The Experts below are selected from a list of 5166 Experts worldwide ranked by ideXlab platform

Barry E. Gidal - One of the best experts on this subject based on the ideXlab platform.

  • Drug-drug interactions and pharmacodynamics of concomitant Clobazam and cannabidiol or stiripentol in refractory seizures.
    Epilepsy & behavior : E&B, 2019
    Co-Authors: Pavel Klein, Dwain Tolbert, Barry E. Gidal
    Abstract:

    Abstract Objective The goal of this study was to characterize the drug–drug interactions between Clobazam and 2 antiseizure drugs, cannabidiol and stiripentol, for treatment of refractory seizures through the use of pharmacokinetic modeling. Methods A population pharmacokinetic/pharmacodynamic model was developed to characterize the combined effect of Clobazam and its active metabolite, N-desmethylClobazam (i.e., N-Clobazam), on seizure protection in patients with Lennox–Gastaut syndrome using data from the phase 3 CONTAIN trial. Drug–drug interactions between Clobazam and cannabidiol were examined by comparing model-generated data to data from a study of 13 patients taking concomitant Clobazam and cannabidiol. Modeling data were also descriptively compared with studies of patients administered both Clobazam and stiripentol. Sedation-related adverse events from CONTAIN were analyzed to determine the exposure–somnolence relationship of Clobazam. Results Exposure-efficacy analysis from the pharmacokinetic/pharmacodynamic model using CONTAIN data indicated that Clobazam (half-maximal effective concentration [EC50], 303 ng/mL) was 3 times more potent than N-Clobazam (EC50, 899 ng/mL). After administration of Clobazam, when both Clobazam and N-Clobazam concentrations were each 1 to 2 times the EC50 value (Clobazam dose, 20 mg), 70.0%–74.9% seizure protection was predicted; when concentrations were > 2 times the EC50 value (Clobazam dose, 40 mg), 74.0%–96.9% seizure protection was predicted. Generalized additive model analyses demonstrated decreased seizure probability with higher plasma concentration of Clobazam. Coadministration of stiripentol and Clobazam resulted in increased respective median plasma concentrations of Clobazam and N-Clobazam (1.1–1.2 times and 5.2–8.2 times) compared with administration of placebo and Clobazam. Probability of somnolence significantly increased with age and higher N-Clobazam plasma concentration. Significance Awareness of drug–drug interactions between Clobazam and cannabidiol is needed when adding cannabidiol or stiripentol to a regimen of Clobazam or vice versa. Based upon our population pharmacokinetic/pharmacodynamic model, we predict that an increase in N-Clobazam levels, which patient data show may enhance efficacy and/or make adverse events such as somnolence more likely.

  • The PK/PD Basis for Clobazam Use in Refractory Seizures: Is There a Need for Clobazam Dosage Reduction in the Presence of Other Antiepileptic Drugs (AEDs)? (P4.266)
    Neurology, 2018
    Co-Authors: Dwain Tolbert, Pavel Klein, Barry E. Gidal, Hui-may Chu, Ene I. Ette
    Abstract:

