SUMMARYPurpose: To evaluate the relative contribution of demographic and epilepsy-related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health-related quality of life (HRQOL) in adults with pharmacoresistant epilepsy. Methods: Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II). Multivariate linear regression models were used to identify variables associated with QOLIE-31 total score and subscale scores. Key Findings: Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the selfassessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE-31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (b = )0.451, p < 0.001) and BDI-II scores (b = )0.398, p < 0.001). These factors were also the strongest predictors of scores in each of the seven QOLIE-31 subscales. Other predictors of HRQOL were age (b = )0.060, p = 0.008), lack of a driving license (b = )0.053, p = 0.018), pharmacoresistance grade, with higher HRQOL in individuals who had failed only one AED (b = 0.066, p = 0.004), and location of the enrolling center. Epilepsy-related variables (seizure frequency, occurrence of tonic-clonic seizures, age of epilepsy onset, disease duration) and number of AEDs had no significant predictive value on HRQOL. The AEP total score was the strongest negative predictor of HRQOL in the subgroup of 362 patients without depressive symptoms (BDI-II score <10), but even in this subgroup the BDI-II score was retained as a significant predictor. Significance: In individuals with pharmacoresistant epilepsy, AEs of medication and depressive symptoms are far more important determinants of HRQOL than seizures themselves. When seizure freedom cannot be achieved, addressing depressive comorbidity and reducing the burden of AED toxicity is likely to be far more beneficial than interventions aimed at reducing the frequency of seizures. KEY WORDS: Antiepileptic drugs, Pharmacoresistance, Depression, Adverse event profile.The primary objective of the management of epilepsy is to restore a normal health-related quality of life (HRQOL). To achieve this goal, complete seizure control without adverse effects (AEs) is the primary prerequisite, but other factors such as comorbidities and psychosocial constraints also need to be addressed (Perucca & Tomson, 2011;Taylor et al., 2011 To date, most studies of HRQOL in epilepsy have been conducted in relatively small or heterogenous populations of patients with controlled and uncontrolled seizures, and have focused on specific factors, most notably the impact of seizures and AEs of treatment (Baker et al., 1997;Gilliam et al., 2004a;Cramer et al., 2007) or seizures and comorbidities...

Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the last 2 decades, the proportion of individuals with pharmacoresistant epilepsy has not been reduced substantially compared with the late 1960s. All currently available AEDs also have limitations in terms of adverse effects and susceptibility to be involved in clinically important drug-drug interactions. Therefore, the search for potentially more effective and better tolerated agents is continuing. This article reviews the pharmacological and clinical profile of the latest compounds to receive marketing authorization. Since the beginning of 2008, three novel AEDs, lacosamide, eslicarbazepine acetate and retigabine (also known as ezogabine), have become commercially available in Europe, with lacosamide and retigabine also being licensed in the US. All three agents are indicated for the adjunctive treatment of focal seizures in adults. Eslicarbazepine acetate is a produg for eslicarbazepine, which acts by blocking voltage-dependent sodium channels. Lacosamide enhances the slow inactivation phase of voltage-dependent sodium channels, and retigabine potentiates neuronal M-currents by opening Kv 7.2-7.5 potassium channels. All three agents, which are well absorbed from the gastrointestinal tract, exhibit linear pharmacokinetics. Lacosamide is also available as an intravenous formulation intended as replacement therapy for patients temporarily unable to take oral medications. All three drugs are eliminated partly unchanged in urine and partly by biotransformation through glucuronide conjugation (eslicarbazepine, retigabine), N-acetylation (retigabine) and oxidative demethylation (lacosamide). The half-life is in the order of 8-20 hours for eslicarbazepine, 12-16 hours for lacosamide and 6-10 hours for retigabine. Based on the limited information available to date, the ability of these agents to cause pharmacokinetic drug interactions appears to be relatively modest, although eslicarbazepine can cause a significant decrease in the blood levels of ethinylestradiol, levonorgestrel and simvastatin. The approved effective dose ranges are 200-400 mg/day in two divided doses for lacosamide, 800-1200 mg/day once daily for eslicarbazepine acetate, and 600-1200 mg/day in three divided doses for retigabine. In phase III, randomized, double-blind, adjunctive therapy trials, responder rates (proportion of patients with ≥50% reduction in seizure frequency vs baseline) at the highest approved dose were comparable for the three drugs (eslicarbazepine acetate: 37-43% vs 13-20% for placebo; lacosamide: 38-41% vs 18-26% for placebo; retigabine: 33-44% vs 16-18% for placebo). The adverse events most commonly reported with active treatment compared with placebo included dizziness, diplopia and nausea for lacosamide; dizziness, somnolence and nausea for eslicarbazepine acetate; and dizziness, somnolence and fatigue for retigabine. The role of these agents in the treatment algorithm will be increasingly defined as clinical experience accumulates. At present, t...

