Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials

PURPOSE: To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state. METHODS: Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000-4000 mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose). RESULTS: Estimated pharmacokinetic values, normalized to a dose of 1 mgkg(-1) b.i.d., were: concentration at 1h (C(1h)) 2.1 microgram ml(-1), concentration at 12h (C(12h)) 0.8 microgram ml(-1), area under the curve from 0 to 12h (AUC(0-12h)) 17.1 microgram ml(-1)h, half-life (t(1/2)) 8.1h, and apparent oral clearance (CL/F) 0.97 mlmin(-1)kg(-1). Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t(1/2) tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest. CONCLUSIONS: Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.     

Placebo responses in randomized trials of antiepileptic drugs

This meta-analysis of published, randomized, controlled trials (RCTs) of antiepileptic drugs in adults with focal drug-resistant epilepsy was performed to estimate a mean placebo effect, to evaluate variability in placebo response rates, to investigate associations between placebo effect rates and study characteristics, and to determine whether there were changes in placebo response rates over recent years in RCTs (so-called “placebo drift”). One hundred ninety-eight potentially appropriate studies were identified after MEDLINE search and carefully reviewed. Twenty-seven RCTs (with 5662 randomized patients, including 1887 patients in placebo arms) were included in the meta-analysis. A random effects meta-analytic model estimated the pooled placebo response at 12.5% (95% CI: 10.03–14.94%). A statistically significant correlation between baseline median seizure frequency and placebo response rates was not observed. “Placebo drift” was not considered statistically significant.     

Influence of enzyme inducing antiepileptic drugs on the pharmacokinetics of levetiracetam in patients with epilepsy

To assess whether levetiracetam elimination is influenced by enzyme inducing antiepileptic drugs (EIAEDs), serum levetiracetam levels were determined at frequent intervals after a single oral 1000mg dose in 15 subjects co-medicated with EIAEDs and 15 matched controls. The EIAED group showed a higher levetiracetam oral clearance (p=0.01) and a shorter half-life (p=0.02) than controls. Although the magnitude of interaction is relatively modest, it could have clinical significance for some patients.     

Seizure-free outcome in randomized add-on trials of the new antiepileptic drugs

PURPOSE: The goal of this study is to (1) provide clinically useful, previously unpublished comparative analyses of seizure-freedom rates for newer antiepileptic drugs (AEDs), and (2) recommend a standard for data presentation and analysis. METHODS: Data were reviewed from placebo-controlled adjunctive trials in refractory patients of gabapentin (GPN), lamotrigine (LTG), topiramate (TOP), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), zonisamide (ZNS), and pregabalin (PGB). Seizure-freedom analyses in these publications, if included at all, consistently included both patients who completed the trial, and those who dropped out prior to completion (last observation carried forward, LOCF). This has the potential to increase reported seizure-free outcomes. Pharmaceutical companies were contacted for the provision of unpublished seizure-free data in the patients who completed the entire study. RESULTS: In most cases, LOCF analysis produced a higher rate of seizure freedom compared to complete analysis. A total of 0%-1.1% of the LOCF population was seizure-free in the GPN trials (complete data not available). For the remaining AEDs, seizure-freedom results in the LOCF versus complete populations were: 0.7% versus 0.8% (LTG trial); 12% versus 2.6% (OXC trial); 3.6%-6.4% versus 3.9%-7.1% (LEV trial); 3.7%-7.9% versus 1.3%-1.4% (PGB trial); and 6.0% versus 3.0% (ZNS trial, minus titration period). CONCLUSIONS: By employing LOCF, a clinically unrealistic picture of seizure-free rates may be reported. Access to complete data is informative, as it includes only those patients who were able to tolerate the drug at doses that produced seizure freedom. Ideally, data from both ITT and complete analyses should be made available.     

Long-lasting antiepileptic effects of levetiracetam against epileptic seizures in the spontaneously epileptic rat (SER): differentiation of levetiracetam from conventional antiepileptic drugs