    Objective: To determine the need for Clobazam dosage reduction in the presence of other approved or investigational antiepileptic drugs (AEDs). Background: Clobazam is approved in the US as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥2 years of age. It is therefore important to understand the pharmacokinetics/pharmacodynamics (PK/PD) of Clobazam when used with other AEDs, including investigational AEDs such as cannabidiol and stiripentol. Design/Methods: Data from Clobazam, cannabidiol, and stiripentol studies were used to evaluate exposure-efficacy (seizure reduction) via nonlinear mixed effect modeling, as well as exposure-somnolence using penalized logistic regression and the Bayesian model averaging approach. Other published stiripentol and cannabidiol data are summarized. Results: PK/PD analyses revealed that Clobazam (EC 50 : 303 ng/mL) is 3× as potent as its main, active metabolite N-Clobazam (EC 50 : 899 ng/mL). Clobazam and N-Clobazam concentrations that are 1–2xEC 50 are predicted to yield 70.0% to 74.9% seizure protection, which increases to 74.0% to 96.9% in patients with Clobazam and N-Clobazam concentrations >2xEC 50 . Based on a comparison of predicted Clobazam/N-Clobazam exposures by population PK modeling, it is predicted that patients with pharmacoresistant seizures (including Dravet syndrome) could benefit from Clobazam dosages of 1–2 mg/kg/day. Older age and high N-Clobazam concentrations were predictors of Clobazam-related somnolence. Patients ≤18 years had Conclusions: These analyses suggest that no Clobazam dose reduction is needed when used in combination with approved AEDs; when used with cannabidiol or stiripentol, it is the dose of those AEDs rather than Clobazam that would likely need to be modulated. Study Supported by: Lundbeck Disclosure: Dr. Tolbert has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Lundbeck LLC employee. Dr. Klein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Klein has served as a consultant to Eisai, Lundbeck, Sunovion, UCB Pharma, and as a consultant to Lundbeck and UCB Pharma. Dr. Klein has received research support from Dr. Klein has received research support from Eisai and Lundbeck. Dr. Gidal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Gidal has served as a consultant and speaker for Eisai, Sunovion, UCB, and Lundbeck, and as a consultant for Upsher-Smith. Dr. Chu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Anoixis Corporation employee. Dr. Ette has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Anoixis Corporation employee.

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome
    Epilepsy & Behavior, 2018
    Co-Authors: Jouko Isojarvi, Barry E. Gidal, Steve Chung, Robert Wechsler
    Abstract:

    Abstract Given the complexities managing Lennox–Gastaut syndrome (LGS)—comorbid conditions, multiple associated seizure types that tend to be refractory to treatment—dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive Clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive Clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal Clobazam lead-in studies. During the lead-in studies, patients received either placebo or Clobazam (0.25, 0.50, or 1.0 mg/kg/d) (maximum 40 mg/d); during OLE, patients received Clobazam up to 2.0 mg/kg/d (maximum 80 mg/d). The post hoc analysis population comprised patients who had ≥ 25%, ≥ 50%, or ≥ 75% seizure reduction from baseline during lead-in Clobazam treatment and ≥ 12 months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥ 20% Clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or > 50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in Clobazam dosage received. The findings of the analysis indicated that Clobazam dosage increases of ≥ 20% during long-term treatment improved seizure control > 80% of patients with LGS who responded to Clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage Clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥ 75%) lead-in response.

  • Optimizing Clobazam treatment in patients with Lennox-Gastaut syndrome.
    Epilepsy & behavior : E&B, 2017
    Co-Authors: Jouko Isojarvi, Barry E. Gidal, Steve Chung, Robert T. Wechsler
    Abstract:

    Given the complexities managing Lennox-Gastaut syndrome (LGS)-comorbid conditions, multiple associated seizure types that tend to be refractory to treatment-dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive Clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive Clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal Clobazam lead-in studies. During the lead-in studies, patients received either placebo or Clobazam (0.25, 0.50, or 1.0mg/kg/d) (maximum 40mg/d); during OLE, patients received Clobazam up to 2.0mg/kg/d (maximum 80mg/d). The post hoc analysis population comprised patients who had ≥25%, ≥50%, or ≥75% seizure reduction from baseline during lead-in Clobazam treatment and ≥12months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥20% Clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or >50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in Clobazam dosage received. The findings of the analysis indicated that Clobazam dosage increases of ≥20% during long-term treatment improved seizure control >80% of patients with LGS who responded to Clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage Clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥75%) lead-in response.

  • Optimizing Clobazam Treatment in Patients with Lennox-Gastaut Syndrome (LGS) (P2.039)
    Neurology, 2016
    Co-Authors: Robert T. Wechsler, Barry E. Gidal, Steve Chung, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had

Jouko Isojarvi - One of the best experts on this subject based on the ideXlab platform.

