Spherazole (itraconazole) / Spherics - LARVOL DELTA

[VIRTUAL] Drug-Drug Interaction of Oral EGFR Inhibitor TAK-788 With Itraconazole and Rifampin in Healthy Volunteers (IASLC-NACLC 2020) - P1 | "The strong CYP3A inhibitor itraconazole significantly increased systemic exposure of TAK‑788 and its 2 active metabolites, while the strong CYP3A inducer rifampin significantly reduced the exposure of TAK-788 and its 2 active metabolites. Hence, coadministration of TAK-788 with moderate and strong CYP3A inhibitors and inducers is not recommended."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

[VIRTUAL] Pharmacokinetics, safety, and efficacy of trastuzumab deruxtecan (T-DXd) with OATP1B/CYP3A inhibitors in patients with HER2-expressing advanced solid tumours (ESMO-BC-I 2020) - P1 | "Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload (DXd; exatecan derivative). There was a small increase in AUC17d for T-DXd and DXd with concomitant ritonavir and itraconazole that was not considered to be clinically meaningful. Efficacy and safety of T-DXd were consistent with previous trials.Legal entity responsible for the study: Daiichi Sankyo Co., Ltd.; AstraZeneca is a collaborator. Funding: Daiichi Sankyo Co., Ltd."

Clinical • PK/PD data • Breast Cancer • Constipation • HER2 Breast Cancer • Immunology • Oncology • Pneumonia • Solid Tumor • HER-2

[VIRTUAL] Pharmacokinetics, safety, and efficacy of trastuzumab deruxtecan (T-DXd) with OATP1B/CYP3A inhibitors in patients with HER2-expressing advanced solid tumours (ESMO-BC-I 2020) - P1 | "Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload (DXd; exatecan derivative). There was a small increase in AUC17d for T-DXd and DXd with concomitant ritonavir and itraconazole that was not considered to be clinically meaningful. Efficacy and safety of T-DXd were consistent with previous trials.Legal entity responsible for the study: Daiichi Sankyo Co., Ltd.; AstraZeneca is a collaborator. Funding: Daiichi Sankyo Co., Ltd."

Clinical • PK/PD data • Breast Cancer • Constipation • HER2 Breast Cancer • Immunology • Oncology • Pneumonia • Solid Tumor • HER-2

Evaluation of drugdrug interaction of itraconazole and ivosidenib (AG-120), an oral, potent, targeted, small molecule inhibitor of mutant IDH1, in healthy subjects (EORTC-NCI-AACR 2018) - P1; "Coadministration of single dose IVO with a strong CYP3A4 inhibitor, itraconazole, resulted in increased AUC but not Cmax. PBPK modeling predicted that the magnitude of DDI with strong CYP3A4 inhibitors at steady state would be a 100% increase in AUC."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

EPIDEMIOLOGY AND TREATMENT APPROACHES OF INVASIVE FUNGAL INFECTIONS MANAGEMENT IN HEMATOLOGICAL MALIGNANCIES: RESULTS FROM A SINGLE-CENTRE STUDY (EHA 2018) - "...Twenty-nine (13%) pts were receiving antifungal prophylaxis (26 posaconazole, 2 fluconazole, 1 itraconazole)...Caspofungin (Caspo) was used in 100 cases, liposomal amphotericin B (L-AmB) in 123 and voriconazole (VCZ) in 93... We described IFI epidemiology and treatment in a large monocentric cohort of consecutive oncohematologic pts, and correlated it with EORTC/MSG criteria, evidencing their potential weakness (high incidence of unclassifiable cases). This epidemiologic survey evidenced a persistent significant necessity of AFT, with high frequency of sequential and combination therapy. Interestingly, we failed to demonstrate an impact on outcome of diagnosis, GM or CT scan positivity, suggesting that the timely and aggressive therapeutic strategy applied seems to be efficacious in hematological diseases with different degree of immunosuppression and for IFI with different aggressiveness."

Clinical • Acute Myelogenous Leukemia

[VIRTUAL] A phase I/II study of hydroxychloroquine and suba-itraconazole in men with biochemical relapse of prostate cancer (HITMAN-PC): dose escalation results (MOGA ASM 2020) - "HCQ/SI demonstrated acceptable safety with MTD 600 mg BD and RP2D 400 mg BD. There is early signal of efficacy and phase II enrolment is to begin."

P1/2 data • Genito-urinary Cancer • Hypertension • Oncology • Prostate Cancer • Solid Tumor

A phase II study of itraconazole in biochemically recurrent prostate cancer. (ASCO-GU 2018) - P2; "Itraconazole can modulate serum PSA levels without lowering serum T in pts with BRPC. However, the magnitude of effect is modest and treatment carries an appreciable risk of toxicities related to mineralocorticoid excess. Exploration of the relationship between mineralocorticoid-related AEs, itraconazole drug levels, and clinical outcomes is ongoing."

