scholarly journals 637. Outcomes by Body Mass Index (BMI) in the STRIVE Phase 2 Trial of Once-Weekly Rezafungin for Treatment of Candidemia and Invasive Candidiasis Compared with Caspofungin

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S378-S379
Author(s):  
Jose A Vazquez ◽  
Shawn Flanagan ◽  
Peter Pappas ◽  
George R Thompson ◽  
Taylor Sandison ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Drug Exposure ◽  
Clinical Signs ◽  
Area Under The Curve ◽  
Panel Member ◽  
Invasive Fungal Disease ◽  
Invasive Disease ◽  
Marrow Transplant ◽  
Important Variable ◽  
Phase 2

Abstract Background There is increasing evidence of antifungal underdosing in the treatment of invasive disease, particularly in special populations such as the obese. Body size is often an important variable affecting drug exposure, and pharmacokinetic (PK) models of antifungal dosing have suggested size-based dose adjustments to achieve target drug exposure. Rezafungin (RZF) is a novel echinocandin in Phase 3 development for treatment of candidemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients. Distinctive PK properties of RZF (e.g., long half-life, extensive tissue distribution, and front-loaded drug exposure) lend themselves to RZF once-weekly (QWk) dosing and antifungal efficacy. In this sub-analysis of the Phase 2 STRIVE trial of RZF in the treatment of candidemia and/or IC, outcomes based on patient BMI were evaluated. Methods The STRIVE trial (NCT02734862) compared the safety and efficacy of RZF QWk compared with once-daily caspofungin (Fig. 1). For this subanalysis, data were stratified by BMI categories of < 30 kg/m2 and ≥ 30 kg/m2. Efficacy (overall response [resolution of clinical signs of infection + mycological eradication], mycological response, and investigator assessment of clinical response) and safety (treatment-emergent adverse events [TEAEs]) endpoints by treatment group were evaluated, as well as PK data (area under the curve [AUC]) from RZF-treated patients. Figure 1. Results Mean BMI values were similar across treatment arms (26.9 kg/m2 in RZF Group 1 and 26.8 kg/m2 in RZF Group 2 and CAS arms). Efficacy outcomes at Day 14 were similar between BMI categories (Table 1). Rates of TEAEs were generally similar between BMI categories as well (Table 2), with no concerning safety trends. Following one dose of RZF 400 mg (Week 1), the ranges of AUCs by BMI category overlapped and there was a minor mean difference of ~20% (lower for those with BMI ≥ 30 kg/m2) (Fig. 2). Table 1 Table 2 Figure 2. Conclusion The safety, efficacy, and PK of RZF in the Phase 2 STRIVE trial was consistent across BMI categories. These results suggest that dose adjustments in obese patients are not necessary. These findings contribute to the evaluation of RZF in a range of patient populations and its ongoing development. Disclosures Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder) Patrick M. Honore, MD, PhD, FCCM, Cidara Therapeutics, Inc. (Scientific Research Study Investigator)

Rezafungin: a novel antifungal for the treatment of invasive candidiasis

2021 ◽  
Vol 16 (1) ◽  
pp. 27-36
Author(s):  
Young Yoon Ham ◽  
James S Lewis ◽  
George R Thompson
Keyword(s):  
Invasive Candidiasis ◽  
Half Life ◽  
Drug Exposure ◽  
Invasive Fungal Disease ◽  
Marrow Transplant ◽  
Phase Iii ◽  
Candida Auris ◽  
Candida Spp ◽  
Phase Iii Trials ◽  
Exceptional Stability

Rezafungin is a novel echinocandin with exceptional stability and solubility and a uniquely long half-life allowing for front-loaded drug exposure with once-weekly dosing. Rezafungin has been shown comparable to other echinocandins, with activity against Candida spp. and Aspergillus spp. including subsets of echinocandin-resistant Candida auris and azole-resistant Aspergillus isolates. Available clinical data show robust safety and promising efficacy. Phase III trials will provide data on efficacy of rezafungin for the treatment of candidemia and invasive candidiasis and for the prevention of invasive fungal disease in blood and bone marrow transplant recipients. Rezafungin is a promising new candidate in the antifungal arsenal that opens up clinical possibilities based on its impressive half-life, such as early hospital discharge for stable patients and use as prophylaxis in immunocompromised patients.

scholarly journals Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Laura L. Kovanda ◽  
Francisco M. Marty ◽  
Johan Maertens ◽  
Amit V. Desai ◽  
Christopher Lademacher ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Drug Exposure ◽  
Area Under The Curve ◽  
Invasive Fungal Disease ◽  
Oral Formulation ◽  
Water Soluble ◽  
Parameter Estimates ◽  
Two Phase ◽  
Population Pk ◽  
The Impact