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome
    Epilepsy & Behavior, 2018
    Co-Authors: Jouko Isojarvi, Barry E. Gidal, Steve Chung, Robert Wechsler
    Abstract:

    Abstract Given the complexities managing Lennox–Gastaut syndrome (LGS)—comorbid conditions, multiple associated seizure types that tend to be refractory to treatment—dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive Clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive Clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal Clobazam lead-in studies. During the lead-in studies, patients received either placebo or Clobazam (0.25, 0.50, or 1.0 mg/kg/d) (maximum 40 mg/d); during OLE, patients received Clobazam up to 2.0 mg/kg/d (maximum 80 mg/d). The post hoc analysis population comprised patients who had ≥ 25%, ≥ 50%, or ≥ 75% seizure reduction from baseline during lead-in Clobazam treatment and ≥ 12 months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥ 20% Clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or > 50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in Clobazam dosage received. The findings of the analysis indicated that Clobazam dosage increases of ≥ 20% during long-term treatment improved seizure control > 80% of patients with LGS who responded to Clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage Clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥ 75%) lead-in response.

  • Optimizing Clobazam treatment in patients with Lennox-Gastaut syndrome.
    Epilepsy & behavior : E&B, 2017
    Co-Authors: Jouko Isojarvi, Barry E. Gidal, Steve Chung, Robert T. Wechsler
    Abstract:

    Given the complexities managing Lennox-Gastaut syndrome (LGS)-comorbid conditions, multiple associated seizure types that tend to be refractory to treatment-dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive Clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive Clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal Clobazam lead-in studies. During the lead-in studies, patients received either placebo or Clobazam (0.25, 0.50, or 1.0mg/kg/d) (maximum 40mg/d); during OLE, patients received Clobazam up to 2.0mg/kg/d (maximum 80mg/d). The post hoc analysis population comprised patients who had ≥25%, ≥50%, or ≥75% seizure reduction from baseline during lead-in Clobazam treatment and ≥12months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥20% Clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or >50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in Clobazam dosage received. The findings of the analysis indicated that Clobazam dosage increases of ≥20% during long-term treatment improved seizure control >80% of patients with LGS who responded to Clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage Clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥75%) lead-in response.

  • Optimizing Clobazam Treatment in Patients with Lennox-Gastaut Syndrome (LGS) (P2.039)
    Neurology, 2016
    Co-Authors: Robert T. Wechsler, Barry E. Gidal, Steve Chung, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome lgs p2 039
    Neurology, 2016
    Co-Authors: Robert Wechsler, Steve Chung, Barry E. Gidal, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had <25[percnt] response were excluded. Results: Seventy-eight of 206 patients with 12-month follow-up data meeting ≥25[percnt], ≥50[percnt], or ≥75[percnt] responder criteria were included. Overall, 75.6[percnt] of patients had a ≥20[percnt] increase in Clobazam dosage, with 61.0[percnt] achieving improved seizure control (73.3[percnt], 55.0[percnt], and 58.3[percnt] in the ≥25[percnt], ≥50[percnt], and ≥75[percnt] responder groups, respectively). Conclusions: For patients who responded to double-blind Clobazam treatment, ≥20[percnt] dosage increases improved seizure control in ≥60[percnt] of patients during the first year of open-label Clobazam treatment. Positive outcome with dosage optimization was most likely in those initially treated with a lower Clobazam dosage and in those with lower initial treatment response. Funding: Lundbeck, LLC Disclosure: Dr. Wechsler has received personal compensation for activities with Cyberonics, Eisai, Gerson Lehrman Group Inc., Lundbeck, Sunovion, UCB Pharma, and Upsher-Smith. Dr. Gidal has received personal compensation for activities with Upsher-Smith. Dr. Chung has received personal compensation for activities with UCB Pharma, Eisai, Lundbeck, and Sunovion. Dr. Peng has received personal compensation for activities with Lundbeck. Dr. Isojarvi has received personal compensation fro activities with Lundbeck LLC.

