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Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil‐derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single‐rising‐dose study (NCT03414008) and two multiple‐rising‐dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug–drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug‐related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra‐proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose‐dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co‐administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

Talaromyces marneffei is a dimorphic fungus that causes substantial disease in Asia, especially among persons infected with the human immunodeficiency virus. In this randomized, controlled trial, initial therapy with amphotericin B was found to be superior to itraconazole. The dimorphic fungus Talaromyces (previously Penicillium ) marneffei causes a life-threatening mycosis in immunocompromised persons living in or traveling to Southeast Asia, China, and India. 1 Talaromycosis (previously penicilliosis) is a major cause of human immunodeficiency virus (HIV)–related death; its prevalence is surpassed only by the prevalence of tuberculosis and cryptococcosis, 2 and it leads to 4 to 15% of HIV-related hospital admissions in regions in which the disease is endemic. 3 – 7 Talaromycosis is increasingly diagnosed among patients who are not infected with HIV but who have other immunodeficiency conditions 8 and is reported to be the second most common cause of all . . .

Eumycetoma is an implantation mycosis characterised by a large subcutaneous mass in the extremities commonly caused by the fungus Madurella mycetomatis. Despite the long duration of treatment, commonly a minimum of 12 months, treatment failure is frequent and can lead to amputation. We aimed to compare the efficacy of two doses of fosravuconazole, a synthetic antifungal designed for use in onychomycosis and repurposed for mycetoma, with standard-of-care itraconazole, both in combination with surgery. This phase 2, randomised, double-blind, active-controlled, superiority trial was conducted in a single centre in Sudan. Patients with eumycetoma caused by M mycetomatis, who were aged 15 years or older, with a set lesion diameter (>2 cm and ≤16 cm) requiring surgery were included. There was a limit of 20 female patients in the initial enrolment, owing to preclinical toxicity concerns. Exclusion criteria included previous surgical or medical treatment for eumycetoma; presence of loco-regional lymphatic extension; osteomyelitis, or other bone involvement; pregnancy or lactation; severe concomitant diseases; a BMI under 16 kg/m2; contraindication to use of the study drugs; pre-existing liver disease; lymphatic extension; osteomyelitis; transaminase levels more than two times the laboratory's upper limit of normal, or elevated levels of alkaline phosphatase or bilirubin; or any history of hypersensitivity to any azole antifungal drug. Patients were randomly allocated in a 1:1:1 ratio to 300 mg fosravuconazole weekly for 12 months (group 1); 200 mg fosravuconazole weekly for 12 months (group 2); or 400 mg itraconazole daily for 12 months (group 3) using a random number list with non-disclosed fixed blocks of size 12, with equal allocation to each of the three arms within a block. To ensure masking between groups, placebo pills were used to disguise the difference in dosing schedules. All groups took pills twice daily with meals. In all groups, surgery was performed at 6 months. The primary outcome was complete cure at end of treatment at the month 12 visit, as evidenced by absence of mycetoma mass, sinuses, and discharge; normal ultrasonography or MRI examination of the eumycetoma site; and, if a mass was present, negative fungal culture from the former mycetoma site. The primary outcome was assessed in the modified intention-to-treat (mITT) population (all patients who received one or more treatment dose with one or more primary efficacy assessment). Safety was assessed in all patients who received one or more doses of the study drug. This study is registered with ClinicalTrials.gov (NCT03086226) and is complete. Between May 9, 2017, and June 10, 2021, 104 patients were randomly allocated (34 in group 1 and 2, respectively, and 36 in group 3). 86 (83%) of 104 patients were male and 18 (17%) patients were female. After an unplanned second interim analysis, the study was terminated early for futility. Complete cure at 12 months in the mITT population was 17 (50%) of 34 (95% CI 32–68) for group 1, 22 (65%) of 34 (47–80) for group 2, and 27 (75%) of 36 (58–88) in group 3. Neither dose of fosravuconazole was superior to itraconazole (p=0·35 for 200 mg fosravuconazole vs p=0·030 for 300 mg fosravuconazole). 83 patients had a total of 205 treatment-emergent adverse events, and two patients had serious adverse events that led to discontinuation, neither related to treatment. Treatment with either dose of fosravuconazole was not superior to itraconazole, and the two doses had a numerically lower efficacy. However, fosravuconazole presented no new safety signals, and its lower pill burden and reduced risk of drug–drug interactions compared with the relatively expensive and inaccessible itraconazole suggests further research into effective treatments with a shorter duration and higher cure rate, without the need for surgery are warranted. Drugs for Neglected Diseases initiative.

