501 Clinical PK of XW10172 for Once Nightly Therapy in Patients with Narcolepsy or Sleep Disorders in Neurodegenerative Diseases

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A197-A198
Author(s):  
Daniel Canafax ◽  
William Xiang ◽  
Jia-Ning Xiang
Keyword(s):  
Adverse Events ◽  
Neurodegenerative Diseases ◽  
Sleep Disorders ◽  
Vital Signs ◽  
Immediate Release ◽  
Sodium Oxybate ◽  
Time Data ◽  
Dose Administration ◽  
Pharmacologic Effect ◽  
Study Participants

Abstract Introduction Patients with narcolepsy and patients with sleep disorders secondary to neurodegenerative diseases have been shown to respond to oxybate. To overcome the limitations of current oxybate therapies, we designed XW10172, a new chemical entity and GABA-B agonist with no sodium or other cation content and for once nightly dosing. The objectives of two clinical studies were to assess the XW10172 pharmacokinetics (PK), pharmacodynamics (PD) and safety/tolerability in normal study participants. Methods Two XW10172 studies in healthy participants assessed ascending single and multiple doses, comparison to sodium oxybate in immediate release (IR) and extended release (ER) formulations. PK parameters were calculated from concentration vs. time data. Safety and tolerability were assessed by monitoring adverse events, laboratory tests, and vital signs. Results To date, 84 study participants received XW10172 and the PK from single and multiple dose administration showed doses of 0.1 to 7.25 g had a mean oxybate half-life range of 0.5 to 1.3 hours. Oxybate levels from the drug were about 6-fold higher than XW10172 levels. Oxybate PK from XW10172 (IR) was the same as from equal molar doses of sodium oxybate. XW10172 (ER) formulations showed delayed Tmax with extended oxybate exposure compatible with single nightly dose therapy. PK-PD assessment of somnolence, the desired pharmacologic effect, showed a concentration-effect relationship (Cmax p=0.0004, AUC p<0.0001). XW10172 was generally well tolerated and adverse events were those known to be associated with oxybate. Conclusion These data support progression of XW10172 (ER) in further clinical development studies to assess this once nightly GABA-B agonist therapy for the treatment of patients with various sleep disorders. Support (if any) XWPharma

scholarly journals Does the sedation regimen affect adverse events during procedural sedation and analgesia in injection drug users?

CJEM ◽  
2013 ◽  
Vol 15 (05) ◽  
pp. 279-288 ◽  
Author(s):  
Frank Xavier Scheuermeyer ◽  
Gary Andolfatto ◽  
Hong Qian ◽  
Eric Grafstein
Keyword(s):  
Adverse Events ◽  
Injection Drug Users ◽  
Drug Users ◽  
Vital Signs ◽  
Injection Drug ◽  
Procedural Sedation ◽  
Secondary Outcome ◽  
Procedural Sedation And Analgesia ◽  
Pearson Coefficient ◽  
Sedation And Analgesia

ABSTRACT Objectives: Injection drug users (IDUs) often undergo procedural sedation and analgesia (PSA) as part of emergency department (ED) treatment. We compared adverse events (AEs) using a variety of sedation regimens. Methods: This was a retrospective analysis of a PSA safety audit in two urban EDs. Consecutive self-reported IDUs were identified, and structured data describing comorbidities, vital signs, sedation regimens (propofol [P], propofol-fentanyl [PF], fentanyl-midazolam [FM], ketofol [1:1 ketamine:propofol, KF], and ketamine-propofol [KP]) and AEs were collected. The primary outcome was the proportion of patients in each sedation group having an AE; the secondary outcome was the proportion of patients having a cardiovascular or respiratory AE. Results: Data were collected on 276 IDUs (78 P, 82 PF, 65 FM, 25 KF, and 26 KP), and 18 patients had AEs (6.5%, 95% CI 4.0–10.3). The AE rates were 0.0%, 8.5%, 9.2%, 12.0%, and 7.6%, respectively, with propofol having a significantly lower rate (Pearson coefficient 14.9, p = 0.007). The cardiovascular/respiratory AE rates were significantly different as well, with P, KP, and KF having the lowest rates (Pearson coefficient 13.3, p = 0.01). Conclusions: For IDU PSA, the overall AE rate was 6.5%, and propofol appeared to have a significantly lower rate.

