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A Phase 1 Open-Label, Fixed-Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects.
Thai, C, Tayo, B, Critchley, D
Clinical pharmacology in drug development. 2021;(11):1279-1289
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Abstract
This pharmacokinetic (PK) drug-interaction trial investigated the effects of repeated dosing of a plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in Europe; 100 mg/mL oral solution) on caffeine clearance via modulation of cytochrome P450 (CYP) 1A2 activity in healthy adults. In this phase 1 open-label, fixed-sequence trial, all subjects received a single 200 mg caffeine dose and placebo on day 1. Subjects then titrated CBD from 250 mg once daily to 750 mg twice daily between days 3 and 11 and took 750 mg CBD twice daily between days 12 and 27. On day 26, subjects received a single 200-mg caffeine dose with their morning CBD dose. Plasma concentrations of caffeine and its CYP1A2-mediated metabolite, paraxanthine, were determined on days 1 and 26 and PK parameters derived using noncompartmental analysis. Safety was monitored throughout. Sixteen subjects enrolled, and 9 completed treatment. When caffeine was administered with steady-state CBD, caffeine exposure increased by 15% for Cmax and 95% for AUC0-∞ , tmax increased from 1.5 to 3.0 hours, and t1/2 increased from 5.4 to 10.9 hours compared with caffeine administered with placebo. Under the same conditions, paraxanthine exposure decreased by 22% for Cmax and increased by 18% for AUC0-∞ , tmax increased from 8.0 to 14.0 hours, and t1/2 increased from 7.2 to 13.7 hours. Overall, there were no unexpected adverse events; diarrhea was most common, and 6 subjects discontinued because of elevated liver transaminases. These data suggest that CBD is an inhibitor of CYP1A2.
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TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101.
Premoli, I, Rossini, PG, Goldberg, PY, Posadas, K, Green, L, Yogo, N, Pimstone, S, Abela, E, Beatch, GN, Richardson, MP
Annals of clinical and translational neurology. 2019;(11):2164-2174
Abstract
OBJECTIVE Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. METHODS TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2-, 4-, and 6-hours post drug intake in a double-blind, placebo-controlled, randomized, two-period crossover study of 20 healthy male volunteers. RESULTS Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15-55 msec after TMS) and at late (150-250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration. INTERPRETATION Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early-stage clinical trials.
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The Lack of Effect of Food on the Pharmacokinetics of ZX008 (Fenfluramine Oral Solution): Results of a Single-dose, Two-period Crossover Study.
Gammaitoni, A, Smith, S, Boyd, B
Clinical therapeutics. 2018;(8):1338-1346
Abstract
PURPOSE Fenfluramine is being developed as a low-dose adjunctive treatment for seizures in patients with Dravet syndrome and other epileptic encephalopathies, including Lennox-Gastaut syndrome. Most patients with Dravet syndrome receive multiple antiepileptic drugs, making it challenging for caregivers to track correct administration times. The present Phase I study was conducted to determine the effect of food on the pharmacokinetic properties of fenfluramine. METHODS Healthy nonsmoking subjects aged 18 to 50 years were enrolled in an open-label, crossover, Phase I pharmacokinetic and safety profile study and received 2 single 0.8-mg/kg doses of ZX008 (fenfluramine hydrochloride oral solution), 1 after a 10-hour overnight fast and the other 30 minutes after the start of consumption of a high-fat breakfast, in a randomly assigned order. A washout period of at least 9 days separated the 2 treatment periods. Venous blood samples were taken before each dose and periodically for 72 hours after each dose for determination of concentrations of fenfluramine and its active metabolite norfenfluramine. Plasma pharmacokinetic parameters were estimated for each subject by noncompartmental analysis. FINDINGS In the 13 subjects completing both treatment periods, food had no effect on the rate or extent of absorption and bioavailability of fenfluramine as assessed by fed vs fasted adjusted geometric mean observed plasma Cmax (59.1 vs 56.7 ng/mL; NS) and AUC0-∞ (1640 vs 1600 ng · h/mL; NS). Additionally, there was no impact of food on systemic exposure of norfenfluramine. Seven subjects reported at least 1 treatment-emergent adverse event; all treatment-emergent adverse events were mild in severity. IMPLICATIONS The bioequivalence and tolerability of single 0.8-mg/kg oral doses of ZX008 in the fed and fasted states support ZX008 administration without regard to meals.
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Tolerability of adjunctive eslicarbazepine acetate according to concomitant lamotrigine or carbamazepine use: A subgroup analysis of three phase III trials in adults with focal (partial-onset) seizures.
