A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies

Kalin, Alexander; Medina-Paraiso, Elvia; Ishizaki, Kaoru; Kim, Alex; Zhang, Yannong; Saita, Takanori; Wasaki, Masahiko

doi:10.1080/21678421.2017.1362440

Cited by 15 publications

(16 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, edaravone has put a limit on how broadly existing placebo data sets like PRO-ACT can be used for historical controls in clinical trials. Contemporary controls captured through automated EMR data abstraction could be one solution to this problem [1, 35, 36].…”

Section: Discussionmentioning

confidence: 99%

Using automated electronic medical record data extraction to model ALS survival and progression

et al. 2018

View full text Add to dashboard Cite

BackgroundTo assess the feasibility of using automated capture of Electronic Medical Record (EMR) data to build predictive models for amyotrophic lateral sclerosis (ALS) outcomes.MethodsWe used an Informatics for Integrating Biology and the Bedside search discovery tool to identify and extract data from 354 ALS patients from the University of Kansas Medical Center EMR. The completeness and integrity of the data extraction were verified by manual chart review. A linear mixed model was used to model disease progression. Cox proportional hazards models were used to investigate the effects of BMI, gender, and age on survival.ResultsData extracted from the EMR was sufficient to create simple models of disease progression and survival. Several key variables of interest were unavailable without including a manual chart review. The average ALS Functional Rating Scale – Revised (ALSFRS-R) baseline score at first clinical visit was 34.08, and average decline was − 0.64 per month. Median survival was 27 months after first visit. Higher baseline ALSFRS-R score and BMI were associated with improved survival, higher baseline age was associated with decreased survival.ConclusionsThis study serves to show that EMR-captured data can be extracted and used to track outcomes in an ALS clinic setting, potentially important for post-marketing research of new drugs, or as historical controls for future studies. However, as automated EMR-based data extraction becomes more widely used there will be a need to standardize ALS data elements and clinical forms for data capture so data can be pooled across academic centers.Electronic supplementary materialThe online version of this article (10.1186/s12883-018-1208-z) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Using automated electronic medical record data extraction to model ALS survival and progression

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Edaravone is an antioxidant that works by preventing oxidative stress‐induced motor neuron death; it also inhibits nitration of tyrosine residues in the cerebrospinal fluid and improves motor functions in vivo 4 . The efficacy and safety of edaravone for ALS has been assessed in several clinical trials 5–14 . In a pivotal phase 3 clinical study in patients with ALS, the primary efficacy end point of the 24‐week ALS Functional Rating Scale–Revised score was significantly improved in the edaravone vs placebo group (mean between‐group difference ± standard error, 2.5 ± 0.8; P = .001), indicating that patients treated with edaravone had significantly less functional loss compared with those who received placebo 6…”

mentioning

confidence: 99%

Evaluation of Pharmacokinetics, Safety, and Drug‐Drug Interactions of an Oral Suspension of Edaravone in Healthy Adults

Shimizu¹,

Nishimura²,

Shiide³

et al. 2021

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

Intravenous (IV) edaravone is approved as an amyotrophic lateral sclerosis (ALS) treatment. Because IV administration places a burden on patients, development of orally administered ALS treatments is needed. Therefore, 2 phase 1 studies of oral formulations of edaravone in healthy subjects examined the pharmacokinetics (PK), safety, racial differences, and drug‐drug interactions (DDIs) and investigated the dose of the oral formulation considered to be bioequivalent to the approved dose of the IV formulation. Study 1 was a placebo‐controlled, randomized, single‐blind study of single‐ascending‐dose oral edaravone with the dose range of 30 to 300 mg (n = 56). Study 2 was conducted in 2 cohorts (n = 84); the first assessed DDIs with multiple‐dose edaravone 120 mg/day given over 5 or 8 days (coadministered with single‐dose rosuvastatin, sildenafil, or furosemide), and the second evaluated PK and racial (Japanese/White) differences in PK parameters with doses of 100‐mg edaravone. The oral formulation of edaravone was well absorbed, and plasma concentrations of unchanged edaravone increased more than dose proportionally within the dose range of 30 to 300 mg. No effect of race on oral edaravone PK and no notable DDI effects possibly caused by orally administered edaravone were observed. The oral edaravone formulations were safe and tolerable under the assessed conditions. Mathematical modeling determined that equivalent exposures in plasma with the approved dose of the IV edaravone formulation, as reported previously, could be achieved when the oral edaravone formulation was administered at a dose of ≈100 mg, with an absolute bioavailability of ≈60%.

show abstract

“…Each subsequent cycle consists of daily dosing for 10 days out of a 14‐day period with a 14‐day drug‐free period. The efficacy and safety of edaravone for ALS was demonstrated in several clinical trials 4–14 . Notably, the effect of edaravone on functional loss of motor neurons differentiates it from other treatments for ALS that provide only symptomatic effects 3,15 .…”

mentioning

confidence: 99%

“…The efficacy and safety of edaravone for ALS was demonstrated in several clinical trials. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 Notably, the effect of edaravone on functional loss of motor neurons differentiates it from other treatments for ALS that provide only symptomatic effects. 3 , 15 In a pivotal phase 3 clinical study, the primary efficacy end point of the 24‐week ALS Functional Rating Scale–Revised score was significantly improved ( P = .001) in patients with ALS who received edaravone compared with placebo, indicating reduced functional loss in edaravone‐treated patients.…”

mentioning

confidence: 99%

Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects

Shimizu¹,

Nishimura²,

Shiide³

et al. 2021

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

The neuroprotective agent edaravone is an intravenous treatment for amyotrophic lateral sclerosis. As intravenous administration burdens patients, orally administered treatments are needed. This phase 1, open‐label, single‐dose crossover study in 42 healthy adults evaluated bioequivalence of a 105‐mg edaravone oral suspension and intravenous edaravone (60 mg/60 min). The evaluation was whether the 90% confidence intervals (CIs) for the ratio of the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to the last quantifiable time point and to infinity of unchanged edaravone were between the bioequivalence limit of 0.80 and 1.25. Metabolic profiles and elimination pathways were also compared between the 2 routes. Geometric mean ratios and 90%CIs of area under the plasma concentration–time curve from time 0 to the last quantifiable time point and to infinity for unchanged edaravone satisfied bioequivalence limits. The geometric mean ratio and its lower limit of 90%CI of Cmax of the 105‐mg oral suspension compared with 60‐mg intravenous formulations for unchanged edaravone fell within bioequivalence limits. Both formulations showed triphasic plasma concentration–time profiles of unchanged edaravone after reaching Cmax. Plasma concentrations of edaravone inactive metabolites after oral administration were higher than with intravenous administration. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary excretion of unchanged edaravone was low, and urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. These findings showed equivalent exposure of the 105‐mg oral suspension of edaravone to the 60‐mg intravenous formulation, supporting further investigation of the oral suspension for treating amyotrophic lateral sclerosis.

show abstract

A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies

Cited by 15 publications

References 14 publications

Using automated electronic medical record data extraction to model ALS survival and progression

Using automated electronic medical record data extraction to model ALS survival and progression

Evaluation of Pharmacokinetics, Safety, and Drug‐Drug Interactions of an Oral Suspension of Edaravone in Healthy Adults

Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects

Contact Info

Product

Resources

About