P2 data • Prostate Cancer

[VIRTUAL] Phase I/II trial assessing hydroxychloroquine and itraconazole in women with advanced platinum-resistant epithelial ovarian cancer (EOC) (HYDRA-01). (ASCO 2020) - P1/2 | "The combination of Itr and H was feasible but did not show antitumour activity in this heavily pre-treated platinum resistant EOC population. Increase of IHC expression in autophagy related proteins was detected in 30% of pts but did not correlate with patient benefit. Research Funding: OICR Ovarian TRI grant"

Clinical • P1/2 data • Basal Cell Carcinoma • Gynecologic Cancers • Hypertension • Oncology • Ovarian Cancer • Solid Tumor • SQSTM1

[VIRTUAL] Neoadjuvant itraconazole (I) in patients (pts) with resectable basal cell carcinoma (BCC): A phase II multistage study. (ASCO 2020) - "Itraconazole showed initial anti-tumor activity in pts with resectable BCC, no safety concerns were observed. Study will proceed to Simon’s second stage. Research Funding: Fundo de Incentivo a Pesquisa e Eventos do Hospital de Clinicas de Porto Alegre"

Clinical • P2 data • Basal Cell Carcinoma • CNS Disorders • Depression • Oncology • Pain • GLI1

[VIRTUAL] Hepatic Manifestations of Disseminated Histoplasmosis (ACG 2020) - "Treatment includes anti-fungal medication such as Itraconazole and amphotericin B. Here we present two patients with history of liver disease and disseminated histoplasmosis...He was started on Isavuconazole...For UC management, patient had received three infusions of Entyvio prior to discontinuation due to pruritus and blood pressure lability; and was subsequently started on methylprednisolone...As these cases show, it is important to detect disseminated histoplasmosis early and to continue to monitor Histo Ag levels throughout treatment course to ensure infection is not progressing. Further studies may show how disseminated histoplasmosis can progress based on cause of infection and treatment course."

Dermatology • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Pruritus • Transplantation • Ulcerative Colitis

[VIRTUAL] A Rare Case of Acute Liver Failure and Hemophagocytic Lymphohistiocytosis Following Disseminated Histoplasmosis (ACG 2020) - "Case Description/ A 42-year-old woman with AS on Infliximab presented with fever, jaundice, and abdominal pain for 1 week...IV liposomal amphotericin B was started but complicated with acute tubular necrosis requiring renal replacement therapy...Dexamethasone and Etoposide were initiated for HLH induced histoplasmosis...Further chemotherapy was not required, she was discharged on a steroid taper and indefinite itraconazole...This case emphasizes histoplasmosis as a cause of granulomatous hepatitis in immunocompromised patients and HLH as a potential complication. Given the rarity and high fatality of HLH, early identification of the underlying trigger and initiation of treatment is of extreme importance to have the best possible outcome."

Clinical • Ankylosing Spondylitis • CNS Disorders • Dyslipidemia • Hematological Disorders • Hepatology • Hypertriglyceridemia • Immunology • Inflammation • Inflammatory Arthritis • Liver Failure • Pain • Respiratory Diseases • Rheumatology • Seronegative Spondyloarthropathies • IL2

[VIRTUAL] Epidemiology, Risk Factors, and Effect of Antifungal Prophylaxis on Early Invasive Fungal Infection in Heart Transplant Recipients (IDWeek 2020) - "444 patients received antifungal prophylaxis which included 32% fluconazole, 34% itraconazole, 18% voriconazole, 15% echinocandin, and < 1% amphotericin or posaconazole... Renal replacement therapy after transplantation is associated with 1-year IFI. Antifungal prophylaxis appears to be protective and further prospective study is warranted to verify this finding."

Clinical • Infectious Disease

[VIRTUAL] Hard to Swallow: Histoplasmosis Causing Oropharyngeal Ulcers in a Patient With Crohn’s Disease on Adalimumab (ACG 2020) - "At the onset of his symptoms, he was initially treated with a course of prednisone and doxycycline with modest improvement...Treatment with itraconazole was initiated with eventual resolution of odynophagia...While this patient had a favorable outcome with initiation of antifungal treatment while off adalimumab, some data suggests resuming anti-TNF agents while on antifungal therapy can be safe with close monitoring. New onset mucosal ulceration in a patient with Crohn’s disease, which persists despite aggressive immunosuppression, should prompt investigation for histoplasmosis as a potential etiology."

Clinical • Crohn's disease • Fatigue • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Bowel Disease • Pain

[VIRTUAL] Histoplasmosis Presenting as Isolated Colonic Granulomas in an Immunocompromised Patient (ACG 2020) - "Case Description/ A 67-year-old asymptomatic man with a history of deceased donor renal transplant on tacrolimus, mycophenolate mofetil, and prednisone was referred for screening colonoscopy...Subsequently, a urine Histoplasma antigen test was negative, and therapy with itraconazole was initiated...More commonly seen is a lymphohistiocytic infiltrate with fungi found within the cytoplasm of macrophages; biopsies in our case revealed well-formed granulomas with actively budding yeast. In conclusion, it is important to consider histoplasmosis when vague GI symptoms occur or ulcers, nodules or masses are found on colonoscopy in immunocompromised patients."

