scholarly journals MSG-10: a Phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis

2019 ◽  
Vol 74 (10) ◽  
pp. 3056-3062 ◽  
Author(s):  
Andrej Spec ◽  
John Pullman ◽  
George R Thompson ◽  
William G Powderly ◽  
Ellis H Tobin ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Standard Of Care ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Global Response ◽  
Target Exposure ◽  
Dosing Regimens ◽  
Orally Bioavailable ◽  
The One ◽  
Synthase Inhibitor

Abstract Objectives To evaluate the safety and efficacy of two dosing regimens of oral ibrexafungerp (formerly SCY-078), a novel orally bioavailable β-glucan synthase inhibitor, in subjects with invasive candidiasis versus the standard of care (SOC) and to identify the dose to achieve target exposure (15.4 μM·h) in >80% of the intended population. Methods In a multinational, open-label study, patients with documented invasive candidiasis were randomized to receive step-down therapy to one of three treatment arms: two dosing regimens of novel oral ibrexafungerp or the SOC treatment following initial echinocandin therapy. Plasma samples were collected to evaluate exposure by population pharmacokinetic (PK) modelling. Safety was assessed throughout the study and global response at the end of treatment. Results Out of 27 subjects enrolled, 7 received ibrexafungerp 500 mg, 7 received ibrexafungerp 750 mg and 8 received the SOC. Five did not meet criteria for randomization. Population PK analysis indicated that an ibrexafungerp 750 mg regimen is predicted to achieve the target exposure in ∼85% of the population. The rate of adverse events was similar among patients receiving ibrexafungerp or fluconazole. Similar favourable response rates were reported among all groups: 86% (n = 6) in the ibrexafungerp 750 mg versus 71% (n = 5) in both the fluconazole and ibrexafungerp 500 mg treatment arms. The one subject treated with continued micafungin had a favourable global response. Conclusions The oral ibrexafungerp dose estimated to achieve the target exposure in subjects with invasive candidiasis is 750 mg daily. This dose was well tolerated and achieved a favourable global response rate, similar to the SOC.

scholarly journals Safety and Efficacy of Anidulafungin in the Treatment of Invasive Candidiasis in Children

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S79-S79
Author(s):  
Emmanuel Roilides ◽  
Fabianne Carlesse ◽  
Heidi Leister-Tebbe ◽  
Umberto Conte ◽  
Jean Li Yan ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Venous Catheter ◽  
Success Rates ◽  
Open Label ◽  
Global Response ◽  
First Line Therapy ◽  
A Site ◽  
To Receive ◽  
Research Grant

Abstract Background Treatment with an echinocandin is recommended as first-line therapy of patients with invasive candidiasis including candidemia (ICC). Little is known about the efficacy and safety of anidulafungin (ANID) for the management of ICC in children. Methods Subjects aged 1 months to 17 years with ICC were enrolled into a prospective, open-label, non-comparative, multi-center, global study (NCT00761267) to receive ANID (3 mg/kg on day 1, 1.5 mg/kg daily thereafter). An interim analysis was completed in children 2–17 years. Subjects were to receive ANID for at least 10 days up to 35 days. A central venous catheter suspected as a site of infection was to be removed. A switch to oral fluconazole could be made after day 10. Treatment was required for at least 14 days after two negative cultures separated by 24 hours. Efficacy, based on a determination of global response (combination of clinical and microbiological response), was assessed at end of IV treatment (EOIVT), end of treatment (EOT), 2- and 6-week follow-up. Safety was assessed through 6-week follow-up. Results In total, 48 subjects (18, 2 to <5 years; 30, 5–17 years) received at least 1 dose of ANID (mean 11 days; range 1–35 days) and were assessed for safety. Forty-seven subjects had microbiologically confirmed ICC and were evaluated for efficacy. The most common baseline pathogens were C. albicans (38%) and C. parapsilosis (26%). Forty-four (93.6%) subjects had candidemia only. Global response success rates at EOIVT and EOT were 72.3 and 74.5%, respectively. All subjects reported at least one treatment emergent adverse event (AE) with diarrhea (22.9%), vomiting (22.9%), and pyrexia (18.8%) being most frequent. Five subjects discontinued treatment due to AEs of which four [increased transaminases (2), vomiting, pruritus generalis] were considered related to ANID. All-cause mortality by the 2- and 6-week follow-up visit was 12.5 and 14.6%, respectively. Of the seven deaths during the study, one was considered related to ICC; two were related to disease progression (Ewing’s sarcoma, medulloblastoma); the remaining were related to other conditions (intracranial hemorrhage, sepsis/septic shock, and respiratory failure). Conclusion Anidulafungin was effective with an acceptable tolerability and safety profile in children aged 2–17 years diagnosed with ICC. Disclosures E. Roilides, Pfizer: Grant Investigator, Investigator, Research Contractor and Speaker’s Bureau, Grant recipient, Research grant and Speaker honorarium. H. Leister-Tebbe, Pfizer: Employee, Salary. U. Conte, Pfizer Inc.: Employee, Salary. J. L. Yan, Pfizer: Employee, Salary. P. Liu, Pfizer: Employee, Salary. M. Tawadrous, Pfizer: Employee, Salary. J. Aram, Pfizer Inc.: Employee, Salary. F. Queiroz-Telles, Pfizer: Grant Investigator, Research grant