This open-label, two-part, phase Ib drug–drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0–t and 2.7-fold for AUC0–∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Pulmonary aspergillosis (PA) presents a substantial therapeutic challenge, especially in immunocompromised patients, where conventional systemic treatments like oral and intravenous routes often result in limited efficacy and increased adverse effects. This study focuses on the development and evaluation of an inhalable itraconazole (ITZ) formulation within a nanoparticles-in-microparticles (NIM) system. Polyvinyl alcohol 500 (PVA), used in varying concentrations, played a crucial role as a stabilizer in both the wet bead milling and spray drying processes, enhancing drug release and aerodynamic performance. The influence of PVA ratios on drug penetration into pulmonary mucus and interactions with pulmonary defense mechanisms were thoroughly investigated through in-vitro simulations. Pharmacokinetic analysis in (SD) rats revealed enhanced distribution of ITZ-NIMs in pulmonary tissues and bronchoalveolar lavage fluid (BALF), representing a significant improvement in localized drug concentration. Efficacy against was confirmed by a reduction in galactomannan levels, inhibition of fungal growth in lung tissues, and increased survival rates. Importantly, pulmonary delivery of ITZ significantly reduced hepatotoxicity markers, including alanine aminotransferase (ALT) and alkaline phosphatase (ALP), when compared to oral administration. The incorporation of PVA in NIM technology demonstrated not only improved pulmonary targeting and drug release but also minimized systemic toxicity, highlighting the potential of nanoparticle-based inhalation systems in treating respiratory fungal infections like aspergillosis. These findings emphasize the pivotal role of PVA in the formulation, stability, and therapeutic efficacy of NIM-based drug delivery systems for pulmonary applications, advancing the use of nanoparticle technology in respiratory drug delivery.

Nanocrystals and nanosuspensions have become realistic approaches to overcome the formulation challenges of poorly water-soluble drugs. They also represent a less-known but versatile platform for multiple therapeutic applications. They can be integrated into a broad spectrum of drug delivery systems including tablets, hydrogels, microneedles, microparticles, or even functionalized liposomes. The recent progresses, challenges, and opportunities in this field are gathered originally together with an informative case study concerning an itraconazole nanosuspension-in-hydrogel formulation. The translational aspects, historical and current clinical perspectives are also critically reviewed here to shed light on the incoming generation of nanocrystal formulations.

In this randomized trial of patients undergoing treatment for acute myelogenous leukemia or the myelodysplastic syndrome, prophylaxis with posaconazole resulted in fewer fungal infections and longer survival than did prophylaxis with fluconazole or itraconazole. The difference was primarily due to a lower rate of invasive aspergillosis in the posaconazole group. In patients undergoing treatment for acute myelogenous leukemia or the myelodysplastic syndrome, prophylaxis with posaconazole resulted in fewer fungal infections and longer survival than did prophylaxis with fluconazole or itraconazole. Invasive fungal infections remain a major cause of illness and death in patients with neutropenia who have hematologic cancers, despite the availability of new antifungal agents. The incidence of proven or probable mold and yeast infections can reach 24% among patients with leukemia. 1 , 2 Reported mortality from candidiasis or aspergillosis ranges from 40 to 50%, and mortality from fusariosis or zygomycosis is 70% or more. 3 – 8 Prophylaxis is a commonly used treatment strategy, because the diagnosis of fungal infection is often delayed or difficult to establish with certainty, and a delay in antifungal treatment increases mortality. 9 – 11 Antifungal prophylaxis with . . .

