Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND AND OBJECTIVES: Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references. METHODS: A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug. RESULTS: Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26]. CONCLUSION: Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

Effectiveness and safety of filgotinib in rheumatoid arthritis patients: data from the GISEA registry.

OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety profile of filgotinib, a JAK1 preferential inhibitor, in rheumatoid arthritis (RA) patients included in Italian GISEA (Group for the Study of Early Arthritis) registry. METHODS: Data from RA patients treated with filgotinib, recorded in the GISEA registry, were analysed. Disease activity scores and patient-reported outcomes (PROs) were assessed at baseline, as well as during 12-month follow-up. A difficult-to-treat (D2T) RA patient was defined according with EULAR criteria. Retention rate of filgotinib was estimated by the Kaplan-Meier method and factors influencing drug discontinuation were estimated by Cox regression models. RESULTS: 246 RA patients (female 89%, 57.6±12.2 years old) started filgotinib, mostly as second (22%) or further (43.9%) b/tsDMARDs line of treatment. At 3 and 12 months, 18.8% and 27.5% of patients achieved Clinical Diseases Activity Index based remission and 30.1% and 37.7% obtained a visual analogue scale of pain ≤20 (all p<0.01 vs. baseline). Filgotinib survival rate was 84.5% at the 6-month and 75.8% at 12-month follow-up, and was comparable either in monotherapy or combination therapy, and irrespective of glucocorticoid intake. b/tsDMARD naive patients had the lowest hazard ratio (HR) of filgotinib discontinuation (HR 0.29, 95%CI 0.14-0.64), while D2T-RA the highest (HR 1.82, 95%CI 1.01-3.3). Eight patients (3.3%) discontinued filgotinib due to adverse events. CONCLUSIONS: In an Italian real-life setting, filgotinib is confirmed to be safe and with a good effectiveness profile both in monotherapy and without glucocorticoids.

Efficacy and safety of filgotinib for ulcerative colitis: A real-world multicenter retrospective study in Japan.

BACKGROUND AND AIMS: While filgotinib, an oral Janus kinase (JAK) 1 preferential inhibitor, is approved for moderately to severely active ulcerative colitis (UC), real-world studies assessing its short- and long-term efficacy and safety are limited. METHODS: This is a multicenter, retrospective study of UC patients who started filgotinib between March 2022 and September 2023. The primary outcome was clinical remission, defined as a partial Mayo score ≤1 with a rectal bleeding score of 0, or Simple Clinical Colitis Activity Index (SCCAI) ≤2 with a blood-in-stool score of 0. Secondary outcomes included clinical response, corticosteroid-free remission, and endoscopic improvement. Outcomes were assessed at 10, 26, and 58 weeks based on patients with available follow-up. Adverse events were evaluated. RESULTS: We identified 238 UC patients and 54% had prior exposure to biologics/JAK inhibitors. The median baseline partial Mayo score and SCCAI were 5 (IQR 3-6) and 4 (IQR 2-7). Clinical remission rates based on per-protocol analysis at 10, 26, and 58 weeks were 47% (70/149), 55.8% (48/86), and 64.6% (31/48), respectively. At a median follow-up of 28 weeks (IQR 10-54) with a discontinuation rate of 39%, the rates of clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement were 39.9% (81/203), 54.7% (111/203), and 36.5% (74/203), and 43.5% (10/23), respectively. These rates were comparable between biologic/JAK inhibitor-naïve and -experienced patients. While three patients (1.3%) developed herpes zoster infection, no cases of thrombosis or death were reported. CONCLUSIONS: Real-world data demonstrate favourable clinical and safety outcomes of filgotinib for UC.

Selinexor in multiple myeloma.