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav

2020 ◽  
Vol 75 (12) ◽  
pp. 3611-3618
Author(s):  
G Mellon ◽  
K Hammas ◽  
C Burdet ◽  
X Duval ◽  
C Carette ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Mixed Effect ◽  
Mean Values ◽  
Two Compartment Model ◽  
Amoxicillin Clavulanate ◽  
Dosing Regimens ◽  
Obese Subjects

Abstract Background Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. Materials and methods Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. Results Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT>MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). Conclusions Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

scholarly journals Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Iwein Gyselinck ◽  
◽  
Laurens Liesenborghs ◽  
Ewout Landeloos ◽  
Ann Belmans ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Cytokine Signaling ◽  
Nasopharyngeal Swab ◽  
The Novel ◽  
Proof Of Concept ◽  
Open Label ◽  
Novel Coronavirus

Abstract Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

scholarly journals A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in COVID-19 patients with Regular Intravenous Immunoglobulin Therapy

2021 ◽  
Author(s):  
Raman R S ◽  
Vijaykumar Bhagwan Barge ◽  
Anil Kumar Darivenula ◽  
Himanshu Dandu ◽  
Rakesh R Kartha ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Randomized Study ◽  
Standard Of Care ◽  
Immunoglobulin Therapy ◽  
Clinical Trial Registry ◽  
Open Label ◽  
Intravenous Immunoglobulin Therapy ◽  
Safety And Efficacy ◽  
Therapeutic Benefits ◽  
Wide Range

Abstract Background Currently, there is no specific drug for the treatment of COVID-19. Therapeutic benefits of intravenous immunoglobin (IVIG) have been demonstrated in wide range of diseases. The present study is conducted to evaluate the safety and efficacy of IVIG in the treatment of COVID-19 patients with moderate pneumonia. Methods An open-label, multicenter, comparative, randomized study was conducted on COVID-19 patients with moderate pneumonia. 100 eligible patients were randomized in 1:1 ratio either to receive IVIG + standard of care (SOC) or SOC. Results Duration of hospital stay was significantly shorter in IVIG group to that of SOC alone (7.7 Vs. 17.5 days). Duration for normalization of body temperature, oxygen saturation and mechanical ventilation were significantly shorter in IVIG compared to SOC. Percentages of patients on mechanical ventilation in two groups were not significantly different (24% Vs. 38%). Median time to RT-PCR negativity was significantly shorter with IVIG than SOC (7 Vs.18 days). There were only mild to moderate adverse events in both groups except for one patient (2%), who died in SOC. Conclusions IVIG was safe and efficacious as an adjuvant with other antiviral drugs in the treatment of COVID-19. The trial was registered under Clinical Trial Registry, India (CTRI/2020/06/026222).

Ferric Citrate Dosing in Iron Deficiency Anemia in Nondialysis-Dependent Chronic Kidney Disease

2021 ◽  
pp. 1-10
Author(s):  
Pablo E. Pergola ◽  
Diogo Belo ◽  
Paul Crawford ◽  
Moustafa Moustafa ◽  
Wenli Luo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Ferric Citrate ◽  
Deficiency Anemia ◽  
Open Label ◽  
Starting Dose ◽  
Dosing Regimens

<b><i>Introduction:</i></b> Ferric citrate (FC) is indicated as an oral iron replacement for iron deficiency anemia in adult patients with chronic kidney disease (CKD) not on dialysis. The recommended starting dose is one 1-g tablet three times daily (TID). This study investigated long-term efficacy and safety of different FC dosing regimens for treating anemia in nondialysis-dependent CKD (NDD-CKD). <b><i>Methods:</i></b> In this phase 4, randomized, open-label, multicenter study, patients with anemia with NDD-CKD (estimated glomerular filtration rate, ≥20 mL/min and &#x3c;60 mL/min) were randomized 1:1 to one FC tablet (1-g equivalent to 210 mg ferric iron) TID (3 g/day) or 2 tablets twice daily (BID; 4 g/day). At week 12, dosage was increased to 2 tablets TID (6 g/day) or 3 tablets BID (6 g/day) in patients whose hemoglobin (Hb) levels increased &#x3c;0.5 g/dL or were &#x3c;10 g/dL. Primary endpoint was mean change in Hb from baseline to week 24. <b><i>Results:</i></b> Of 484 patients screened, 206 were randomized and 205 received FC. Mean (standard deviation) changes from baseline in Hb at week 24 were 0.77 (0.84) g/dL with FC TID 3 g/day and 0.70 (0.98) g/dL with FC BID 4 g/day. <b><i>Discussion/Conclusions:</i></b> FC administered BID and TID for 48 weeks was safe and effective for treating anemia in this population, supporting potentially increased dosing flexibility.

scholarly journals High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly HIV-positive Ugandan adults: a phase II open-label randomised controlled trial

2021 ◽  
Author(s):  
Fiona V Cresswell ◽  
David B Meya ◽  
Enock Kagimu ◽  
Daniel Grint ◽  
Lindsey te Brake ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Geometric Mean ◽  
Standard Of Care ◽  
Hiv Positive ◽  
High Dose ◽  
Open Label ◽  
Dose Oral ◽  
Csf Levels

Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P&lt;0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p&lt;0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC

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)

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