Levetiracetam therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new anti-epileptic drug (AED) levetiracetam in a cohort of 100 adult patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two groups, otherwise comparable for age, gender, weight-adjusted daily dose of levetiracetam, and dosing frequency: group A (n = 65), receiving levetiracetam plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin; group B (n = 35), receiving levetiracetam plus AEDs without inducing properties of CYP metabolism, namely valproic acid and lamotrigine. Plasma levetiracetam concentrations were measured by HPLC with spectrophotometric detection. Median morning trough levetiracetam plasma concentrations were significantly lower in patients of group A than in patients of group B (10.4 microg/mL versus 14.7 microg/mL, P < 0.001). Median weight-normalized levetiracetam apparent oral clearance (CL/F) was 1.3-fold in patients receiving AED inducers compared with patients on AED noninducers (1.93 versus 1.45 mL x min(-1) x kg, P < 0.001). No gender-related difference was observed in CL/F values. Levetiracetam plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 500 to 5000 mg/d, although at a given daily dose an appreciable interpatient variability was observed in matched plasma drug concentrations. Concomitant AED inducers can contribute to variability in levetiracetam disposition in patients with epilepsy. The observed differences were moderate and possibly of minor clinical significance.     

Topiramate serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and monitoring implications

The influence of age and concomitant antiepileptic drugs (AEDs) on the trough steady-state serum concentration of topiramate, normalized to 1 mg/kg body weight or concentration-to-dose ratio (TPM-CDR), was assessed using multivariate methods in samples from 94 epileptic patients (38 under 11 years and 56 over 11 years of age), most of whom were outpatients receiving either just TPM (n = 20) or TPM in combination with other AEDs (n = 74). Analysis of the covariance showed that the age of the patients was influential (P < 0.001) and also showed a difference in TPM-CDR between the non-inducers group (TPM or TPM + lamotrigine or valproate) and the inducers group (TPM + carbamazepine, phenobarbital, or phenytoin) (P < 0.001). The TPM-CDR was 0.4 +/- 0.1 in patients under 11 years with inducers (n = 7), 0.8 +/- 0.3 in patients over 11 years with inducers (n = 32), 1.1 +/- 0.4 in patients under 11 years with noninducers (n = 30), and 1.8 +/- 0.6 in patients over 11 years with noninducers (n = 21). A two-way analysis of the variance showed differences between patients under 11 years and those over 11 years (P < 0.001), and between the noninducers and inducers groups (P < 0.001). TPM-CDR was nearly 50% lower in patients under 11 years than in patients over 11 years, and in patients with TPM + inducers than in patients with TPM or TPM + noninducers, in both children and adults. To achieve the same serum concentration of TPM, children will need double the daily dose per kilogram of TPM required by adults, and both children and adults taking enzyme-inducing AEDs will require double the dose needed by those who do not take them.     

Influence of concomitant antiepileptic drugs on plasma lamotrigine concentration in adult Japanese epilepsy patients

Lamotrigine (LTG) is an antiepileptic drug (AED) that was approved in Japan in 2008. We evaluated the influence of AEDs that induce hepatic enzymes (including phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ)), valproic acid (VPA), and various combinations of these drugs, on plasma LTG concentration in adult Japanese epilepsy patients. A total of 621 patients (mean age 34.4±11.8 years) were evaluated retrospectively. We calculated the concentration to dose ratio (CD ratio) for LTG with different AED regimens, and employed multiple regression analysis to determine factors influencing the LTG concentration. There was a linear correlation between the dose and concentration of LTG in patients treated with LTG (group I), LTG+VPA (group II), LTG+inducers (group III), or LTG+VPA+inducers (group IV). The mean CD ratio of patients on LTG monotherapy was 1.43±0.4 (μg/mL)/(mg/kg). When LTG was combined with VPA, the CD ratio increased about 2.2-fold, but there was no significant correlation between the CD ratio and VPA concentration. The mean CD ratios calculated in patients receiving LTG+PHT, LTG+PB, and LTG+CBZ were 0.56, 0.84, and 0.91, respectively. Addition of PHT significantly reduced the CD ratio in a concentration-dependent manner, in comparison with PB and CBZ (p<0.005 and p<0.001, respectively). Stepwise multiple regression analysis showed that the coefficient of determination of groups I, II, III, and IV were 0.94, 0.94, 0.90, and 0.91, respectively. In the clinical setting, these findings can help to estimate LTG concentrations and predict the inducing or inhibiting effects of concomitant AEDs.     