INTRODUCTION: Selinexor, an XPO1 inhibitor, has emerged as a promising therapeutic option in the challenging landscape of relapsed/refractory multiple myeloma (RRMM). AREAS COVERED: This article provides a review of selinexor, with a focus on available clinical studies involving MM patients and its safety profile. Clinical trials, such as STORM and BOSTON, have demonstrated its efficacy, particularly in combination regimens, showcasing notable overall response rates (ORR) and prolonged median progressionfree survival (mPFS). Selinexor's versatility is evident across various combinations, including carfilzomibdexamethasone (XKd), lenalidomidedexamethasone (XRd), and pomalidomidedexamethasone (XPd), with efficacy observed even in tripleclass refractory and highrisk patient populations. However, challenges, including resistance mechanisms and adverse events, necessitate careful management. Realworld evidence also underscores selinexor's effectiveness in RRMM, though dose adjustments and supportive measures remain crucial. Ongoing trials are exploring selinexor in diverse combinations and settings, including pomalidomidenaïve patients and postautologous stem cell transplant (ASCT) maintenance. EXPERT OPINION: The evolving landscape of selinexor's role in the sequencing of treatment for RRMM, its potential in highrisk patients, including those with extramedullary disease, as revealed in the most recent international meetings, and ongoing investigations signal a dynamic era in myeloma therapeutics. Selinexor emerges as a pivotal component in multidrug strategies and innovative combinations.

Cushing syndrome and tertiary adrenal insufficiency from prolonged concomitant use of budesonide and posaconazole.

Budesonide is a 'non-absorbable' corticosteroid often used for gut graft versus host disease. Systemic exposure is usually minimal because of metabolism by cytochrome (CYP) 3A4 in enterocytes and the liver. However, concomitant use of posaconazole and voriconazole, inhibitors of CYP3A4 commonly used as antifungal prophylaxis in allograft patients receiving immunosuppression, can lead to substantial systemic steroid exposure. This paper describes a case of severe iatrogenic Cushing syndrome and tertiary adrenal insufficiency because of this interaction, highlighting the necessity for improved awareness of this phenomenon.

Efficacy and Safety of a Dispersible Tablet of GPO-Deferasirox Monotherapy among Children with Transfusion-Dependent Thalassemia and Iron Overload.

The study aimed to determine efficacy and safety of generic deferasirox monotherapy. Deferasirox was administered in transfusion-induced iron overloaded thalassemia. Efficacy was defined as responders and nonresponders by ≤ 15 reduced serum ferritin from baseline. Adverse events were also monitored. Fifty-two patients with mainly Hb E/ß-thalassemia at the mean (SD) age of 8.7 (4.1) years, were enrolled. The mean (SD) daily transfusion iron load was 0.47 (0.1) mg/kg and maximum daily deferasirox was 35.0 (6.2) mg/kg. Altogether, 52, 40 and 18 patients completed the first, second and third years of study, respectively. The median baseline serum ferritin 2,383 ng/mL decreased to 1,478, 1,038 and 1,268 ng/mL at the end of first, second and third years, respectively, with overall response rate at 73.1% (38/52). Patients with baseline serum ferritin >2,500 ng/mL showed a change in serum ferritin higher than those ≤2,500 ng/mL starting from the 9th month of chelation. Adverse events were found in 5 of 52 patients (9.6%) including transaminitis (n = 2), one each of proteinuria, rash and proximal tubular dysfunction which resolved after transient stopping or decreasing the chelation dose. Generic deferasirox was effective and safe among pediatric patients with transfusion-induced iron overloaded thalassemia.

The impact of chelation compliance in health outcome and health related quality of life in thalassaemia patients: a systematic review.

Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.

Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent ß-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial.

INTRODUCTION: Despite the improvement in medical management, many patients with transfusion-dependent ß-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent ß-thalassaemia with very high iron overload. METHODS AND ANALYSIS: This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent ß-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures. ETHICS AND DISSEMINATION: Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals. TRIAL REGISTRATION NUMBER: The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).

Cardiac effects of deferasirox in transfusion-dependent patients with myelodysplastic syndromes: TELESTO study.

Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Effectiveness and safety of filgotinib in rheumatoid arthritis: a real-life multicentre experience.