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome lgs p2 039
    Neurology, 2016
    Co-Authors: Robert T. Wechsler, Barry E. Gidal, Steve Chung, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had <25[percnt] response were excluded. Results: Seventy-eight of 206 patients with 12-month follow-up data meeting ≥25[percnt], ≥50[percnt], or ≥75[percnt] responder criteria were included. Overall, 75.6[percnt] of patients had a ≥20[percnt] increase in Clobazam dosage, with 61.0[percnt] achieving improved seizure control (73.3[percnt], 55.0[percnt], and 58.3[percnt] in the ≥25[percnt], ≥50[percnt], and ≥75[percnt] responder groups, respectively). Conclusions: For patients who responded to double-blind Clobazam treatment, ≥20[percnt] dosage increases improved seizure control in ≥60[percnt] of patients during the first year of open-label Clobazam treatment. Positive outcome with dosage optimization was most likely in those initially treated with a lower Clobazam dosage and in those with lower initial treatment response. Funding: Lundbeck, LLC Disclosure: Dr. Wechsler has received personal compensation for activities with Cyberonics, Eisai, Gerson Lehrman Group Inc., Lundbeck, Sunovion, UCB Pharma, and Upsher-Smith. Dr. Gidal has received personal compensation for activities with Upsher-Smith. Dr. Chung has received personal compensation for activities with UCB Pharma, Eisai, Lundbeck, and Sunovion. Dr. Peng has received personal compensation for activities with Lundbeck. Dr. Isojarvi has received personal compensation fro activities with Lundbeck LLC.

Dwain Tolbert - One of the best experts on this subject based on the ideXlab platform.

  • Drug-drug interactions and pharmacodynamics of concomitant Clobazam and cannabidiol or stiripentol in refractory seizures.
    Epilepsy & behavior : E&B, 2019
    Co-Authors: Pavel Klein, Dwain Tolbert, Barry E. Gidal
    Abstract:

    Abstract Objective The goal of this study was to characterize the drug–drug interactions between Clobazam and 2 antiseizure drugs, cannabidiol and stiripentol, for treatment of refractory seizures through the use of pharmacokinetic modeling. Methods A population pharmacokinetic/pharmacodynamic model was developed to characterize the combined effect of Clobazam and its active metabolite, N-desmethylClobazam (i.e., N-Clobazam), on seizure protection in patients with Lennox–Gastaut syndrome using data from the phase 3 CONTAIN trial. Drug–drug interactions between Clobazam and cannabidiol were examined by comparing model-generated data to data from a study of 13 patients taking concomitant Clobazam and cannabidiol. Modeling data were also descriptively compared with studies of patients administered both Clobazam and stiripentol. Sedation-related adverse events from CONTAIN were analyzed to determine the exposure–somnolence relationship of Clobazam. Results Exposure-efficacy analysis from the pharmacokinetic/pharmacodynamic model using CONTAIN data indicated that Clobazam (half-maximal effective concentration [EC50], 303 ng/mL) was 3 times more potent than N-Clobazam (EC50, 899 ng/mL). After administration of Clobazam, when both Clobazam and N-Clobazam concentrations were each 1 to 2 times the EC50 value (Clobazam dose, 20 mg), 70.0%–74.9% seizure protection was predicted; when concentrations were > 2 times the EC50 value (Clobazam dose, 40 mg), 74.0%–96.9% seizure protection was predicted. Generalized additive model analyses demonstrated decreased seizure probability with higher plasma concentration of Clobazam. Coadministration of stiripentol and Clobazam resulted in increased respective median plasma concentrations of Clobazam and N-Clobazam (1.1–1.2 times and 5.2–8.2 times) compared with administration of placebo and Clobazam. Probability of somnolence significantly increased with age and higher N-Clobazam plasma concentration. Significance Awareness of drug–drug interactions between Clobazam and cannabidiol is needed when adding cannabidiol or stiripentol to a regimen of Clobazam or vice versa. Based upon our population pharmacokinetic/pharmacodynamic model, we predict that an increase in N-Clobazam levels, which patient data show may enhance efficacy and/or make adverse events such as somnolence more likely.