•TPN171 is a self-developed PDE5 inhibitor used to treat Pulmonary arterial hypertension and erectile dysfunction with the advantages of high activity, good selectivity, low toxicity, rapid oral absorption, and long half-life in vivo.•The Cmax and AUC0-∞ for TPN171 were increased by 76.00% and 185.67% when combined with itraconazole versus TPN171 alone, and reduced by 74.53% and 90.14% when combined with rifampin versus TPN171 alone.•Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects.•TPN171 demonstrated a favorable safety profile and was well-tolerated in healthy subjects, whether administered as monotherapy or co-administered with the CYP3A4 inhibitor itraconazole or inducer rifampicin.•TPN171 exhibits a significant interaction with CYP3A4 inhibitors/inducers. TPN171, a novel, highly selective, and potent phosphodiesterase type 5 (PDE5) inhibitor, is currently under clinical development for the treatment of pulmonary arterial hypertension (PAH) and erectile dysfunction (ED). The drug is mainly metabolized by the cytochrome P450 (CYP) enzyme 3A4. We evaluated the pharmacokinetic (PK) profile and safety of TPN171, both alone and in combination with itraconazole (a CYP3A4 potent inhibitor) or rifampin (a CYP3A4 potent inducer), in healthy Chinese volunteers. In this open-label, fixed-sequence study, TPN171 (10 mg) was administered orally once daily on Days 1 and 6 in Cohort 1, followed by oral itraconazole (200 mg) once daily from Days 3 to 6. Cohort 2 received oral TPN171 (20 mg) once daily on Days 1 and 10, with concurrent oral rifampin (600 mg) once daily administered from Days 3 to 10. Twenty-four healthy subjects were enrolled (12 per cohort). The PK parameters of TPN171 were estimated through noncompartmental analysis with its plasma concentration detection. Comparisons of the maximum plasma concentration (Cmax) and the area under the concentration–time curve extrapolated to infinity (AUC0-∞) for TPN171 were conducted between conditions with and without coadministration of itraconazole or rifampin. The Cmax and AUC0-∞ for TPN171 were increased by 76.00% (least squares geometric mean ratios (LSGMR), 176.00% [90% CI, 160.37%–193.15%]) and 185.67% (LSGMR, 285.67% [90% CI, 261.87%–311.64%]) when combined with itraconazole versus TPN171 alone. The Cmax and AUC0-∞ of TPN171 were reduced by 74.53% (LSGMR, 25.47% [90% CI, 21.98%–29.50%]) and 90.14% when combined with rifampin versus TPN171 alone (LSGMR, 9.86% [90% CI, 9.08%–10.71%]). Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects. CYP3A4 potent inhibitors and inducers can significantly affect the exposure level of TPN171, especially the inducers. Therefore, when taking TPN171, it is recommended to avoid concomitant administration with CYP3A4 potent inhibitors or potent/moderate inducers, or adjust the dosage of TPN171.

Some patients with severe asthma are immunologically sensitized to one or more fungi, a clinical entity categorized as severe asthma with fungal sensitization (SAFS). It is not known whether SAFS responds to antifungal therapy. To evaluate the response of SAFS to oral itraconazole. Patients with severe asthma sensitized to at least one of seven fungi by skin prick or specific IgE testing were recruited. All had total IgE less than 1,000 IU/ml and negative Aspergillus precipitins. They were treated with oral itraconazole (200 mg twice daily) or placebo for 32 weeks, with follow-up for 16 weeks. The primary end point was change in the Asthma Quality of Life Questionnaire (AQLQ) score, with rhinitis score, total IgE, and respiratory function as secondary end points. Fifty-eight patients were enrolled, of whom 41% had been hospitalized in the previous year. Baseline mean AQLQ score was 4.13 (range, 1-7). At 32 weeks, the improvement (95% confidence interval) in AQLQ score was +0.85 (0.28, 1.41) in the antifungal group, compared with a -0.01 (-0.43, 0.42) change in the placebo group (P = 0.014). Rhinitis score improved (-0.43) in the antifungal, and deteriorated (+0.17) in the placebo group (P = 0.013). Morning peak flow improved (20.8 L/minute, P = 0.028) in the antifungal group. Total serum IgE decreased in the antifungal group (-51 IU/ml) but increased in placebo group (+30 IU/ml) (P = 0.001). No severe adverse events were observed, but seven patients developed adverse events requiring discontinuation, five in the antifungal group. SAFS responds to oral antifungal therapy as judged by large improvements in quality of life in about 60% of patients.