Hyponatremia induced by antiepileptic drugs in patients with epilepsy

Introduction: Hyponatremia induced by antiepileptic drugs (AEDs) has not received sufficient attention in patients with epilepsy.

Areas covered: We reviewed articles between 1966 and 2015 about hyponatremia as an adverse effect of AEDs in patients with epilepsy. The incidence, clinical symptoms, onset times of AEDs-induced hyponatremia are discussed in detail, as are the risk factors associated with AEDs-induced hyponatremia and mechanisms underlying its development. We also briefly describe strategies for treating AED-induced hyponatremia.

Expert opinion: Carbamazepine and oxcarbazepine are the most common AEDs which induce hyponatremia in patients with epilepsy. Recently, other AEDs, such as eslicarbazepine, sodium valproate, lamotrigine, levetiracetam and gabapentin have also been reported to cause hyponatremia. Understanding the risk associated with AED-induced hyponatremia and taking effective measures to combat serum sodium imbalance induced by AED therapy are necessary.     

Evaluation of therapeutic drug monitoring of antiepileptic drugs

Results of the therapeutic drug monitoring (TDM) of the concentration of antiepileptic drugs (AEDs), performed at Aseer Central Hospital over a 1-year period were evaluated. Most of the requests were for phenytoin (PHT) determination followed by carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB). Serum concentrations of PB, CBZ, VPA and PHT within the presumed therapeutic range constituted 87%, 73%, 45% and 33%, respectively. Valproic acid exhibited age differences in the proportion of concentrations below the presumed therapeutic range, such that subtherapeutic concentrations increased while therapeutic concentrations decreased with age. When the requests were related to particular patients, 71% of patients were on monotherapy with PHT as the most commonly used single drug and PB the least. Patients using 2 AEDs were found to constitute 23.5% of all patients with "PHT + CBZ" and "CBZ + VPA" being the most commonly prescribed 2 drugs combination. The frequency of concentrations within the therapeutic ranges decreased when 1 or 2 more drugs were used with either PHT or VPA. In addition, combination with PHT was associated with a reduction in mean CBZ concentration, while combination with CBZ was associated with a reduction in mean VPA concentration.     

抗癫痫药物监测的规范化实践

目的：探讨抗癫痫药（AEDs）治疗监测的规范化体系。方法：对常用抗癫痫药卡马西平、苯妥因、苯巴比妥、扑米酮和丙戊酸的血药浓度开展规范化监测。结果：AEDs治疗监测应明确监测指征,做好样品的采集和血药浓度测定,及时报告监测结果,并给予简明的分析、解释及具体建议。结论：建立AEDs治疗监测的规范化质量保证体系,对抗癫痫治疗可起到积极的作用。     

Sexual dysfunction related to antiepileptic drugs in patients with epilepsy

Introduction: Epilepsy is a common disease that is mostly treated with antiepileptic drugs (AEDs). However, the sexual dysfunction (SD) side effects related to the use of AEDs have not received sufficient attention.

Areas covered: The purpose of this review is to examine the current evidence on SD-related side effects of AEDs. The incidence, clinical features and major types of SD are summarized. Furthermore, various AEDs that may cause SDs are addressed in detail. Finally, we briefly summarize the treatments for SD related to AEDs.