ABSTRACT Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUCave]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.

scholarly journals 1174. Phase 2 STRIVE Clinical Trial of Rezafungin for Treatment of Candidemia and/or Invasive Candidiasis Demonstrates Consistent Trough Concentrations Across Diverse Patient Populations

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S612-S613
Author(s):  
Shawn Flanagan ◽  
Christopher M Rubino ◽  
Taylor Sandison
Keyword(s):  
Body Weight ◽  
Invasive Candidiasis ◽  
Fungal Infections ◽  
Standard Of Care ◽  
Geographic Region ◽  
Continuous Variables ◽  
Phase 2 ◽  
Double Blind ◽  
Wide Range ◽  
Diverse Patient Populations

Abstract Background Rezafungin is a novel echinocandin antifungal in development for treatment as well as prevention (prophylaxis) of invasive fungal infections. STRIVE (NCT02734862) is a global, randomized, double-blind, placebo-controlled, Phase 2 trial evaluating safety and efficacy of IV rezafungin once weekly (QWk) for treatment of candidemia and/or invasive candidiasis compared with standard-of-care (IV caspofungin once daily with optional oral stepdown). Here we report pharmacokinetic (PK) data from the completed STRIVE trial analyzed by patient demographics at baseline. Methods Rezafungin Day 8 trough (Cmin) concentrations from patients treated with rezafungin were summarized categorically by race (black or white), sex (male or female), and geographic region (North America [NA], or Europe [EU]), or plotted versus continuous variables of age, body weight, body mass index (BMI), and body surface area (BSA). As the first dose of rezafungin was 400 mg for all rezafungin-treated patients, data from both dose groups (Group 1: 400 mg QWk; Group 2: 400 mg in Week 1 followed by 200 mg QWk) were combined in this analysis. Results Rezafungin mean Cmin (SD) values were 1.8 (0.7) and 2.3 (1.2) in black and white patients, 1.9 (1.0) and 2.6 (1.2) in males and females, and 1.9 (0.6) and 2.4 (1.3) in patients from NA and EU. There were small differences in point estimates between the groups, but there was a great deal of overlap and the differences are not expected to be clinically meaningful (Figure). Similarly, no trends in Cmin values were observed across a range of ages (20-80 years), weights (~40-155 kg), BMI (~15-65 kg/m2), and BSA (~1.4-2.4 m2). Figure Conclusion No meaningful differences in rezafungin Cmin values were observed in patients grouped by sex, race, or geographic region, or across a wide range of patient factors, including age and body weight and size. These findings indicate that a single rezafungin dose regimen can be expected to provide consistent PK across diverse patient populations. Disclosures Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Christopher M. Rubino, PharMD, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

scholarly journals 43. A Pharmacoepidemiologic Evaluation of Echinocandin Use

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S45-S45
Author(s):  
Jinhee Jo ◽  
Joshua Hendrickson ◽  
Anne J Gonzales-Luna ◽  
Nicholas D Beyda ◽  
Kevin W Garey
Keyword(s):  
Hospital Admission ◽  
Invasive Candidiasis ◽  
Research Study ◽  
Medical Center ◽  
Significant Proportion ◽  
Scientific Research ◽  
Panel Member ◽  
Research Support ◽  
Study Investigator ◽  
Days Of Therapy

Abstract Background Invasive candidiasis (IC) is a common healthcare-associated infection. Rates of IC caused by drug-resistant Candida spp., designated by the CDC as a serious threat, are increasing, and Candida auris alone was recently added as an urgent threat. Echinocandins are guideline-preferred for the treatment of invasive candidiasis due to in vitro potency, a favorable toxicity profile, and convenient dosing. The purpose of this study was to perform a pharmacoepidemiologic analysis on patterns of echinocandin use at a large, quaternary care medical center. Methods Data reporting echinocandin use, pharmacy data, and clinical microbiologic data obtained from 2017–19 were pooled. Monthly days of therapy (DOT) per 1,000 patient days were calculated during the study period along with number of unique orders. Investigators evaluated the proportion of echinocandin-treated patients with or without positive Candida cultures; the relationship between echinocandin use and hospital admission and discharge dates was also evaluated. Results Echinocandin monthly DOT/1,000 patient days present averaged 26 (± 5) DOT and did not change appreciably during the study period. Of the patients with microbiologic evidence of Candida, 842 (51%) received echinocandin courses. Length of echinocandin therapy was significantly longer for patients with positive Candida cultures (5.5 ± 5.9 days) compared to those without positive cultures (3.9 ± 5.0 days; p< 0.001). Of 1,659 echinocandin courses evaluated, 549 courses (33%) were initiated within 2 days of hospital admission and the average time from hospital admission to echinocandin start was 9 (± 13) days. A total of 505 (24%) echinocandin courses were continued until the day of discharge. Conclusion The rate of echinocandin use did not change appreciably during the study period. A significant proportion of echinocandin courses were either started upon hospital admission or were continued until the day of discharge. Further studies to evaluate antifungal stewardship opportunities for the echinocandin pharmacologic class are warranted. Disclosures Nicholas D. Beyda, PharmD, BCPS, Astellas (Advisor or Review Panel member)Cidara (Grant/Research Support, Scientific Research Study Investigator) Kevin W. Garey, PharMD, MS, FASHP, Merck & Co. (Grant/Research Support, Scientific Research Study Investigator)