scholarly journals IV fosphenytoin in obese patients

2016 ◽  
Vol 7 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Sarah L. Clark ◽  
Megan R. Leloux ◽  
Ross A. Dierkhising ◽  
Gregory D. Cascino ◽  
Sara E. Hocker
Keyword(s):  
Body Weight ◽  
Adverse Events ◽  
Vital Signs ◽  
Drug Distribution ◽  
Retrospective Chart Review ◽  
Current Method ◽  
Liver Function Tests ◽  
Excess Body Weight ◽  
Obese Patients ◽  
Bonferroni Adjustment

AbstractBackground:Previous studies evaluated the disposition of IV phenytoin loading doses and found that obese patients had increased drug distribution into excess body weight, larger volumes of distribution, and longer half-lives when compared to their nonobese counterparts. We assess the safety and efficacy of fosphenytoin loading doses in patients with different body mass indices (BMIs).Methods:A retrospective chart review was conducted in 410 patients who received fosphenytoin. Patients were divided into 2 groups: BMI <30 (nonobese) and BMI ≥30 (obese). Patient demographics, fosphenytoin dose administered in mg/kg body weight, renal and liver function tests, fosphenytoin drug levels, and pre- and post-fosphenytoin administration vital signs were collected to assess for adverse events. Necessity of additional antiepileptic loading doses was used as a surrogate for clinical efficacy.Results:The median dose of fosphenytoin administered was 19 mg/kg (interquartile range 15–20). The most frequently encountered adverse event was hypotension, which occurred in 39% of the cohort. Using a Bonferroni adjustment for multiple comparisons, there were no differences in adverse events between the 2 groups. The need for additional antiepileptic loading doses was not different between the 2 groups (p = 0.07).Conclusions:The incidence of adverse events and the need for repeat loading antiepileptic medications was similar between the 2 groups. From our findings, the patients in our study did not receive empiric loading dose adjustments and the current method of loading fosphenytoin achieves similar outcomes, regardless of the patient's BMI.

scholarly journals Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses

2012 ◽  
Vol 56 (6) ◽  
pp. 3086-3091 ◽  
Author(s):  
Benjamin Miller ◽  
Ellie Hershberger ◽  
David Benziger ◽  
MyMy Trinh ◽  
Ian Friedland
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Healthy Adult ◽  
Volume Of Distribution ◽  
Dose Administration ◽  
Mean Values ◽  
Multiple Doses ◽  
Dosing Regimens ◽  
Dose Levels ◽  
Dose Limiting Toxicity

ABSTRACTThe pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.

scholarly journals Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis

Neurology ◽  
2019 ◽  
Vol 92 (23) ◽  
pp. e2661-e2673 ◽  
Author(s):  
James F. Howard ◽  
Vera Bril ◽  
Ted M. Burns ◽  
Renato Mantegazza ◽  
Malgorzata Bilinska ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myasthenia Gravis ◽  
Vital Signs ◽  
Standard Of Care ◽  
Placebo Treatment ◽  
Phase 2 ◽  
Double Blind ◽  
Severity Scores ◽  
Quality Of Life Scale ◽  
Life Scale

ObjectiveTo investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.MethodsA phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.ResultsOf the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.ConclusionsEfgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.Classification of evidenceThis study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.

Comprehensive ambulatory monitoring during immunotherapy in patients with advanced melanoma: A prospective trial (CAMP-IT).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1589-TPS1589
Author(s):  
Milan Kos ◽  
Laurien Buffart ◽  
Jan Willem de Groot ◽  
Hans Westgeest ◽  
Wouter Dercksen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Real Time ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Ambulatory Monitoring ◽  
Vital Signs ◽  
Advanced Melanoma ◽  
Smartphone App ◽  
Survival Outcomes ◽  
Activity Data