  • The PK/PD Basis for Clobazam Use in Refractory Seizures: Is There a Need for Clobazam Dosage Reduction in the Presence of Other Antiepileptic Drugs (AEDs)? (P4.266)
    Neurology, 2018
    Co-Authors: Dwain Tolbert, Pavel Klein, Barry E. Gidal, Hui-may Chu, Ene I. Ette
    Abstract:

    Objective: To determine the need for Clobazam dosage reduction in the presence of other approved or investigational antiepileptic drugs (AEDs). Background: Clobazam is approved in the US as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥2 years of age. It is therefore important to understand the pharmacokinetics/pharmacodynamics (PK/PD) of Clobazam when used with other AEDs, including investigational AEDs such as cannabidiol and stiripentol. Design/Methods: Data from Clobazam, cannabidiol, and stiripentol studies were used to evaluate exposure-efficacy (seizure reduction) via nonlinear mixed effect modeling, as well as exposure-somnolence using penalized logistic regression and the Bayesian model averaging approach. Other published stiripentol and cannabidiol data are summarized. Results: PK/PD analyses revealed that Clobazam (EC 50 : 303 ng/mL) is 3× as potent as its main, active metabolite N-Clobazam (EC 50 : 899 ng/mL). Clobazam and N-Clobazam concentrations that are 1–2xEC 50 are predicted to yield 70.0% to 74.9% seizure protection, which increases to 74.0% to 96.9% in patients with Clobazam and N-Clobazam concentrations >2xEC 50 . Based on a comparison of predicted Clobazam/N-Clobazam exposures by population PK modeling, it is predicted that patients with pharmacoresistant seizures (including Dravet syndrome) could benefit from Clobazam dosages of 1–2 mg/kg/day. Older age and high N-Clobazam concentrations were predictors of Clobazam-related somnolence. Patients ≤18 years had Conclusions: These analyses suggest that no Clobazam dose reduction is needed when used in combination with approved AEDs; when used with cannabidiol or stiripentol, it is the dose of those AEDs rather than Clobazam that would likely need to be modulated. Study Supported by: Lundbeck Disclosure: Dr. Tolbert has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Lundbeck LLC employee. Dr. Klein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Klein has served as a consultant to Eisai, Lundbeck, Sunovion, UCB Pharma, and as a consultant to Lundbeck and UCB Pharma. Dr. Klein has received research support from Dr. Klein has received research support from Eisai and Lundbeck. Dr. Gidal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Gidal has served as a consultant and speaker for Eisai, Sunovion, UCB, and Lundbeck, and as a consultant for Upsher-Smith. Dr. Chu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Anoixis Corporation employee. Dr. Ette has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Anoixis Corporation employee.

  • A Thorough QT/QTc Study of Clobazam in Healthy Volunteers.
    Clinical therapeutics, 2017
    Co-Authors: Dwain Tolbert, Mark Walzer, Ihor Bekersky, Judy Gordon, Stuart I Harris, Susan Reid
    Abstract:

    Abstract Purpose A thorough QT study was conducted to assess the proarrhythmic potential of Clobazam and its active metabolite, N-desmethylClobazam (N-CLB). Methods In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: Clobazam 40 mg/d (maximum therapeutic dosage), Clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control). Findings Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (Clobazam 40 mg/d, n = 66; Clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with Clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that Clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time–concentration profile of Clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time–concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the Clobazam and N-CLB Cmax values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the Clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the Clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively). Implications The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with Clobazam.

  • drug metabolism mechanism knowledge based population pharmacokinetic approach for characterizing Clobazam drug drug interactions
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Dwain Tolbert, Hui-may Chu, Ihor Bekersky, Ene I. Ette
    Abstract:

    A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with Clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with Clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of Clobazam and its metabolite, N-desmethylClobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of Clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with Clobazam in the treatment of LGS patients had negligible to no effect on Clobazam PK in this study, dosage adjustments may not be required for Clobazam in the presence of the AEDs investigated here.