PURPOSE: Some evidence suggests that levetiracetam (LEV) possesses antiepileptogenic characteristics. The purpose of this study was to investigate the time course of seizure protection by LEV compared with that of phenytoin (PHT), phenobarbital (PB), valproate (VPA), and carbamazepine (CBZ) in the spontaneously epileptic rat (SER). The SER is a double mutant (tm/tm, zi/zi) showing both tonic convulsions and absence-like seizures. METHODS: The effect of single (40, 80, and 160 mg/kg, i.p.) and 5-day (80 mg/kg/day, i.p.) administration of LEV on tonic convulsions and absence-like seizures in SERs were studied. Tonic convulsions induced by blowing air onto the animal's head at 5-min intervals for 30 min and spontaneous absence-like seizures characterized by 5- to 7-Hz spike-wave-like complexes in the cortical and hippocampal EEG were recorded for 30 min. In the single-administration study, observations for seizure activity were performed once before and 3 times (45, 75, and 135 min) after drug administration. In the 5-day administration study, seizure observation was performed 4 times for 30 min (once before and 3 times after drug administration) during the 5-day drug-administration period, and continued once a day until 8 days after the final administration. The antiepileptic effects of 5-day administration of conventional AEDs (PHT, PB, VPA, and CBZ) were examined by using similar methods. RESULTS: Tonic convulsions and absence-like seizures were inhibited by a single administration of LEV at 80 and 160 mg/kg, i.p., but not significantly at 40 mg/kg, i.p. When LEV was repeatedly administered at 80 mg/kg/day, i.p., for 5 days to SERs, the inhibitory effects on seizures increased with administration time. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1% and 38.4% compared with previous values, respectively, after 5-day LEV administration. Furthermore, significant inhibition of tonic convulsions was detected 相似文献   

Levetiracetam and partial seizure subtypes: pooled data from three randomized, placebo-controlled trials

PURPOSE: To determine the effect of levetiracetam (LEV) on partial seizure subtypes (simple partial, complex partial, and secondarily generalized seizures) in patients with refractory epilepsy. METHODS: Pooled results from three placebo-controlled trials were analyzed. RESULTS: A statistically significant reduction in the frequency of all partial seizures and all seizure subtypes was observed in the LEV group (p < 0.001 vs. placebo). The proportion of patients in whom secondarily generalized seizures could be prevented over and above the reduction of partial seizures was significantly greater in the LEV group as compared with placebo, with an odds ratio of 1.83 [95% confidence interval (CI), 1.10-3.05]. CONCLUSIONS; LEV reduces frequency of simple and complex partial seizures. In addition, it demonstrates a specific, independent reduction of secondarily generalized seizures.     

The influence of antiepileptic drugs on cognition: a comparison of levetiracetam with topiramate

Levetiracetam (LEV) and topiramate (TPM) are considered highly effective novel antiepileptic drugs (AEDs) in the treatment of focal epilepsies. To explore potential side effects, this study investigated their influence on cognitive functions comparatively by means of a standardized neuropsychological test battery assessing several cognitive domains. In this observational study, cognitive changes were explored in 30 consecutively recruited patients with focal epilepsy treated with LEV and in 21 patients treated with TPM, comparing functions assessed prior to gradual initiation and after reaching steady state of the individual target dosage. Before titration, patient groups did not differ significantly with respect to cognitive performance. Whereas the LEV group manifested no change in cognitive performance after AED titration, the TPM group worsened in the cognitive domains of cognitive speed and verbal fluency, as well as short-term memory. These findings suggest that TPM, unlike LEV, may impair frontal lobe functions. The lack of cognitive side effects related to LEV treatment may be relevant for treatment decisions.     

When clinical trials make history: Demonstrating efficacy of new antiepileptic drugs as monotherapy

Regulatory requirements to demonstrate the efficacy of novel antiepileptic drugs (AEDs) as monotherapy differ between Europe and the United States. European regulators require a comparison with an established, optimally dosed AED, typically using a noninferiority design, whereas the U.S. Food and Drug Administration (FDA) demands demonstration of superiority versus a comparator. Because placebo cannot be used as sole therapy and it is unrealistic to expect that a new AED will be more efficacious than established agents at full dosages, superiority monotherapy trials in epilepsy have traditionally relied on inclusion of controls treated with a suboptimal (low‐dose) comparator. In the most common design, refractory patients are randomized to conversion to monotherapy with a full dose of the investigational agent or a low‐dose active control, and are required to exit the trial if seizures deteriorate. Efficacy is demonstrated when exit rates are lower in the full‐dose group than in controls. Although this design is efficient in demonstrating superiority, the use of suboptimal treatments has been increasingly criticized on ethical grounds. A meta‐analysis has now demonstrated that patients randomized to suboptimal treatments in all previous trials had similar outcomes, thereby allowing the build up of a dataset of historical controls against which response to investigational AEDs can be compared in future trials. Use of historical controls has been accepted by the FDA, subject to compliance with rigorous methodologic requirements. Although the avoidance of suboptimal treatments in future trials is a welcome development, the conversion‐to‐monotherapy design is still far from being fully satisfactory and is not exempt from methodologic concerns.     

