-ITZ: fasted (100 mg ITZ) C-ITZ: fed (100 mg ITZ) 

Median Tmax,hours (range)

2.50 (1.50 –5.00) 7.50 (4.50 –24)

3.00 (1.50 –4.52)

5.00 (2.50 –11.00) 3.50 (2.00 –6.00) 9.00 (4.50 –  24) 4.00 (1.50 – 5.50) 5.50 (2.50 – 12.00)

Cmax,ng/ml

111.910 (44%) 50.299 (50%)

74.362 (57%)

62.224 (55%) 180.514 (31%) 85.902 (36%) 133.969 (46%) 100.818 (41%)
AUCinf, ng · h/ml 1,006.534 (45%) 684.773 (46%) 879.762 (57%) 754.350 (58%) 1,934.418 (48%) 1,186.126 (50%) 1,656.887 (60%) 1,301.073 (59%)
Thalf, hours 31.45 (23%) 32.48 (26%) 29.95 (22%) 34.02 (30%) 8.90 (47%) 7.77 (38%) 12.43 (45%) 8.52 (44%)

Cmax: maximum concentration; AUCinf: area under the curve extrapolated to infinity;  Thalf: half-life; Tmax: time to reach Cmax after administration (expressed as the arithmetic mean coefficient of variation [CV%])

S-ITZ and C-ITZ showed decreased relative bioavailability when food was present. When S-ITZ was provided after the study meal, the mean AUCinf and Cmax for both ITZ and OH-ITZ were lower (31 and 40% for AUCinf; 57 and 54% for Cmax); a similar drop was observed in C-ITZ (10 and 18% for AUCinf; 14 and 22% for Cmax) for ITZ and OH-ITZ, respectively.

Adverse Events

Common Adverse Events (S-ITZ Fasted vs. S-ITZ Fed vs. C-ITZ Fasted vs. C-ITZ Fed): headache (5.9% vs. 4.0% vs. 5.8% vs. 9.8%), somnolence (5.9% vs. 6.0% vs. 9.6% vs. 7.8%)

Serious Adverse Events: ECG PR shortened (1 S-ITZ Fed patient, 1 C-ITZ Fasted patient), ECG QT prolonged (1 S-ITZ Fasted, 1 C-ITZ Fasted, 1 C-ITZ Fed), ECG T wave abnormal (1 S-ITZ Fasted), Hypotension (1 C-ITZ Fasted), Tachycardia (1 S-ITZ Fasted, 3 C-ITZ Fasted), Bradycardia (1 C-ITZ Fed)

Study Author Conclusions

This study demonstrated less variability of S-ITZ compared to C-ITZ capsules under fasted conditions.

InpharmD Researcher Critique

The small study sample may limit the generalizability of the results. Due to the crossover design, the effects of one treatment may potentially alter the response to subsequent treatments.

References:

Rauseo AM, Mazi P, Lewis P, Burnett B, Mudge S, Spec A. Bioavailability of Single-Dose SUBA-Itraconazole Compared to Conventional Itraconazole under Fasted and Fed Conditions. Antimicrob Agents Chemother. 2021;65(8):e0013421. doi:10.1128/AAC.00134-21

 

Retrospective Studies Evaluating SUBA-itraconazole

Reference Population Intervention Major Results

Abbotsford et al., 2021

 

N= 19

A retrospective analysis was conducted to evaluate pediatric patients prescribed SUBA-itraconazole between May 2018 and February 2020 at a tertiary pediatric hospital. The recommended initial treatment dose for patients was 5 mg/kg twice daily, capped at 400 mg/day, rounded to the nearest capsule size. For prophylaxis, the recommended dose was 2.5 mg/kg/day.

The median dose administered was 8.5 mg/kg/day for a median duration of 6 weeks.

Indications for use included allergic bronchopulmonary aspergillosis (ABPA; 16 patients), sporotrichosis (1 patient), cutaneous fungal infection (1 patient), and prophylaxis (1 patient).

Nearly 60% (10/17) achieved therapeutic levels among patients with measured serum levels, with 3 requiring one dose adjustment and 7 reaching therapeutic levels after the initial dose. Adherence to dose-adjustment recommendations was poor among the seven patients who did not initially achieve therapeutic levels.

Among patients with ABPA, 81% (13/16) demonstrated a therapeutic response in IgE levels. SUBA-itraconazole was well-tolerated, with no treatment cessations related to adverse effects. One patient developed a rash that resulted in temporary interruption, but completed treatment successfully without recurrence of rash.

Author's Conclusion: SUBA-itraconazole is well tolerated in children, with rapid attainment of therapeutic levels in the majority of patients, and may represent a superior formulation for children in whom itraconazole is indicated for treatment or prevention of fungal infection.

Whitmore et al., 2021 N= 150

A retrospective analysis was conducted on lung transplant patients receiving systemic antifungal prophylaxis from December 2016 through December 2019, following a switch from posaconazole to itraconazole as standard practice.

The initial dose chosen empirically was 100 mg twice daily of SUBA-itraconazole, based on dosing recommendations in pulmonary aspergillosis. This dose was reduced by 50% due to the twofold higher bioavailability of SUBA-itraconazole compared to previous formulations, with dosing then adjusted based on therapeutic drug monitoring. Additionally, all patients routinely received gastric acid suppression with proton pump inhibitors following lung transplantation.

Four episodes of proven or possible invasive fungal infections (IFI) occurred during the study period. One patient developed proven IFI with sino-orbital mucormycosis while on SUBA-itraconazole prophylaxis and high-dose oral prednisolone for possible giant cell arteritis. The patient was switched to intravenous liposomal amphotericin but later deteriorated and died.