TPS1589 Background: The emergence of immune checkpoint inhibitors has improved survival outcomes for patients with advanced melanoma. However, these treatment modalities are also associated with specific immune-related toxicities. These are often reversible after prompt recognition and initiation of appropriate management, but can result in severe morbidity and hamper health-related quality of life (HRQoL) if left undetected. Hence, accurate and regular monitoring of these patients is critical. Recent advances in mHealth technologies and the rapidly expanding armamentarium of wearable devices allow for real-time objective (vital signs and physical activity) data and patient-reported outcome measurement (PROMs) collection and, hence, serve this purpose. We hypothesize that collection of real-time objective data adds to the early detection of disease- and treatment-related adverse events. The primary objective of this study is to determine the feasibility of collecting real-time PROMs, vital signs, and physical activity data in advanced melanoma patients receiving immunotherapy using a comprehensive ambulatory monitoring platform (CAMP) that consists of a smartphone app, activity monitor, digital thermometer, and online dashboard for physicians. Methods: In this prospective multi-center trial, patients (n = 50) with advanced melanoma, scheduled to receive immunotherapy with immune checkpoint inhibitors, and with access to a smartphone are eligible for inclusion. Consenting patients will be asked to wear a FitBit Versa 2.0 during waking hours, collect daily temperature measurements using a Withings Smart Temporal thermometer, and answer weekly toxicity questionnaires (NCI PRO-CTCAE) using the smartphone app for the duration of the study (12 weeks). Primary outcome is feasibility in terms of (i) participation rates, (ii) wear-time, (iii) compliance rates with in-app questionnaires and temperature measurements, and (iv) satisfaction with the platform. Secondary exploratory outcomes include associations between CAMP-derived parameters and clinical outcomes: performance status (PS), HR-QoL scores (EORTC QLQ-C30 questionnaire), unplanned hospitalizations, physician-assessed adverse events, and 1-year survival outcomes. PS and HR-QoL will be rated at baseline, mid-study, and end-of-study. The occurrence of adverse events will be documented up to 12 months from baseline. Survival outcomes will be compared to a propensity score matched group from the Netherlands Cancer Registry. Accrual has started in February 2021. Clinical trial information: NL8827.

Abstract 14387: Dose-Related Reductions in Blood Pressure With a RNA Interference (RNAi) Therapeutic Targeting Angiotensinogen in Hypertensive Patients: Interim Results From a First-In-Human Phase 1 Study of ALN-AGT01

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Stephen A Huang ◽  
Jorg Taubel ◽  
Giuseppe Fiore ◽  
Peter Dewland ◽  
George L Bakris ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Single Dose ◽  
Adverse Events ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Therapeutic Targeting ◽  
Dose Administration ◽  
Hypertensive Patients ◽  
Single Dose Administration ◽  
Angiotensin Peptides

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions >90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

scholarly journals 1374. Integrated Safety Summary of Omadacycline: A Novel Aminomethylcycline Antibiotic

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S421-S421 ◽  
Author(s):  
Steven Opal ◽  
Thomas M File ◽  
Tom Van Der Poll ◽  
Paul McGovern ◽  
Evan Tzanis ◽  
...  
Keyword(s):  
Adverse Events ◽  
Fungal Infections ◽  
Vital Signs ◽  
Study Drug ◽  
Drug Discontinuation ◽  
Once Daily ◽  
Atypical Pathogens ◽  
Safety Parameters ◽  
Study Drug Discontinuation ◽  
Electrocardiogram Ecg