scholarly journals Silent Mastoiditis Associated with Pneumococcal Meningitis

2021 ◽  
Vol 27 (2) ◽  
pp. 1-6
Author(s):  
Ashikin Mohd Nordin ◽  
Jean Jun Ong ◽  
Juriza Ismail ◽  
Norazlin Kamal Nor ◽  
Sau Wei Wong ◽  
...  
Keyword(s):  
Brain Imaging ◽  
Pneumococcal Meningitis ◽  
Wide Spectrum ◽  
Clinical Signs ◽  
Invasive Disease ◽  
Upper Respiratory Tract ◽  
Slow Recovery ◽  
Acute Mastoiditis ◽  
Focus Of Infection ◽  
Upper Respiratory

Streptococcus pneumoniae (S pneumoniae) can cause a wide spectrum of diseases which includes upper respiratory tract infection as well as more severe invasive disease such as meningitis. Meningitis may be caused by invasion of the organism through the blood brain barrier, either via haematological spread or from an adjacent focus of infection such as the ears. We describe two infants with pneumococcal meningitis and silent mastoiditis. They both presented with a classical history to suggest meningitis with no apparent focus of infection. A brain imaging was done in the first infant to look for the underlying cause of his focal seizure and in the second infant, to assess for complications of meningitis, as he had a slow recovery. While they did not have any clinical signs to point towards the diagnosis, they were both diagnosed to have acute mastoiditis from brain imaging. We would like to highlight the importance of brain imaging in excluding silent mastoiditis in infants with meningitis, particularly in those whose clinical course appears atypical.

scholarly journals Alterations of human lung and gut microbiome in non-small cell lung carcinomas and distant metastasis

2020 ◽  
Author(s):  
Hui Lu ◽  
Na L. Gao ◽  
Chunhua Wei ◽  
Jiaojiao Wang ◽  
Fan Tong ◽  
...  
Keyword(s):  
Distant Metastasis ◽  
Mixed Models ◽  
Area Under The Curve ◽  
Disease Diagnosis ◽  
Invasive Disease ◽  
Small Cell ◽  
Small Cell Lung ◽  
Microbial Biomarkers ◽  
Distinct Disease ◽  
Nsclc Patients

AbstractBackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Although dysbiosis of lung and gut microbiota have been associated with NSCLC, their relative contributions are unclear; in addition, their roles in distant metastasis (DM) are still illusive.ResultsWe surveyed the fecal and sputum (as a proxy for lung) microbiota in healthy controls and NSCLC patients of various stages, and found significant perturbations of gut- and sputum-microbiota in patients with NSCLC and DM. Machine-learning models combining both microbiota (mixed models) performed better than either dataset in patient stratification, with the highest area under the curve (AUC) value of 0.842. Sputum-microbiota contributed more than the gut in the mixed models; in addition, sputum-only models performed similarly to the mixed models in most cases. Several microbial-biomarkers were shared by both microbiota, indicating their similar roles at distinct body sites. Microbial-biomarkers of distinct disease stages were mostly shared, suggesting biomarkers for distant metastasis could be acquired early. Furthermore, Pseudomonas aeruginosa, a species previously associated with wound infections, was significantly more abundant in brain metastasis, indicating distinct types of DMs could have different microbial-biomarkers.ConclusionOur results indicate that alterations of sputum-microbiota have stronger relationships with NSCLC and distant metastasis than the gut, and strongly support the feasibility of metagenome-based non-invasive disease diagnosis and risk evaluation.

scholarly journals Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer's Perspective

2021 ◽  
Vol 11 ◽  
Author(s):  
Tong Zhu
Keyword(s):  
Drug Development ◽  
Drug Exposure ◽  
Phase 1 ◽  
Drug Candidate ◽  
Phase 2 ◽  
Medical Needs ◽  
Clinical Drug Development ◽  
Human Pharmacology ◽  
Exposure Target ◽  
Target Binding

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

scholarly journals Detection of Aspergillus species in bone marrow transplant patients