ICWCNS, Basel, and if1.P.A.S. SA, Stubio, Switzerland Summary: Purpose: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives.Methods: Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mglday) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 p,g ethinylestradiol (EE) and 250 tJ-g levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle.Results: Compared with placebo, areas under the plasma concentration curves (AUC,,,,, geometric means) decreased by 47% for both EE (from 1,677 to 886 pgWml; p < 0.01) and LN(from 137 to 73 ngWml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < O.Ol), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p i 0.01).Conclusions: OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.

SUMMARYPurpose: To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy. Methods: Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14. The doubleblind phase was followed by an open-label follow-up. Key Findings: Nine of 38 patients (23.7%) were responders in the levetiracetam group, compared with one of 21 (4.8%) in the placebo group (p = 0.08). Seven of 38 patients (18.4%) were free from clinical and EEG seizures during the last 4 days of the trial (including 24-h EEG monitoring on day 14) compared with none of the patients treated with placebo (p = 0.04). Seventeen patients remained seizure-free on levetiracetam after 1 year follow-up. Of the 41 patients who discontinued levetiracetam due to lack of efficacy (n = 39) or adverse events (n = 2), 34 became seizure-free on other treatments. Significance: Although superiority to placebo just failed to reach statistical significance for the primary end point, the overall findings are consistent with levetiracetam having modest efficacy against absence seizures. Further controlled trials exploring larger doses and an active comparator are required to determine the role of levetiracetam in the treatment of absence epilepsy.

Summary:Purpose: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy.Methods: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 p,g/ml for PHT, 1 5 4 0 pg/ml for PB, 4-11 pg/ml for CBZ, and 40-100 pg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated.Results: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of I16 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61 %), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups.Conclusions: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome, and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to he more rewarding than routine measurements in a large clinic population.

Summary:Purpose: To characterize the metabolic profile of topiramate (TPM) in humans and to assess the influence of enzyme induction by carbamazepine (CBZ) on the pharmacokinetics and metabolic profile of TPM.Methods: Twelve healthy subjects received a single oral dose of TPM (200 mg) on two randomized occasions. On one occasion, TPM was administered alone, and on the other, it was given on day 18 of a 24-day treatment with CBZ (maintenance dosage, 600 mg/day). Blood and urine samples were collected for ≥72 h after dosing. TPM and its metabolites were assayed in plasma and urine by a specific liquid chromatography-mass spectroscopy (LC-MS) method.Results: Mean TPM oral clearance (CL/F) increased from 1.2 L/h (control) to 2.2 L/h after CBZ treatment. Mean TPM halflife decreased from 29 h to 19 h. TPM was excreted extensively in urine both under noninduced (56%) and CBZ-induced conditions (40%). 2,3-O-Des-isopropylidene-TPM (2,3-diol-TPM) was identified as the most prominent urinary metabolite, with a recovery accounting for 3.2% and 7.9% of the TPM dose under noninduced and induced conditions, respectively. Corresponding recovery values for 10-hydroxy-TPM (10-OH-TPM) were 1.2% and 1.8%, respectively. The control AUC metabolite /AUC drug ratio for 2,3-diol-TPM and 10-OH-TPM were 1.5% and 0.6%, and they increased by threefold and twofold, respectively, after CBZ treatment.Conclusions: TPM remains appreciably excreted unchanged in urine (41%) under CBZ-induced conditions, even though TPM CL/F increased by twofold. Although 2,3-diol-TPM and 10-OH-TPM were measured in unconjugated form, the significant increases in their AUC and urinary excretion are consistent with the twofold increase in TPM clearance. Key Words: Topiramate-CarbamazepinePharmacokinetics-Metabolism-Drug interaction-Enzyme induction-Healthy subjects.Topiramate (TPM) is a broad-spectrum secondgeneration antiepileptic drug (AED), which is approved for adjunctive therapy or monotherapy or both in >95 countries worldwide (1-4). It also is approved for use as migraine prophylaxis and is under evaluation as a potential treatment in a variety of other neurologic and psychiatric disorders (3).The pharmacokinetics of TPM has been investigated mostly under noninduced conditions and is characterized by linearity over the 100-to 800-mg/day dose range, a low oral clearance (22-36 ml/min), largely accounted for by renal clearance of unchanged drug (10-20 ml/min), and a relatively long half-life (19-25 h) (5-7). The absolute bioavailability of TPM is 81-95%, and it is not affected by food (8). Although TPM is not extensively metabolized when administered in monotherapy (fraction metabolized, <30%) (5,9), when TPM is administered with enzyme-inducing AEDs such as phenytoin and carbamazepine (CBZ), its oral clearance increases up to twofold, and its half-life is reduced by ∼50% (10-12). The magnitude of increase in total clearance implies that the formation clearance of metabolites produced via inducible pathways (P-450 oxidation or glucuronide conjugation or both) ca...

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