Abou-Khalil, B, Klein, P, Shah, A, Ryvlin, P, Specchio, LM, Gama, H, Rocha, F, Blum, D, Grinnell, T, Cheng, H, et al
Epilepsy research. 2018;:80-86
Abstract
OBJECTIVE To evaluate and compare the effects of concomitant lamotrigine (LTG) or carbamazepine (CBZ) on the incidence of treatment-emergent adverse events (TEAEs) in patients taking adjunctive eslicarbazepine acetate (ESL) for focal (partial-onset) seizures (FS). METHODS These post-hoc analyses of data pooled from three randomized, double-blind, placebo-controlled studies of adjunctive ESL (BIA-2093-301, -302 and -304) included adults (≥16 years) with FS refractory to 1-3 antiepileptic drugs (AEDs). Patients were randomized equally to placebo, ESL 400 mg (Studies 301 and 302 only), 800 mg, or 1200 mg once daily (8-week baseline, 2-week titration, and 12-week maintenance periods). TEAEs, TEAEs leading to discontinuation, and serious AEs (SAEs) were evaluated in patients taking, or not taking, LTG (excluding those taking CBZ or phenytoin [PHT]; i.e., the +LTG and -LTG/-CBZ subgroups), or CBZ (excluding those taking LTG or PHT; i.e., the +CBZ and -LTG/-CBZ subgroups) at baseline. RESULTS LTG was used concomitantly by 248 patients (+LTG; placebo, n = 81; ESL, n = 167) and CBZ by 613 patients (+CBZ; placebo, n = 172; ESL, n = 441); 361 patients were taking neither LTG nor CBZ (-LTG/-CBZ; placebo, n = 109; ESL, n = 252). The overall incidence of TEAEs with ESL (any dose) was numerically higher for +CBZ (77%) than for +LTG (73%) or -LTG/-CBZ (68%; statistical significance not tested). Among patients taking ESL, dizziness, diplopia, and vomiting were reported more frequently in the +CBZ subgroup (30%, 14%, and 10%, respectively) than in the +LTG (16%, 8%, 5%) or -LTG/-CBZ (11%, 3%, 5%) subgroups. The overall incidence of TEAEs leading to discontinuation with ESL was higher for +CBZ (21%) than for +LTG (13%) or -LTG/-CBZ (15%). Dizziness leading to discontinuation with ESL was reported more frequently in the +CBZ subgroup than in the +LTG or -LTG/-CBZ subgroups (9%, 3%, and 3%, respectively). The overall incidence of SAEs in patients taking ESL was comparable across subgroups (+LTG, 5%; +CBZ, 6%; -LTG/-CBZ, 5%). The results were similar when evaluating placebo-adjusted incidences. CONCLUSION There was a potential pharmacodynamic interaction between AEDs with a putatively similar mechanism of action, with a seemingly lesser interaction between ESL and LTG versus ESL and CBZ. If combining ESL with LTG or CBZ, clinicians should be aware of the potential risk for an increased incidence of TEAEs typically associated with voltage-gated sodium channel inhibitors (e.g., dizziness, blurred vision, vertigo, diplopia, headache, or vomiting).
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Clinical features of benign epilepsy of childhood with centrotemporal spikes in chinese children.
Liu, MJ, Su, XJ, Md, XS, Wu, GF, Zhang, YQ, Gao, L, Wang, W, Liao, JX, Wang, H, Mai, JN, et al
Medicine. 2017;(4):e5623
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Abstract
This multicenter clinical trial was conducted to examine current practice of benign epilepsy with centrotemporal spikes and especially address the question that in what circumstances 1 antiepileptic drug (AED) should be preferred.Twenty-five medical centers participate in this clinical trial. The general information, clinical information, and treatment status were collected under the guidance of clinicians and then analyzed. Difference between different treatment groups was compared, and usefulness of the most commonly used AEDs was evaluated.A total of 1817 subjects were collected. The average age of the subject was 8.81 years. The average age of onset is 6.85 years (1-14 years). Male-to-female ratio is 1.13:1. A total of 62.9% of the patients are receiving monotherapies, and 10.6% are receiving multidrug therapy. Both age and course of disease of treated rolandic epilepsy (RE) patients are significantly different from those of untreated patients. Bilateral findings on electroencephalography (EEG) are less seen in patients with monotherapy compared with patients with multidrug therapy. Except for 25.4% patients not taking any AEDs, oxcarbazepine (OXC), sodium valproate (VPA), and levetiracetam (LEV) are the most commonly used 3 AEDs. VPA and LEV are commonly used in add-on therapy. OXC and LEV are more effective as monotherapy than VPA.Age of onset of Chinese RE patients is 6.85 years. Bilateral findings on EEG could be a risk factor to require multidrug therapy. In Chinese patients, OXC, VPA, and LEV are most commonly used AEDs as monotherapy and OXC and LEV are more effective than VPA.