  • Pharmacokinetic Drug Interactions Between Clobazam and Drugs Metabolized by Cytochrome P450 Isoenzymes
    Pharmacotherapy, 2012
    Co-Authors: Mark Walzer, Ihor Bekersky, Robert A. Blum, Dwain Tolbert
    Abstract:

    Study objective To investigate potential drug-drug interactions between Clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers. Design Two, prospective, open-label, single-center, drug-drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II-III trials. Setting Clinical research unit. Participants Fifty-four healthy adult volunteers were enrolled in the two drug-drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox-Gastaut syndrome. Participants in these studies received Clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine. Intervention In the first drug-drug interaction study, 36 participants received a single oral dose of Clobazam 10 mg on day 1, followed by either ketoconazole 400 mg once/day or omeprazole 40 mg once/day on days 17-22, with a single dose of Clobazam 10 mg coadministered on day 22, to study the effects of CYP3A4 or CYP2C19 inhibition, respectively, on Clobazam and its active metabolite N-desmethylClobazam (N-CLB). In the second study, 18 participants received a drug cocktail consisting of caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg, and midazolam 4 mg on days 1 and 19, and Clobazam 40 mg/day on days 4-19, to study Clobazam's effects on CYP1A2, CYP2C9, CYP2D6, and CYP3A4. Measurements and main results In the first DDI study, coadministration of ketoconazole (a CYP3A4 inhibitor) and Clobazam increased Clobazam's area under the concentration time curve from time zero extrapolated to infinity (AUC(0-∞) ) 54% and decreased Clobazam's maximum plasma concentration (C(max) ) by 15% versus administration of Clobazam alone, but the combination affected these pharmacokinetic parameters for N-CLB to a lesser degree. The CYP2C19 inhibitor omeprazole increased AUC(0-∞) and C(max) of N-CLB by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of Clobazam. At steady state, N-CLB has 3-4 times greater exposure than Clobazam. In the second DDI study, no clinically significant drug-drug interactions were observed between Clobazam 40 mg and the CYP probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1-hydroxymidazolam metabolite, however, decreased by 27% and increased 4-fold, respectively. Clobazam increased dextromethorphan (CYP2D6) AUC(0-∞) by 95% and C(max) by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce CYP3A4 or CYP2C19, or inhibit CYP2C19, had negligible effects on Clobazam or N-CLB. Clobazam did not affect valproic acid or lamotrigine exposures. Conclusion These findings suggest no clinically meaningful drug-drug interactions between Clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9. Concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox-Gastaut syndrome, without meaningful changes in Clobazam pharmacokinetics that would require dosage adjustment.

Steve Chung - One of the best experts on this subject based on the ideXlab platform.

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome
    Epilepsy & Behavior, 2018
    Co-Authors: Jouko Isojarvi, Barry E. Gidal, Steve Chung, Robert Wechsler
    Abstract:

    Abstract Given the complexities managing Lennox–Gastaut syndrome (LGS)—comorbid conditions, multiple associated seizure types that tend to be refractory to treatment—dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive Clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive Clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal Clobazam lead-in studies. During the lead-in studies, patients received either placebo or Clobazam (0.25, 0.50, or 1.0 mg/kg/d) (maximum 40 mg/d); during OLE, patients received Clobazam up to 2.0 mg/kg/d (maximum 80 mg/d). The post hoc analysis population comprised patients who had ≥ 25%, ≥ 50%, or ≥ 75% seizure reduction from baseline during lead-in Clobazam treatment and ≥ 12 months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥ 20% Clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or > 50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in Clobazam dosage received. The findings of the analysis indicated that Clobazam dosage increases of ≥ 20% during long-term treatment improved seizure control > 80% of patients with LGS who responded to Clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage Clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥ 75%) lead-in response.

  • Optimizing Clobazam treatment in patients with Lennox-Gastaut syndrome.
    Epilepsy & behavior : E&B, 2017
    Co-Authors: Jouko Isojarvi, Barry E. Gidal, Steve Chung, Robert T. Wechsler
    Abstract:

    Given the complexities managing Lennox-Gastaut syndrome (LGS)-comorbid conditions, multiple associated seizure types that tend to be refractory to treatment-dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive Clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive Clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal Clobazam lead-in studies. During the lead-in studies, patients received either placebo or Clobazam (0.25, 0.50, or 1.0mg/kg/d) (maximum 40mg/d); during OLE, patients received Clobazam up to 2.0mg/kg/d (maximum 80mg/d). The post hoc analysis population comprised patients who had ≥25%, ≥50%, or ≥75% seizure reduction from baseline during lead-in Clobazam treatment and ≥12months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥20% Clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or >50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in Clobazam dosage received. The findings of the analysis indicated that Clobazam dosage increases of ≥20% during long-term treatment improved seizure control >80% of patients with LGS who responded to Clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage Clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥75%) lead-in response.