OBJECTIVES: We investigated the effectiveness and safety of filgotinib in a real-life multicentre cohort of rheumatoid arthritis (RA) patients. METHODS: RA patients were evaluated at baseline and after 12 and 24 weeks and were stratified based on previous treatments as biologic disease-modifying anti-rheumatic drug (bDMARD)-naive and bDMARD-insufficient responders (IR). Concomitant usage of methotrexate (MTX) and oral glucocorticoids (GC) was recorded. At each timepoint we recorded disease activity, laboratory parameters and adverse events. RESULTS: 126 patients were enrolled. 15.8% were bDMARD-naive (G0), while 84% were bDMARD-IR (G1). In G0, 45% of patients were in monotherapy (G2) and 55% were taken MTX (G3). In G1, 50% of patients were in monotherapy (G4) and 50% used MTX (G5).A significant reduction in all parameters at 12 weeks was observed; in the extension to 24 weeks the significant reduction was maintained for patient global assessment (PGA), examiner global assessment (EGA), visual analogue scale (VAS) pain, VAS fatigue, disease activity score (DAS)28- C-reactive protein (CRP) and CRP values. Filgotinib in monotherapy showed better outcomes in bDMARD-naive patients, with significant differences for patient reported outcomes (PROs) and DAS28-CRP. At 12 weeks, low disease activity (LDA) and remission were achieved in a percentage of 37.2 % and 10.7 % by simplified disease activity index (SDAI), 42.6 % and 5.7 % by clinical disease activity index (CDAI), 26.8 % and 25.2 % by DAS28-CRP, respectively. A significant decrease in steroid dose was evidenced in all patients. We observed a major adverse cardiovascular event in one patient and an increase in transaminase in another. No infections from Herpes Zoster were reported. CONCLUSIONS: Our real-world data confirm the effectiveness and safety of filgotinib in the management of RA, especially in bDMARD-naive patients.

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial.

Importance: Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease. Objective: To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants: A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions: Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures: The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results: Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance: In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT01953588.

Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial.

BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. FINDINGS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). INTERPRETATION: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. FUNDING: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.

Characterization and real-live results of nebulized voriconazole: A single-center observational study.

OBJECTIVE: Pulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. METHOD: This is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. RESULTS: The pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, 9 adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12-24 h. The median duration of treatment was 139 (range: 26-911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. CONCLUSION: Voriconazole nebulization is well-tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy.

Difference in immunosuppressant dose requirement when transitioning to isavuconazole from other azoles in thoracic transplant recipients.

The triazole antifungal isavuconazole (ISAVU) is used for prevention and treatment of fungal infections in solid organ transplant (SOT). SOT recipients commonly need to transition from one azole to another due to breakthrough infection, toxicity, or other reasons. The purpose of our study was to evaluate the effect of ISAVU on immunosuppressant concentrations in thoracic transplant recipients when ISAVU was started de novo or transitioned from another azole. We conducted a single-center retrospective cohort study including 68 patients (51 lung, 14 heart, and 3 heart/lung transplant). Concentration to dosage ratios (C/D) of immunosuppressants were assessed at baseline, day 3, and weekly for 9 weeks. When starting ISAVU de novo, we observed a temporary doubling of tacrolimus exposure. Cyclosporine and sirolimus required dose decreases. Tacrolimus C/D increased by 110% at day 3 in patients started on ISAVU de novo then returned to baseline C/D ± 17% weeks 2-9 (n = 8). One cyclosporine patient started on ISAVU de novo had variable C/D, and C/D increased by 219% ± 72% in 2 sirolimus patients. When transitioning from other azoles, tacrolimus and cyclosporine required about twice the initial dose. After week 1, tacrolimus C/D decreased by 53% ± 6% in patients transitioned from posaconazole (n = 33), voriconazole (n = 14), or fluconazole (n = 2). Cyclosporine C/D decreased by 45% ± 16% in patients transitioning from other azoles (posaconazole [n = 2], voriconazole [n = 2], fluconazole [n = 1]). Sirolimus C/D decreased by 73% ± 13% in patients transitioned from posaconazole (n = 7). Aside from the initial loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in adjustments for the 4-week period after initiating antifungal therapy with ISAVU or switching from another agent.

Supratherapeutic posaconazole concentrations associated with hyperlipidemia in a patient with HSCT.