Metrifonate therapy in Alzheimer's disease: a pooled analysis of four randomized, double-blind, placebo-controlled trials

This retrospective analysis assessed the efficacy of metrifonate in the treatment of mild to moderate Alzheimer's disease (AD). Those four studies meeting Food and Drug Administration guidelines for establishing the efficacy of an AD therapeutic agent were pooled for further analysis. Data were included from all patients valid for the intent-to-treat analyses (last observation carried forward). Patients received once daily placebo (n = 550), metrifonate 30-60 mg (by weight, n = 769) or 60/80 mg (by weight, n = 197). Metrifonate 60/80 mg significantly improved the cognitive abilities [AD Assessment Scale - Cognitive Subscale (ADAS-Cog), p = 0.0001; Mini Mental State Examination (MMSE), p = 0.0001], psychiatric and behavioral disturbances (Neuropsychiatric Inventory, p = 0.039; ADAS - Noncognitive Subscale, p = 0.0001), performance of instrumental and basic activities of daily living (Disability Assessment for Dementia, p = 0.0002) and global status (Clinician's Interview-Based Impression of Change with Caregiver Input, p = 0.0001) of AD patients when compared with placebo. Metrifonate effects across these domains were dose related. Metrifonate 60/80 mg significantly improved the cognitive performance relative to both placebo and to baseline as evaluated by both the ADAS-Cog and the MMSE. Metrifonate is the first cholinesterase inhibitor consistently shown under prospective, placebo-controlled conditions to improve significantly behavior in addition to cognition, function in activities of daily living and global functional status of patients with mild to moderate AD.     

The impact of background antiepileptic drugs on the efficacy and safety of pregabalin in treating partial-onset seizures: a post hoc analysis of combined clinical trials

Pregabalin is used as adjunctive treatment for partial-onset seizures and is often combined with multiple antiepileptic drugs (AEDs) from different classes. The objectives of this post hoc analysis were to evaluate the efficacy and safety of pregabalin when added to different AED regimens and to identify specific AED combinations that in conjunction with pregabalin yield high responder rates. Data from six double-blind, randomized studies of pregabalin in patients with partial-onset seizures were pooled for analysis (N=1775). When the treatment groups (placebo, 150mg, 300mg, 600mg, and flexible dose) were stratified by the number of concomitant AEDs (one, two or three or more), modeling results suggested that the magnitude of improvement on either ≥50% responder rate or mean response ratio remained consistent regardless of the number of concomitant AEDs. Adverse events were typical of pregabalin and, in general, did not vary as the number of concomitant AEDs increased. A cluster analysis was performed to identify possible combinations of AEDs that yielded high ≥50% responder rates. The majority of patients (>90%) fell within two clusters that yielded high responder rates, while <10% of the patients fell within two clusters that yielded low responder rates. Numerous AED combinations, ranging from 6 to 11, occurred within each cluster. In summary, pregabalin provided a consistent improvement in seizure reduction and comparable tolerability in patients with partial-onset epilepsy regardless of the number of concomitant AEDs.     

Quality-of-life and behavioral outcome measures in randomized controlled trials of antiepileptic drugs: a systematic review of methodology and reporting standards

PURPOSE: To review the methodology and use of quality-of-life and behavioral measures used in randomized controlled trials (RCTs) of antiepileptic drugs in patients with epilepsy. METHODS: Trial reports were found by searching a previously developed comprehensive database of epilepsy RCTs and searching through journals by hand. Inclusion and exclusion criteria were applied, and methodological and quality-of-life and behavioral measure data were extracted. RESULTS: There were 52 different measures used in 46 trials, with the Profile of Mood States, the Minnesota Multiphasic Personality Inventory, and the Washington Psychosocial Seizure Inventory being applied the most frequently. Overall, evidence of the reliability, validity, and sensitivity of measures used in populations of people with epilepsy was sparse. There was also little information on the clinical interpretation of the results. CONCLUSION: Our results highlight a consistent failure to apply quality-of-life and behavioral measures in RCTs in a systematic way. We found repeated evidence of researchers' failure to review the use of previous measures and selection of measures without evidence of their appropriateness for use in a population with epilepsy. We recommend the use of quality-of-life and behavioral measures in RCTs with proven psychometric properties in a population with epilepsy.     

Self-rating data as a selecting factor in clinical trials of psychotropic drugs

Summary In psychiatry the relationship between rating by others and self-rating has been discussed again and again. The question has been raised as to the influence of complete data material (all patients with self-rating and rating by others) on results, in comparison to results where patients without self-rating are not taken into evaluation. This question was answered by conducting a double-blind study which included two pharmacologically active substances (amitriptylinoxide and trazodone) and two sub-samples of patients (patients with rating by others and self-rating, and patients with rating by others alone). The trial was performed in a total of 57 in-patients suffering from endogenous depression (ICD 296.1) who received drug treatment for 21 days. The effect was assessed multi-methodically. While no differences between the two drugs were seen in the sub-sample self-rating and rating by others, amitriptylinoxide proved to be superior to trazodone in the sub-sample rating by others. On the basis of these findings the use of rating by others and self-rating procedures will be considered.