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Quantification of the impact of enzyme-inducing antiepileptic drugs on irinotecan pharmacokinetics and SN-38 exposure.
Berg, AK, Buckner, JC, Galanis, E, Jaeckle, KA, Ames, MM, Reid, JM
Journal of clinical pharmacology. 2015;(11):1303-12
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Abstract
The population pharmacokinetic model reported here was developed using data from 2 phase 2 trials of irinotecan for treatment of malignant glioma to quantify the impact of concomitant therapy with enzyme-inducing antiepileptic drugs (EIAEDs) on irinotecan pharmacokinetics. Patients received weekly irinotecan doses of 100 to 400 mg/m(2) , and plasma samples were collected and analyzed for irinotecan and its APC, SN-38, and SN-38G metabolites. Nonlinear mixed-effects modeling was employed for population pharmacokinetic analysis. Concomitant therapy with phenytoin, phenobarbital, or carbamazepine increased the clearances of irinotecan, SN-38, and SN-38G but not APC. SN-38 clearance was 2-fold higher with concomitant EIAED use, resulting in 40% lower SN-38 exposure. Evaluation of additional covariates revealed no clinically relevant effects of sex or concomitant corticosteroid use. The population pharmacokinetic model suggests that a 1.7-fold increase in irinotecan dose may compensate for decreases in SN-38 exposure in the presence of concomitant EIAEDs. Although slightly more conservative, this dose adjustment is consistent with those recommended based on increases in the maximally tolerated dose for malignant glioma patients receiving EIAEDs and may be an appropriate starting point for further investigation when extrapolating to other cancer types or alternative regimens.
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Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.
Jacobson, MP, Pazdera, L, Bhatia, P, Grinnell, T, Cheng, H, Blum, D, ,
BMC neurology. 2015;:46
Abstract
BACKGROUND Eslicarbazepine acetate (ESL, Aptiom®) is a once-daily (QD) anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). It is extensively converted after oral administration to eslicarbazepine, and is believed to exert its effect through inhibition of voltage-gated sodium channels. The possible role of ESL as monotherapy to treat POS has not yet been established. METHODS This study was an 18-week, multicenter, randomized double-blind trial of gradual conversion to ESL monotherapy in adults with POS not well controlled by 1-2 antiepileptic drugs (AEDs), using historical data as the control. The study comprised an 8-week baseline period, a 2-week titration period, a 6-week AED conversion period, a 10-week monotherapy period, and either a 1-week taper period or optional entry to an open-label extension study. The primary endpoint compared the Kaplan-Meier (KM)-estimated 112-day exit rate with a threshold value calculated from the historical controls. RESULTS There were 172 randomized patients; 154 (90%) entered the AED conversion period and 121 (70%) completed the study. The KM-estimated exit rates [confidence interval (CI)] were 15.6% [8.1-28.7%] for ESL 1200 mg, and 12.8% [7.5-21.5%] for ESL 1600 mg. The upper limits of the 95% CI KM-estimates were below the pre-specified threshold for historical control of 65.3%, indicating that ESL was efficacious in reducing seizure-related exits, compared with historical control. During the 18-week double-blind treatment period, median reductions in standardized seizure frequency occurred with ESL 1200 mg (36.1%) and ESL 1600 mg (47.5%). The responder rates (a 50% or greater reduction in seizure frequency from baseline) during the 18-week double-blind period and the monotherapy period, respectively, were 35.2% and 38.9% for ESL 1200 mg, and 46.0% and 46.0% for ESL 1600 mg. The overall adverse event profile was consistent with the known safety profile of ESL. CONCLUSIONS These findings indicate that ESL monotherapy (1200 and 1600 mg QD) was efficacious and well tolerated in this study. TRIAL REGISTRATION NCT01091662 ; EudraCT No. 2010-018684-42.
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Rufinamide as an adjuvant treatment in children with Lennox-Gastaut syndrome.