Abstract Background Omadacycline (OMC) is a novel aminomethylcycline with activity against Gram-positive, many Gram-negative, anaerobic, and atypical pathogens. It is in clinical development as once-daily oral (PO) and intravenous (IV) monotherapy for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Cumulative safety results from Phase 3 clinical trials are reported. Methods This pooled safety analysis is based on 2,150 subjects: OASIS-1 (N = 645), OASIS-2 (N = 735) in ABSSSI; OPTIC (N = 770) in CABP. Comparators were linezolid (LZD) 600 mg IV then PO in ABSSSI (n = 689); moxifloxacin (MOX) 400 mg IV then PO in CABP (n = 388). Safety parameters included treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, and electrocardiogram (ECG) findings. Results A total of 1,073 subjects received OMC: 705 received OMC IV then PO (ABSSSI, n = 323; CABP, n = 382); 368 received OMC PO only for ABSSSI. Overall, 60.6% were male and 91.6% white; mean age ranges were 44.7–45.1 and 60.9–62.1 years in ABSSSI and CABP studies, respectively. TEAEs were observed in 47.5% (OMC), 41.2% (LZD), and 48.5% (MOX) of subjects, with gastrointestinal events the most common TEAEs. Serious TEAEs were low (3.6% OMC, 1.9% LZD, 6.7% MOX). Nausea (14.9% OMC, 8.7% LZD, 5.4% MOX) and vomiting (8.3% OMC, 3.9% LZD, 1.5% MOX) were the most frequently reported TEAEs. Diarrhea was observed in 2.4% OMC, 2.9% LZD, and 8.0% MOX subjects, with no cases of Clostridium difficile in OMC-treated subjects. Most TEAEs were mild to moderate and did not result in study drug discontinuation (3.1% OMC, 1.5% LZD, 7.0% MOX); 4 OMC, 1 LZD, and 0 MOX subjects discontinued for nausea and vomiting. Frequency of hepatic TEAEs was similar for OMC, LZD, and MOX: 4.3% OMC, 4.1% LZD, and 4.5% MOX subjects had post-baseline ALT &gt;3× upper limit of normal. Vital signs and ECGs had comparable clinically notable values post-baseline in each treatment group. Known tetracycline class adverse events such as fungal infections were similar in all groups. Conclusion Pooled analyses demonstrate a favorable OMC safety profile, consistent with its tetracycline heritage. OMC was generally well tolerated in subjects with ABSSSI and CABP, with infrequent treatment discontinuations. Disclosures T. M. File Jr., BioMerieux: Consultant, Consulting fee; Curetis: Consultant, Consulting fee; Melinta Therapeutics: Consultant, Consulting fee; Merck: Consultant, Consulting fee; Motif Bio: Consultant, Consulting fee; Nabriva Therapeutics: Consultant and Investigator, Consulting fee and Research grant; Paratek Pharmaceuticals: Consultant, Consulting fee; Pfizer: Consultant, Consulting fee. T. Van Der Poll, Paratek Pharmaceuticals: Consultant, Consulting fee. P. McGovern, Paratek Pharmaceuticals: Employee, Salary. E. Tzanis, Paratek Pharmaceuticals: Employee, Salary.

scholarly journals Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review

CNS Drugs ◽  
2019 ◽  
Vol 33 (12) ◽  
pp. 1167-1186 ◽  
Author(s):  
Frank M. C. Besag ◽  
Michael J. Vasey ◽  
Kim S. J. Lao ◽  
Ian C. K. Wong
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Sleep Disorders

scholarly journals An Analysis of Exertional Safety After Blood Donation in Active Duty Military Personnel—A Feasibility Study

2020 ◽  
Author(s):  
Brandon M Carius ◽  
Mohamad Umar ◽  
James K Aden ◽  
Steve G Schauer
Keyword(s):  
Heart Rate ◽  
Adverse Events ◽  
Feasibility Study ◽  
Blood Donation ◽  
Vital Signs ◽  
Physical Fitness Test ◽  
Resuscitation Fluid ◽  
Baseline Testing ◽  
Military Populations ◽  
Armed Services

ABSTRACT Introduction Whole blood (WB) is the optimal resuscitation fluid in hemorrhagic shock. Military research focuses on mortality benefits of WB acquired through walking blood banks (WBBs). Few military-based studies on donation effects exist, almost exclusively performed on small special operation forces. No Department of Defense regulations for postdonation precautions in nonaviation crew members exist. Further study is warranted regarding safety and limitations in postdonation populations. Materials and Methods A feasibility (n = 25) prospective interventional study examined the safety of exertion (defined as a 1.6-km treadmill run at volunteers’ minimum passing pace for the Army Physical Fitness Test) following 1 unit of WB donation. Subjects served as their own controls, performing baseline testing 7 days before donation, with repeat testing 1 h following donation conducted by Armed Services Blood Program personnel. Adverse events, pre- and postexertion vital signs (VS) were evaluated. Results There were no adverse events throughout testing. Only resting heart rate (68 vs. 73 beats · min−1, p &lt; 0.01) and postexertion heart rate were significantly different among pre- and postdonation VS. Additional significant findings were time to attain postexertion normocardia (116 vs. 147 seconds, p &lt; 0.01). A small but statistically significant change in Borg perceived exertional scores was noted (10.3 vs. 10.8, p &lt; 0.05). Conclusions This feasibility study demonstrates the first safety test of regular military populations performing exertion immediately following the standardized WB donation. VS changes may translate into a small but significant increase in perceived postdonation exertion. Future studies should expand duration and intensity of exertion to match combat conditions.

Sign in / Sign up

Export Citation Format

Share Document