  • Optimizing Clobazam Treatment in Patients with Lennox-Gastaut Syndrome (LGS) (P2.039)
    Neurology, 2016
    Co-Authors: Robert T. Wechsler, Barry E. Gidal, Steve Chung, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome lgs p2 039
    Neurology, 2016
    Co-Authors: Robert Wechsler, Steve Chung, Barry E. Gidal, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had <25[percnt] response were excluded. Results: Seventy-eight of 206 patients with 12-month follow-up data meeting ≥25[percnt], ≥50[percnt], or ≥75[percnt] responder criteria were included. Overall, 75.6[percnt] of patients had a ≥20[percnt] increase in Clobazam dosage, with 61.0[percnt] achieving improved seizure control (73.3[percnt], 55.0[percnt], and 58.3[percnt] in the ≥25[percnt], ≥50[percnt], and ≥75[percnt] responder groups, respectively). Conclusions: For patients who responded to double-blind Clobazam treatment, ≥20[percnt] dosage increases improved seizure control in ≥60[percnt] of patients during the first year of open-label Clobazam treatment. Positive outcome with dosage optimization was most likely in those initially treated with a lower Clobazam dosage and in those with lower initial treatment response. Funding: Lundbeck, LLC Disclosure: Dr. Wechsler has received personal compensation for activities with Cyberonics, Eisai, Gerson Lehrman Group Inc., Lundbeck, Sunovion, UCB Pharma, and Upsher-Smith. Dr. Gidal has received personal compensation for activities with Upsher-Smith. Dr. Chung has received personal compensation for activities with UCB Pharma, Eisai, Lundbeck, and Sunovion. Dr. Peng has received personal compensation for activities with Lundbeck. Dr. Isojarvi has received personal compensation fro activities with Lundbeck LLC.

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome lgs p2 039
    Neurology, 2016
    Co-Authors: Robert T. Wechsler, Barry E. Gidal, Steve Chung, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had <25[percnt] response were excluded. Results: Seventy-eight of 206 patients with 12-month follow-up data meeting ≥25[percnt], ≥50[percnt], or ≥75[percnt] responder criteria were included. Overall, 75.6[percnt] of patients had a ≥20[percnt] increase in Clobazam dosage, with 61.0[percnt] achieving improved seizure control (73.3[percnt], 55.0[percnt], and 58.3[percnt] in the ≥25[percnt], ≥50[percnt], and ≥75[percnt] responder groups, respectively). Conclusions: For patients who responded to double-blind Clobazam treatment, ≥20[percnt] dosage increases improved seizure control in ≥60[percnt] of patients during the first year of open-label Clobazam treatment. Positive outcome with dosage optimization was most likely in those initially treated with a lower Clobazam dosage and in those with lower initial treatment response. Funding: Lundbeck, LLC Disclosure: Dr. Wechsler has received personal compensation for activities with Cyberonics, Eisai, Gerson Lehrman Group Inc., Lundbeck, Sunovion, UCB Pharma, and Upsher-Smith. Dr. Gidal has received personal compensation for activities with Upsher-Smith. Dr. Chung has received personal compensation for activities with UCB Pharma, Eisai, Lundbeck, and Sunovion. Dr. Peng has received personal compensation for activities with Lundbeck. Dr. Isojarvi has received personal compensation fro activities with Lundbeck LLC.

Robert T. Wechsler - One of the best experts on this subject based on the ideXlab platform.