Clinical • Gastrointestinal Disorder • Pain • Transplantation

Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review. (PubMed, Bioorg Chem) - "The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Activities of Nine Antifungal Agents against Candida auris Biofilms. (PubMed, Mycoses) - "Triazoles, echinocandins and liposomal amphotericin B appear to have less activity against C. auris biofilms than deoxycholate amphotericin B. Our in vitro model provides evidence for intrinsic C. auris biofilm resistance to antifungal agents."

Journal

Do high MICs predict the outcome in invasive fusariosis? (PubMed, J Antimicrob Chemother) - "Our study did not show any correlation between MIC and mortality at 6 weeks in patients with IF."

Biomarker • Journal • Hematological Disorders • Neutropenia

Drug-drug interaction between itraconazole capsule and efavirenz in adults with HIV for talaromycosis treatment. (PubMed, J Antimicrob Chemother) - "Concomitant administration of itraconazole capsule with efavirenz significantly reduced itraconazole and hydroxyitraconazole exposures. The clinical impact of this drug-drug interaction on talaromycosis treatment or prophylaxis in the era of potent ART needs further evaluation."

Clinical • Journal • Human Immunodeficiency Virus • Infectious Disease

Candida duobushaemulonii: An Old But Unreported Pathogen. (PubMed, J Fungi (Basel)) - "We found that one isolate previously identified in 1996 as Candida intermedia was C. duobushaemulonii, being one of the oldest isolates of this species described to date. We also found that this isolate had reduced susceptibility to fluconazole, itraconazole, and amphotericin B."

Journal • Candidiasis

Physiologically Based Precision Dosing Approach for Drug-Drug-Gene Interactions: A Simvastatin Network Analysis. (PubMed, Clin Pharmacol Ther) - "Here, a whole-body PBPK network of simvastatin was established, including three polymorphisms (SLCO1B1 (rs4149056), ABCG2 (rs2231142), and CYP3A5 (rs776746)) and four perpetrator drugs (clarithromycin, gemfibrozil, itraconazole, and rifampicin). Furthermore, the network model is easily extendable to cover additional DDGIs. Overall, the presented work is a first step toward a vision on comprehensive precision dosing based on PBPK models in daily clinical practice, where it could drastically reduce the risk of ADRs."

Journal • ABCG2 • CYP3A5

Differential impacts of azole antifungal drugs on the pharmacokinetic profiles of dasatinib in rats by LC-MS-MS. (PubMed, Curr Drug Metab) - "These data indicated that ketoconazole, posaconazole and voriconazole should be cautiously co-administered with dasatinib or close therapeutic drug monitoring of dasatinib concentration, which might cause the drug-drug interaction."

Journal • PK/PD data • Preclinical • Hematological Malignancies • Leukemia • Oncology

Prediction of itraconazole minimum inhibitory concentration for Fonsecaea pedrosoi using Fourier Transform Infrared Spectroscopy (FTIR) and chemometrics. (PubMed, PLoS One) - "This is the first study to propose the use of FTIR and chemometric analyses according to the M38-A2 CLSI protocol to predict ITC MICs of F. pedrosoi. Considering the limitations of the conventional methods to test in vitro susceptibility, this is a promising methodology to be used for other microorganisms and drugs."

Journal • Dermatology

Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs. (PubMed, PLoS One) - "We previously identified a series of oxysterol derivatives and phenanthridine-6-one derivatives as pharmacological chaperones, i.e., small molecules that can rescue folding-defective phenotypes of mutated NPC1, opening up an avenue to develop chaperone therapy for Niemann-Pick disease type C. Here, we present an improved image-based screen for NPC1 chaperones and we describe its application for drug-repurposing screening. We identified some azole antifungals, including itraconazole and posaconazole, and a kinase inhibitor, lapatinib, as probable pharmacological chaperones...Competitive photo-crosslinking experiments suggested that oxysterol-based chaperones and itraconazole share the same or adjacent binding site(s), and the sensitivity of the crosslinking to P691S mutation in the sterol-sensing domain supports the hypothesis that their binding sites are located near this domain. Although the azoles were less effective in reducing cholesterol accumulation than the..."

Journal • CNS Disorders • Frontotemporal Lobar Degeneration • Metabolic Disorders

A case report of aspergillosis accompanied by saccular bronchodilation after bronchial thermoplasty in a 19-year-old woman. (PubMed, BMC Pulm Med) - "It is necessary to consider the possibility of respiratory tract infections including fungal infections after BT. Detailed observations of the entire bronchus and sample collection for microbial culture are highly recommended."

Clinical • Journal • Asthma • Infectious Disease • Respiratory Diseases

Development and validation of an in vitro resazurin-based susceptibility assay against Madurella mycetomatis. (PubMed, Antimicrob Agents Chemother) - "Lowest MICs were obtained for itraconazole and posaconazole (MIC50 of 0.016 μg/mL) followed by voriconazole (MIC50 of 0.063 μg/mL). Amphotericin B, micafungin, and terbinafine appeared much less effective."

Journal • Preclinical