Kim, SH, Eun, SH, Kang, HC, Kwon, EJ, Byeon, JH, Lee, YM, Lee, JS, Eun, BL, Kim, HD
Seizure. 2012;(4):288-91
Abstract
PURPOSE To evaluate the efficacy of rufinamide as an add-on treatment in children and adolescents with Lennox-Gastaut syndrome (LGS). METHODS The study was an open-label, observational clinical trial of rufinamide as an add-on treatment in intractable LGS patients. This intent-to-treat trial included 4 weeks of scheduled titrated doses and a 12-week maintenance phase with a target dose of 20-40 mg/kg rufinamide, adjusted according to its effectiveness and tolerability after a baseline period of 4 weeks. The primary outcome was measured by the seizure-reduction rate according to individual seizure type over the 12-week maintenance period. RESULTS One hundred and twenty-eight patients with LGS who were determined to be unresponsive to one or more antiepileptic drugs or dietary therapy were enrolled. Of the 128 patients enrolled, 112 (87.5%) completed the study. After add-on rufinamide treatment, 46 patients (35.9%) achieved a more than 50% reduction in seizure frequency and 10 (7.8%) patients became seizure-free. When we identified those who responded with an at least 50% reduction in seizure frequency, 39.4% of the responders reported reductions in convulsive seizures, 36.4% in drop attacks, 33.3% in myoclonic seizures, and 20.0% in epileptic spasms. Overall, 32.8% of patients reported adverse effects, which were mostly mild and transient in nature. The most common adverse effects were fatigue (15 patients, 11.7%) and poor appetite (9 patients, 7.0%). Twenty-one (16.4%) patients experienced an increased seizure frequency. CONCLUSIONS Rufinamide appears to be a safe and effective adjuvant treatment for many cases of intractable LGS.
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The effect of vitamin B supplementation on homocysteine metabolism and clinical state of patients with chronic epilepsy treated with carbamazepine and valproic acid.
Bochyńska, A, Lipczyńska-Łojkowska, W, Gugała-Iwaniuk, M, Lechowicz, W, Restel, M, Graban, A, Lipska, B, Ryglewicz, D
Seizure. 2012;(4):276-81
Abstract
PURPOSE To investigate the influence of vitamin B supplementation on the plasma total homocysteine (p-tHcy), serum folate (s-FA), serum B12 (s-B12), and clinical state of patients with chronic epilepsy. METHODS Beck Depression Inventory (BDI) scores and p-tHcy, s-B12, and s-FA levels were assessed at baseline, after 1 year of supplementation (G1), and before and after 1 year of VPA or CBZ therapy (G2). RESULTS Eighty-one patients participated in the study: 51 patients with chronic epilepsy (G1) treated with carbamazepine (CBZ) or valproic acid (VPA), and 30 patients with newly diagnosed epilepsy (G2). At baseline, mean p-tHcy level was significantly higher in G1 than G2 (p=0.0001) with no significant differences in s-FA or s-B12 levels. p-tHcy level significantly decreased in CBZ-treated G1 patients (p=0.00002) after 1 year of supplementation and increased in G2 after 1 year of anti-epileptic drug (AED) therapy without supplementation. BDI scores in G1 decreased significantly after 1 year of supplementation (p=0.0001) and increased significantly in VPA-treated G2 patients after 1 year of AED therapy (p=0.02). The number of hyperhomocysteinemic patients significantly decreased in G1 after vitamin B supplementation (p=0.01) and increased in G2 (p=0.002). We also observed improved BDI scores and reduced seizure frequency in patients with chronic epilepsy. CONCLUSIONS These data support the hypothesis that AEDs play a major role in hyperhomocysteinemia development in patients with epilepsy. Adding folate and vitamin B12 to AED therapy is a safe and inexpensive way to reduce the risk of hyperhomocysteinemia.
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Valproate sodium enhances body weight gain in patients with childhood epilepsy: a pathogenic mechanisms and open-label clinical trial of behavior therapy.
Kanemura, H, Sano, F, Maeda, Y, Sugita, K, Aihara, M
Seizure. 2012;(7):496-500
Abstract
OBJECTIVES Excessive weight gain associated with valproate sodium (VPA) may predispose patients with epilepsy to other health problems such as insulin resistance. The purpose of this study was to examine the changes in body weight and several biochemical parameters in children receiving VPA treatment. The effects of behavior therapy for epileptic children with VPA-induced weight gain are discussed. METHODS Fifteen patients newly diagnosed with epilepsy were included in the study. The following parameters were measured: body weight, body mass index (BMI), serum glucose, serum insulin, serum VPA concentration and serum free carnitine. In addition, behavior therapy was introduced at the initiation of VPA therapy, and lasted at least for 2 years. RESULTS After 6 months of follow-up, there were eight (53%) patients in whom weight gain was demonstrated. Significant increases in the serum insulin level and the insulin/glucose ratio were observed in the weight gain group (p<0.01). All patients with significant weight gain showed increased appetite. However, BMI stopped increasing with intensive behavior therapy. CONCLUSIONS These findings suggest that an increase in serum insulin and insulin/glucose levels may cause weight gain, possibly by stimulating appetite, and that weight changes seem to be reversible with intensive behavior therapy without discontinuation of VPA.