Expert opinion: SD related to AEDs is common. Symptoms include erectile dysfunction (ED), hyposexuality, hypersexuality and ejaculatory dysfunction. Traditional AEDs such as valproate and enzyme-inducing AEDs (EIAEDs) may produce high incidences of decreased libido. Recently, sexual function changes related to new AEDs have been reported. Topiramate, pregabalin and gabapentin may cause SD, whereas oxcarbazepine, lamotrigine and levetiracetam may improve sexual function. Although the treatment for SD related to AEDs remains unclear, switching to another AED may be an option. Further studies are necessary to better understand and treat SD related to AEDs.     

Negative effects of antiepileptic drugs on mood in patients with epilepsy.

With the introduction of several new antiepileptic drugs into clinical practice, renewed attention has been focussed on treatment-emergent adverse effects, including mood disorders. There are several possible causes of psychiatric disorders in patients with epilepsy, including antiepileptic drugs, and it is often difficult to determine whether psychopathological manifestations, especially depressive symptoms, are due to drug therapy or to multiple other factors. Assessment of the negative effects of antiepileptic drugs on mood should always consider all potential factors. Case series, audits and open observational studies can identify psychopathological features, case-control studies are useful for identifying the endophenotypes of patients at risk of adverse effects on mood, and controlled clinical trials give good estimates of incidence of such effects, adjusted for the spontaneous occurrence of symptoms. The barbiturates, vigabatrin and topiramate show greater associations with the occurrence of depressive symptoms than other antiepileptic drugs, presenting in up to 10% of all patients, but even more so in susceptible patients. Data on zonisamide are scarce but it seems that mood disorders may occur in approximately 7% of patients who are receiving high dosages of this drug. In most cases, the use of monotherapy, with slow titration schedules, can significantly reduce the incidence of mood disorders. Tiagabine, levetiracetam and felbamate present an intermediate risk, with prevalence of depression of about 4% or lower. Phenytoin, ethosuximide, carbamazepine, oxcarbazepine, gabapentin, sodium valproate, pregabalin and lamotrigine are all associated with low risks for depression (<1%), and several of these antiepileptic drugs seem to have a positive effect on mood. Antiepileptic drugs can negatively affect mood and behaviour by different mechanisms: potentiation of GABA neurotransmission, folate deficiency, pharmacodynamic interactions with other antiepileptic drugs in polytherapy regimens, forced normalisation. Individuals with a personal or family history of depression should be carefully followed after initiation of therapy with a new antiepileptic drug, especially if structural brain abnormalities such as hippocampal sclerosis are present.     

Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy.

We retrospectively collected plasma level assessments performed in 96 adult patients with epilepsy on stable monotherapy, including 9 patients on clobazam (CLB), 34 on carbamazepine (CBZ), 24 on phenobarbital (PB), 9 on phenytoin (PHT), and 20 on valproate (VPA); these results were compared to those obtained in 54 adult patients on stable bitherapy with the association of CLB with either CBZ (n = 17), PB (n = 17), PHT (n = 5), or VPA (n = 15). Our results show that CLB has no significant effect on the level to dose ratio (LDR) of CBZ, PB, PHT, or VPA. Conversely, CBZ, PB, and PHT significantly decrease the LDR of CLB. CBZ and PHT significantly increase the LDR of N-desmethylclobazam (NCLB), the major metabolite of CLB. A significant increase in the NCLB/CLB ratio was found in CBZ + CLB, PB + CLB, and PHT + CLB bitherapies. These findings are of clinical significance: clobazam is useful as adjunctive treatment in human epilepsy and is often chosen as the benzodiazepine adjunctive drug in chronic resistant epilepsy. Sedative side effects may occur, especially in patients treated by a CBZ + CLB or PHT + CLB bitherapy, and both CLB and NCLB plasma levels should be monitored in such patients.     

