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Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy.

ABSTRACT: Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects?6years with high PTE risk treated with LEV 55mg/kg/day orally, nasogastrically or intravenously for 30days starting ?8h after injury in a phase II safety and pharmacokinetic study. Forty-one subjects (26 adults and 15 children) were randomized to PK studies on treatment days 3 and 30. Thirty-six out of forty-one randomized subjects underwent PK study on treatment day 3, and 24/41 subjects underwent PK study on day 30. On day 3, mean T(max) was 2.2h, C(max) was 60.2?g/ml and AUC was 403.7?g/h/ml. T(max) was longer in the elderly than in children and non-elderly adults (5.96h vs. 1.5h and 1.8h; p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4?g/h/ml vs. 461.4?g/h/ml and 450.2?g/h/ml; p=0.08). C(max) trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4?g/ml vs. 59?g/ml and 48.2?g/ml; p=0.07). AUC of n.g. and i.v. administrations was 79% and 88% of AUC of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.

SUBMITTER: Klein P

PROVIDER: S-EPMC4561854 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy.

Klein Pavel P Herr Daniel D Pearl Phillip L PL Natale JoAnne J Levine Zachary Z Nogay Claude C Sandoval Fabian F Trzcinsky Stacey S Atabaki Shireen M SM Tsuchida Tammy T van den Anker John J Soldin Steven J SJ He Jianping J McCarter Robert R

Epilepsy & behavior : E&B 20120707 4

Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects≥6years with high PTE risk treated with LEV 55mg/kg/day orally, nasogastrically or intravenously for 30days starting ≤8h after injury in a phase II safety and pharmacokinetic study. Forty-one subjects (26 adults and 15 children) were randomized to PK studies on treatm ...[more]

PMID: 22771222

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Project description:BackgroundPost-traumatic stress disorder (PTSD) is a distressing and disabling condition that affects significant numbers of children and adolescents. Youth exposed to multiple traumas (eg, abuse, domestic violence) are at particular risk of developing PTSD. Cognitive therapy for PTSD (CT-PTSD), derived from adult work, is a theoretically informed, disorder-specific form of trauma-focused cognitive-behavioural therapy. While efficacious for child and adolescent single-event trauma samples, its effectiveness in routine settings with more complex, multiple trauma-exposed youth has not been established. The Delivery of Cognitive Therapy for Young People after Trauma randomised controlled trial (RCT) examines the effectiveness of CT-PTSD for treating PTSD following multiple trauma exposure in children and young people in comparison with treatment as usual (TAU).Methods/designThis protocol describes a two-arm, patient-level, single blind, superiority RCT comparing CT-PTSD (n=60) with TAU (n=60) in children and young people aged 8-17 years with a diagnosis of PTSD following multiple trauma exposure. The primary outcome is PTSD severity assessed using the Children's Revised Impact of Event Scale (8-item version) at post-treatment (ie, approximately 5 months post-randomisation). Secondary outcomes include structured interview assessment for PTSD, complex PTSD symptoms, depression and anxiety, overall functioning and parent-rated mental health. Mid-treatment and 11-month and 29-month post-randomisation assessments will also be completed. Process-outcome evaluation will consider which mechanisms underpin or moderate recovery. Qualitative interviews with the young people, their families and their therapists will be undertaken. Cost-effectiveness of CT-PTSD relative to TAU will be also be assessed.Ethics and disseminationThis trial protocol has been approved by a UK Health Research Authority Research Ethics Committee (East of England-Cambridge South, 16/EE/0233). Findings will be disseminated broadly via peer-reviewed empirical journal articles, conference presentations and clinical workshops.Trial registrationISRCTN12077707. Registered 24 October 2016 (http://www.isrctn.com/ISRCTN12077707). Trial recruitment commenced on 1 February 2017. It is anticipated that recruitment will continue until June 2021, with 11-month assessments being concluded in May 2022.

Project description:Importance:More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown. Objective:To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy. Design, Setting, and Participants:The Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age. Exposures:Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure. Main Outcomes and Measures:The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations. Results:Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n?=?117) were older at the time of the first seizure than those treated with phenobarbital (n?=?38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P?<?.001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P?=?.01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]). Conclusions and Relevance:Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

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Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy.

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Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy.

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