Posaconazole is a potent, extended-spectrum triazole antifungal used for the treatment and prophylaxis of serious fungal infections. Previous reports have demonstrated hyperlipidemia resulted in significant changes in posaconazole pharmacokinetics and tissue distribution in rats. However, the effect of hyperlipidemia on the pharmacokinetics of posaconazole in patients has not yet been reported. We report a case of a 34-year-old woman who experienced a supratherapeutic posaconazole trough concentration (PTC) associated with hyperlipidemia after haploidentical hematopoietic stem cell transplantation (HSCT). The patient was admitted 13 months after HSCT for recurrent cough and sputum. She was treated with caspofungin due to developing invasive fungal infection of Candida tropicalis. After 10 days, caspofungin was discontinued due to the poor therapeutic efficacy and replaced with amphotericin B. Afterwards, the condition of the patient improved significantly and she was switched to daily oral posaconazole tablet. Therapeutic drug monitoring (TDM) of posaconazole showed a PTC was 3.2 mg/L. After discharge, she continued to receive posaconazole tablet as antifungal treatment. Two months later, laboratory tests at outpatient showed her blood lipid levels were significantly elevated and PTC was increased to 9.38 mg/L. Therefore, the posaconazole tablet was discontinued and she received lipid-lowering therapy. A few days later, the PTC was down to 5.22 mg/L. No medication errors and significant drug interactions were found. Hence, supratherapeutic PTC for this patient may be caused by hyperlipidemia which altered pharmacokinetics of posaconazole. Our findings highlight the need for close TDM in order to avoid supratherapeutic PTC if hyperlipidimia occurs during posaconazole use.

Comparative study of posaconazole and voriconazole for primary antifungal prophylaxis in patients with pediatric acute leukemia.

Posaconazole and voriconazole are commonly used for preventing invasive fungal disease (IFD), but few studies compared posaconazole with voriconazole for primary antifungal prophylaxis (PAP) in pediatric acute leukemia. To compare posaconazole with voriconazole for PAP in pediatric acute leukemia. This retrospective observational study enrolled pediatric patients with non-M3 acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) between December 2017 and November 2019 in the Second Affiliated Hospital of Anhui Medical University. The patients received voriconazole or posaconazole for PAP. The primary outcome was the breakthrough of IFD. The secondary outcome was the overall survival (OS) and IFD-free survival of patients. A total of the 275 patients were enrolled, of which 120 patients taking voriconazole (43.6%) and 155 patients taking posaconazole (56.4%). The breakthrough of IFD occurred in 19 (15.8%) patients taking voriconazole and in 12 (7.7%) patients taking posaconazole (P = 0.035). There was no significant differences in IFD-free survival (P = 0.336) or OS (P = 0.069) between the patients taking voriconazole and posaconazole. In the subgroup of AML patients, the OS of patients taking posaconazole was better than those receiving voriconazole (P = 0.017). Posaconazole and voriconazole were comparable for PAP in patients with pediatric acute leukemia regarding the OS and IFD-free survival, but posaconazole might achieve a lower IFD breakthrough rate.

Association of Torsade de Pointes and QT Prolongation With Antifungal Triazoles: Analysis Using a Pharmacovigilance Database.

BACKGROUND/AIM: Torsade de pointes (TdP)/QT prolongation (QTP) is one of the most life-threatening adverse effects of antifungal triazoles. The aim of the present study was to evaluate the association of antifungal triazoles with TdP/QTP by age group and the profile of the time of TdP/QTP onset by analyzing the spontaneous adverse event database for Japan. PATIENTS AND METHODS: Data registered in the Japanese Adverse Drug Event Report database (JADER) from April 2004 to March 2022 were analyzed. The association between the administration of antifungal triazoles and TdP/QTP according to age was evaluated using an adjusted reporting odds ratio (aROR). In addition, the time-to-onset of TdP/QTP after antifungal triazole treatment was analyzed using the Weibull distribution according to the route of administration. RESULTS: Antifungal triazole treatment was associated with TdP/QTP (aROR=1.77, 95% confidence interval=1.52-2.07). In the subgroup analyses by age group, antifungal triazole treatments in patients ≤29 years old and ≥50 (except ≥90) years old were associated with TdP/QTP. The medians (quartiles) of time-to-onset for intravenous and oral antifungal triazole treatment were 8 (6-12) and 23 (8-86) days, respectively. In addition, the shape parameter in the Weibull distribution analysis of oral triazole treatment revealed that the hazard exhibited an early failure profile. CONCLUSION: TdP/QTP is associated with antifungal triazoles even in young patients, and patients should be monitored for the development of TdP/QTP, especially early after the initiation of treatment.

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. RESULTS: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. CONCLUSIONS: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.