2010 ◽  
Vol 4 (08) ◽  
pp. 511-516 ◽  
Author(s):  
Parisa Badiee ◽  
Abdolvahab Alborzi
Keyword(s):  
Bone Marrow ◽  
Real Time ◽  
Bone Marrow Transplant ◽  
Real Time Pcr ◽  
Clinical Signs ◽  
Marrow Transplant ◽  
Aspergillus Species ◽  
Pcr Assay ◽  
Blood Samples ◽  
Transplant Patients

Introduction:  Invasive aspergillosis is a severe complication of cytotoxic chemotherapies and bone marrow transplantation (BMT). The aim of this study was to assess the utility of a real-time PCR assay for the early diagnosis of Aspergillus species in blood samples from BMT patients. Methodology: Blood specimens (n = 993) from patients (n = 82) scheduled for BMT were collected prior to transplant and for 100 days post transplantation.  The specimens were later tested using an Aspergillus-specific real-time PCR assay. Cultures of clinical samples, along with sonography and computerized tomographic scans, were performed as standard of care. Results: Aspergillus DNA was positive in 94 sequential blood samples from 13 patients with clinical and radiological signs of infection. Samples from three of these patients were PCR-positive for Aspergillus in the first week of admission, prior to transplantation. Four patients with aspergillosis were cured with antifungal agents and nine died. An additional 12 patients without clinical signs of infection were PCR-positive on one occasion each, while two patients with clinical signs of infection were PCR-negative. Compared to routine methods of aspergillosis diagnosis, the respective sensitivity, specificity, negative, and positive predictive values of the PCR method by patient were 86.6%, 82%, 96.5% and 52%. Conclusions: The results show that Aspergillus infections in the blood of bone marrow transplant patients can be dectected by PCR methods. Early detection of Aspergillus infections by PCR has the potential to positively impact patient mortality rate and provide cost savings to hospitals.

Decision Support Tool Identifies Ulcerative Colitis Patients Most Likely to Achieve Remission With Vedolizumab vs Adalimumab

2021 ◽  
Author(s):  
Parambir S Dulai ◽  
Emily C L Wong ◽  
Walter Reinisch ◽  
Jean-Frederic Colombel ◽  
John K Marshall ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Decision Support ◽  
Confidence Interval ◽  
Drug Exposure ◽  
Area Under The Curve ◽  
Decision Support Tool ◽  
Support Tool ◽  
Predicted Probability ◽  
Baseline Probability ◽  
Probability Of Response

Abstract Background & Aims We have previously validated a clinical decision support tool (CDST) (vedolizumab CDST [VDZ-CDST]) for clinical and endoscopic remission with VDZ in ulcerative colitis (UC). We aim to expand the validation for predicting histoendoscopic mucosal improvement (HEMI) with VDZ vs adalimumab (ADA). Methods In a post hoc analysis of a clinical trial for VDZ vs ADA in moderate to severe UC (VARSITY trial; NCT02497469), comparative accuracy was evaluated for the VDZ-CDST among an external validation cohort of VDZ- and ADA-treated patients for week 52 HEMI (Mayo endoscopic subscore 0-1 and Geboes score <3.2). Comparative effectiveness of VDZ and ADA was assessed after stratifying the cohort by baseline probability of response to VDZ using the VDZ-CDST. Results A total of 419 patients were included. The majority of patients enrolled in the VARSITY trial had a high (61%) or intermediate (29%) baseline predicted probability of response to VDZ. The baseline VDZ-CDST score was significantly more likely to predict week 52 HEMI for VDZ (area under the curve , 0.712; 95% confidence interval, 0.636-0.787) relative to ADA-treated patients (area under the curve, 0.538; 95% confidence interval, 0.377-0.700; P < .001 for AUC comparison). A significant (P < .001) association was observed between the VDZ-CDST and measured VDZ drug exposure over 52 weeks. Superiority of VDZ to ADA was only observed in patients with a high baseline predicted probability of response to VDZ. Conclusions Superiority of VDZ to ADA is dependent on baseline probability of response, and a VDZ-CDST is capable of identifying UC patients most appropriate for VDZ vs ADA.

scholarly journals Rezafungin versus Caspofungin in a Phase 2, Randomized, Double-Blind Study for the Treatment of Candidemia and Invasive Candidiasis- The STRIVE Trial

2020 ◽  
Author(s):  
George R Thompson ◽  
Alex Soriano ◽  
Athanasios Skoutelis ◽  
Jose A Vazquez ◽  
Patrick M Honore ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Double Blind Study ◽  
Phase 2 ◽  
Double Blind ◽  
Once Daily ◽  
Secondary Endpoints ◽  
Intent To Treat ◽  
Cure Rates ◽  
Treat Population

Abstract Background Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). Methods Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤ 4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. Results Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. Conclusions RZF was safe and efficacious in the treatment of candidemia and/or IC.

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