526例癫痫患儿用药情况调查

目的 了解我院癫痫患儿抗癫痫药物的使用情况,为临床用药及个体化给药提供参考。方法 对我院门诊526例癫痫患儿的抗癫痫药物的药品品种、血药浓度、症状控制情况进行统计、归纳和讨论。结果 我院抗癫痫药物以丙戊酸钠和卡马西平使用最多,两药对血药浓度控制较好,86%患儿的症状得到控制。结论 我院抗癫痫药物的使用基本合理,在用药过程中还应该加强药学服务和个体化给药。     

Topiramate pharmacokinetics in children and adults with epilepsy: a case-matched comparison based on therapeutic drug monitoring data

OBJECTIVE: To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting. STUDY DESIGN: Retrospective, case-matched pharmacokinetic evaluation. PATIENTS: Seventy children (aged 1-17 years) with epilepsy and 70 adult controls (aged 18-65 years) with epilepsy, matched for sex and comedication. METHODS: Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney's U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed. RESULTS: In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 +/- 21.0 vs 28.4 +/- 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 +/- 35.1 vs 46.1 +/- 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis. CONCLUSION: Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.     

Topiramate: its pharmacological properties and therapeutic efficacy in epilepsy

Since 1990 eight new antiepileptic drugs (AEDs) have been developed. Among these new drugs, Topiramate (TPM) is one of the latest AEDs available for treating drug resistant partial epilepsy both in adults and in children. The mechanisms underlying TPM antiepileptic activity are still incompletely understood. However, TPM, a sulfamate-substituted derivative of the naturally occurring monosaccharide D-fructose, has a different structure from other known AEDs. The antiepileptic activity of TPM in animal models of partial and generalized tonic-clonic seizures has been shown to be more effective as compared to other AEDs. Proposed mechanisms of action include reduction of epileptiform discharges through a voltage-dependent block of Na(+) channels, enhancement of the activity of gamma-aminobutyrate at some subtypes of gamma-aminobutyrate receptors, and antagonism of non- N-methyl-D-aspartate (NMDA) glutamate receptors. The pharmacokinetic profile of TPM, which is characterized by its rapid and almost complete absorption after oral administration, linear pharmacokinetics, minimal protein binding and predominantly renal excretion, makes the drug a good option for the treatment. TPM was found to be effective and well tolerated in many studies conducted in adults and pediatric patients suffering from epilepsy. This review, summarising the main studies in this field, provides an overview of the current knowledge about the relevant pharmacological and clinical information on the efficacy and tolerability of TPM.     

No effect of co-administered antiepileptic drugs on in-vivo protein binding parameters of valproic acid in patients with epilepsy

Objectives The aim of this study was to establish the population protein binding parameters of valproic acid (VPA) in patients with epilepsy receiving VPA monotherapy and those receiving VPA combined with other antiepileptic drugs. Methods One hundred and thirty nine data sets from 63 Japanese patients with epilepsy were analysed. These patients were separated into two groups: VPA monotherapy and VPA combined with other binding‐sensitive antiepileptic drugs, including phenytoin, clonazepam, clobazam, carbamazepine and phenobarbital (VPA polytherapy). The population protein‐binding parameters of VPA were obtained by non‐linear least‐squares method in each group. Key findings The mean (95% confidence interval) dissociation constants were 38.9 µm (33.2–44.6 µm ) and 36.9 µm (26.7–47.1 µm ), and the numbers of binding sites were 1.36 (1.27–1.44) and 1.33 (1.19–1.47) in the monotherapy and polytherapy groups, respectively. No significant differences in the binding parameters of VPA to serum albumin were observed between the two groups. Conclusions The steady‐state serum albumin binding of VPA in Japanese patients with epilepsy is not affected by co‐administration of other antiepileptic drugs. These findings suggest that serum VPA concentration is stable at the steady state with regard to interaction by protein binding, even when other antiepileptic drugs with moderate‐to‐high binding properties are co‐administered.     