Another patient developed probable invasive pulmonary aspergillosis while on SUBA-itraconazole but later switched to posaconazole with full recovery.

Prophylaxis target trough concentrations were achieved in 56% of those on SUBA®-itraconazole. Notably, no adverse reactions attributable to itraconazole were reported, and all adverse events noted were grade 1 or 2.

Author's Conclusion: SUBA-itraconazole appears to be a safe and effective empiric antifungal prophylaxis agent in lung transplant recipients, though further prospective assessment and formalized therapeutic drug monitoring to ensure attainment of therapeutic levels is recommended, as well as further validation in a larger patient population.

Lindsay et al., 2021

N= 204

Cohort A (n= 129)

Cohort B (n= 75)

A retrospective cohort study was conducted at 2 Australian centers to evaluate the safety, tolerability, and effectiveness of SUBA-itraconazole as primary antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients without grade 2–4 acute graft vs. host disease, from day 1 until approximately day 100 (Cohort A) or day 1 until neutrophil engraftment (Cohort B).

The initial dose was 200 mg twice a day (q12h) in both cohorts and trough plasma itraconazole concentrations were measured twice weekly aiming for a therapeutic range between 500 and 2,000 ng/mL.

The incidence of breakthrough proven/probable invasive fungal disease (IFD) at day 180 was 1.0% (95% confidence interval [CI] 0.2% to 3.2%), with 1.6% in cohort A and 0% in cohort B. Overall fungal-free survival of proven/probable IFD was 82.9% (95% CI 76.8% to 87.4%).

Preengraftment early permanent SUBA-itraconazole discontinuation was 3.4%, with no significant difference between cohorts. No patients required cessation due to gastrointestinal intolerance attributed to SUBA-itraconazole.

The geometric mean trough plasma itraconazole concentration was 1,130 ng/mL (interquartile range [566–1,801 ng/mL]; coefficient of variation 56.57%), and the median time to achieve therapeutic levels was 10 days.

Author's Conclusion: SUBA-itraconazole is a safe and well-tolerated oral formulation and is a novel alternative for primary IFD prophylaxis after HCT.

Nield et al., 2019

N= 74 A retrospective cohort study was conducted between June 2016 and April 2018 to assess therapeutic drug concentrations, safety and tolerability of a standard prophylactic dose of SUBA-itraconazole (itraconazole 200 mg [4 × 50 mg capsules] prophylaxis at 8 am and 8 pm on a full stomach) in patients undergoing stem cell transplantation or treatment for hematological malignancies.

The median duration of prophylaxis was 15.5 days, with autoHSCT patients receiving the shortest duration of 12 days.

33% of patients experienced grade 3 or 4 mucositis, with 14% requiring total parenteral nutrition.

Trough concentrations approached steady-state at 14 days, with a mean trough concentration of 1.00 ± 0.53 mg/L (95% CI 0.83 to 1.16 mg/L). No significant differences in serum trough concentrations were found based on sex, age, weight, or neutrophil count at initiation of prophylaxis. Additionally, no significant differences in obtained mean trough concentrations were observed between patients receiving different types of therapy when adjusted for median duration of prophylaxis therapy.

One patient was changed to anidulafungin prophylaxis due to moderate to severe elevation in liver function tests (Drug-Induced Liver Injury Network [DILIN] 3+) following initiation of SUBA-itraconazole prophylaxis. Two patients met the criteria for moderate liver injury (DILIN 2+) during SUBA®-itraconazole prophylaxis, both of which resolved without change in therapy.

During SUBA-itraconazole therapy, 4% of patients died due to their underlying malignancies.

One patient was switched to voriconazole due to respiratory concerns, despite not meeting IFI criteria. The single confirmed IFI was Candida glabrata fungemia, occurring after stopping SUBA-itraconazole with an average trough concentration of 1.35 mg/L during the prophylaxis period.

Authors' Conclusion: SUBA-itraconazole achieved rapid therapeutic trough concentrations, was associated with low rates of IFI and was well tolerated in the study population. This formulation should be considered a realistic and safe first-line agent for the prevention of IFIs in those undergoing HSCT and intermediate/high-risk therapy for hematological malignancies.

References:

[1] Abbotsford J, Foley DA, Goff Z, Bowen AC, Blyth CC, Yeoh DK. Clinical experience with SUBA-itraconazole at a tertiary pediatric hospital. J Antimicrob Chemother. 2021;76(1):249-252. doi:10.1093/jac/dkaa382
[2] Whitmore TJ, Yaw M, Lavender M, Musk M, Boan P, Wrobel J. A novel highly bio-available itraconazole formulation (SUBA®-Itraconazole) for anti-fungal prophylaxis in lung transplant recipients. Transpl Infect Dis. 2021;23(4):e13587. doi:10.1111/tid.13587
[3] Lindsay J, Othman J, Kong Y, et al. SUBA-Itraconazole for Primary Antifungal Prophylaxis After Allogeneic Hematopoietic Cell Transplantation. Open Forum Infect Dis. 2021;8(11):ofab502. Published 2021 Nov 23. doi:10.1093/ofid/ofab502
[4] Nield B, Larsen SR, van Hal SJ. Clinical experience with new formulation SUBA®-itraconazole for prophylaxis in patients undergoing stem cell transplantation or treatment for hematological malignancies. J Antimicrob Chemother. 2019;74(10):3049-3055. doi:10.1093/jac/dkz303