  • Optimizing Clobazam treatment in patients with Lennox-Gastaut syndrome.
    Epilepsy & behavior : E&B, 2017
    Co-Authors: Jouko Isojarvi, Barry E. Gidal, Steve Chung, Robert T. Wechsler
    Abstract:

    Given the complexities managing Lennox-Gastaut syndrome (LGS)-comorbid conditions, multiple associated seizure types that tend to be refractory to treatment-dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive Clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive Clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal Clobazam lead-in studies. During the lead-in studies, patients received either placebo or Clobazam (0.25, 0.50, or 1.0mg/kg/d) (maximum 40mg/d); during OLE, patients received Clobazam up to 2.0mg/kg/d (maximum 80mg/d). The post hoc analysis population comprised patients who had ≥25%, ≥50%, or ≥75% seizure reduction from baseline during lead-in Clobazam treatment and ≥12months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥20% Clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or >50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in Clobazam dosage received. The findings of the analysis indicated that Clobazam dosage increases of ≥20% during long-term treatment improved seizure control >80% of patients with LGS who responded to Clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage Clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥75%) lead-in response.

  • Optimizing Clobazam Treatment in Patients with Lennox-Gastaut Syndrome (LGS) (P2.039)
    Neurology, 2016
    Co-Authors: Robert T. Wechsler, Barry E. Gidal, Steve Chung, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had

  • optimizing Clobazam treatment in patients with lennox gastaut syndrome lgs p2 039
    Neurology, 2016
    Co-Authors: Robert T. Wechsler, Barry E. Gidal, Steve Chung, Guangbin Peng, Jouko Isojarvi
    Abstract:

    Objective: To determine the rate of successfully optimized Clobazam dosing in patients with LGS stratified by responder status, an analysis of individual patient dosages, and seizure response over the initial 12 months of open-label, flexible treatment with adjunctive Clobazam. Background: Clobazam is FDA approved as adjunctive treatment (10-40mg/day) in patients with LGS ≥2years of age. Higher Clobazam dosages (up to 80mg/day) were allowed in a phase 3, multicenter, open-label study OV-1004 (NCT01160770) in which patients were dosed to response. Methods: Patients were stratified by partial responder status, determined in a phase 3 lead-in trial (OV-1012; NCT00518713): ≥25[percnt] (25[percnt]-49[percnt]), ≥50[percnt] (50[percnt]-74[percnt]), or ≥75[percnt] (75[percnt]-99[percnt]) reduction in average weekly rate of drop seizures. Patients previously received blinded treatment with placebo or Clobazam high [1.0mg/kg; max 40mg/day], medium [0.50mg/kg; max 20mg/day], or low [0.25mg/kg; max 10mg/day] dosages in OV-1012 before transitioning to open-label Clobazam (0.5mg/kg for 48 hours). Dosage changes up to 2.0mg/kg (maximum 80mg/day) were determined by the investigator. Dosage optimization was defined as ≥20[percnt] Clobazam dosage increase with improved responder status or >50[percnt] additional seizure-frequency reduction (months 3-12). Patients who were previously treated with placebo in OV-1012, seizure-free with Clobazam, or had <25[percnt] response were excluded. Results: Seventy-eight of 206 patients with 12-month follow-up data meeting ≥25[percnt], ≥50[percnt], or ≥75[percnt] responder criteria were included. Overall, 75.6[percnt] of patients had a ≥20[percnt] increase in Clobazam dosage, with 61.0[percnt] achieving improved seizure control (73.3[percnt], 55.0[percnt], and 58.3[percnt] in the ≥25[percnt], ≥50[percnt], and ≥75[percnt] responder groups, respectively). Conclusions: For patients who responded to double-blind Clobazam treatment, ≥20[percnt] dosage increases improved seizure control in ≥60[percnt] of patients during the first year of open-label Clobazam treatment. Positive outcome with dosage optimization was most likely in those initially treated with a lower Clobazam dosage and in those with lower initial treatment response. Funding: Lundbeck, LLC Disclosure: Dr. Wechsler has received personal compensation for activities with Cyberonics, Eisai, Gerson Lehrman Group Inc., Lundbeck, Sunovion, UCB Pharma, and Upsher-Smith. Dr. Gidal has received personal compensation for activities with Upsher-Smith. Dr. Chung has received personal compensation for activities with UCB Pharma, Eisai, Lundbeck, and Sunovion. Dr. Peng has received personal compensation for activities with Lundbeck. Dr. Isojarvi has received personal compensation fro activities with Lundbeck LLC.