传统抗癫痫药物与新抗癫痫药物对癫痫患者身体成分及脂代谢的影响

目的比较新抗癫痫药物与传统抗癫痫药物对患者身体成分及脂代谢的影响。方法收集我院癫痫患者112例。患者均服用新抗癫痫药(左乙拉西坦、拉莫三嗪、加巴喷丁)或传统抗癫痫药(丙戊酸钠、卡马西平、苯妥英钠)至少6个月。单一用药治疗73例,其中,服用左乙拉西坦片14例、丙戊酸钠15例、卡马西平20例、苯妥英钠24例。其余患者采用联合用药治疗。评估患者身体成分,包括体脂量、瘦干体质量(Lean dry mass,LDM),记录总体液量(Total body water,TBW)、细胞内液(Intracellular water,ICW)、细胞外液(Extracellular water,ECW)、基础代谢率(Basal metabolic rate,BM R),检测生化指标参数。结果左乙拉西坦组患者LDM较丙戊酸钠组患者降低(P<0.05),而其他身体成分与丙戊酸钠组、卡马西平组、苯妥英钠组比较差异无统计学意义(P>0.05)。与对照组比较,丙戊酸钠治疗组LDM及细胞外液较高;其余抗癫痫药物单一用药治疗组的身体成分与对照组比较差异无统计学意义(P>0.05)。传统抗癫痫药物单一治疗及联合新型药治疗组患者的LDM高于对照组(P<0.05),血清TC、三酰甘油也高于对照组(P<0.05)。结论抗癫痫药物对身体成分及脂代谢的影响作用可能影响其对癫痫患者(特别是身体成分发生变化的患者)的治疗反应。由于样本量的限制,以上结论需进一步大样本及前瞻性研究。     

Behavioral adverse effects of antiepileptic drugs in epilepsy

Patient tolerability is a significant limiting factor in the treatment of epilepsy and adverse effect profiles often determine drug retention rates. A full appreciation of the behavioral effects of a wide range of antiepileptic drugs (AEDs) is therefore essential to make informed treatment decisions. In this timely review, we highlight key alterations in mood, emotional experience, and other behavioral/psychiatric features, which can exert a crucial impact on patients' quality of life and well-being. With a view to prescribing both in general and in relation to more specific clinical characteristics, the evidence reviewed indicates that the incidence and characteristics of behavioral effects may be related to age, epilepsy type, the presence of learning disability, and previous psychiatric history. Medication parameters including dosage, titration rate, efficacy in controlling seizures, and concurrent AEDs can also contribute to the occurrence of behavioral effects. However, there are a number of limitations in drawing conclusions from the available literature. These include variation in study design, treatment group, and assessment tools that lead to difficulties comparing findings across studies, and problems with the consistency of available information relating to the study methodology. Future longitudinal studies assessing the impact of tolerance or developmental change on behavioral effects and specific studies comparing the effects of commonly prescribed agents across subgroups of patients with epilepsy will make an informative contribution to the available literature. A valuable outcome of further research may be the development of specific instruments that are sensitive to the behavioral effects associated with particular AEDs.     

The effect of epilepsy and antiepileptic drugs on sexual,reproductive and gonadal health of adults with epilepsy

Epilepsy is a common chronic medical illness. Hyposexuality is the most frequent abnormality in men and women with epilepsy. In men with epilepsy, hypoandrogenimia, hypogonadism and sperm abnormalities are common. Testicular atrophy was also infrequently reported. In women with epilepsy, hyperandrogenism, polycystic ovaries (PCOs) and PCO syndrome are frequent. Decreased serum free testosterone, dehydroepiandrosterone levels, free androgen index and free testosterone/leutinizing hormone (LH) ratio and increased sex hormone binding globulin, estradiol, prolactin, LH, follicle stimulating hormone (FSH) levels and LH/FSH ratio are common with epilepsy. Disturbance of central and/or peripheral control of hypothalamic-pituitary-gonadal axis and alteration of central neurotrasmitters (GABA, glutamate and serotonin) by epileptic discharges or antiepileptic drugs (AEDs), direct gonadal toxicity by AEDs and pcyshicatric/psychosocial factors are all incriminated in sexual, reproductive and gonadal abnormalities associated with epilepsy. Patients may benefit from multidisplinary evaluation, tight seizure control, change the AED, androgen therapy, genital vasodilators, L-carnitine supplementation and psychotherapy.