New antiepileptic drugs: review on drug interactions.

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.     

Topiramate 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 antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.     

Pharmacokinetics and metabolism of topiramate

The pharmacokinetics and pharmacokinetic interactions of topiramate (TPM) in humans have been studied quite extensively. The available information on TPM pharmacokinetics is derived from studies that were specifically designed for this purpose. In contrast to most conventional antiepileptic drugs, the pharmacokinetic profile of TPM combines most of the properties that are desirable for an antiepileptic drug. Topiramate is rapidly absorbed, with a high bioavailability that is not affected by concomitant food intake. The volume of distribution is 0.6-0.8 l/kg, suggesting distribution into total body water. The binding of TPM to serum proteins is low, which precludes the displacement interactions that are seen between highly bound drugs such as valproate and phenytoin. The elimination kinetics of TPM are strictly linear and, accordingly, there is a linear relationship between maintenance dose and steady-state plasma levels. Topiramate is excreted predominantly by the kidneys as unmetabolized drug. This is generally associated with lower interpatient variability in elimination kinetics. Approximately 20% of orally administered TPM is metabolized in the liver and this fraction may increase up to 50% in the presence of enzyme-inducing drugs, such as phenytoin or carbamazepine. During chronic ingestion of TPM, there is no clinically significant accumulation of any active metabolite, even in patients taking enzyme-inducing drugs. The elimination half-life of TPM is relatively long and does not require more frequent than twice-daily dosing. Finally, TPM has a relatively low potential for drug interactions. The clinically significant pharmacokinetic interactions between TPM and other antiepileptic drugs are limited to an increase in the clearance of TPM when inducing drugs such as phenytoin or carbamazepine are added. TPM has little or no effect on the pharmacokinetics of other antiepileptic drugs, but it can increase the clearance of the estrogenic component of oral contraceptives by up to 30%.     

Topiramate potentiates the antiseizure activity of some anticonvulsants in DBA/2 mice

Topiramate (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in DBA/2 mice in a dose-dependent manner. Topiramate at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by topiramate was greatest for diazepam, phenobarbital and valproate, less for lamotrigine and phenytoin and not significant for carbamazepine and felbamate. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of the combination of all drugs+topiramate was more favourable than that of antiepileptics+ saline, with the exception of carbamazepine or felbamate+topiramate. Since topiramate did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that topiramate can modify the clearance from the brain of the anticonvulsant drugs studied cannot be excluded. In addition, topiramate did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, topiramate showed an additive effect when administered in combination with some classical anticonvulsants, most notably diazepam, phenobarbital, lamotrigine, phenytoin and valproate.     

Antiepileptic drug interactions - principles and clinical implications

Antiepileptic drugs (AEDs) are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants). Conversely, the serum concentrations of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs (as macrolides or isoniazid) and decreased by other mechanisms as induction, reduced absorption or excretion (as oral contraceptives, cimetidine, probenicid and antacides). Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives. Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should be implemented with caution, as it is not meant to oversimplify fact matters. Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually not necessary. Updated knowledge regarding drug interactions is important to predict the potential for harmful or lacking effects involving AEDs.     

Serum concentrations of topiramate in patients with epilepsy: influence of dose,age, and comedication

Topiramate is a new antiepileptic drug (AED) approved as add-on therapy. Previous studies have shown that topiramate has only a limited effect on other AEDs, but its own metabolism can be induced by enzyme-inducing drugs. The aim of this study was to investigate the influence of topiramate dose, age, and comedication, especially of carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, and valproic acid (VPA) on topiramate serum concentrations in patients with epilepsy. In total, 480 samples of 344 inpatients who fulfilled the inclusion criteria (e.g., trough concentration, body weight available) were investigated. The topiramate serum concentration in relation to topiramate dose per body weight (level-to-dose ratio) was calculated and compared for patients receiving topiramate monotherapy and for patients receiving topiramate plus one other AED. Analysis of covariance (using age as covariate) showed that comedication had a highly significant influence on the topiramate serum concentrations. Regression analysis including all 480 samples confirmed that in combinations with phenytoin, carbamazepine, phenobarbital, and oxcarbazepine, the topiramate concentrations were significantly lower compared with topiramate monotherapy, whereas VPA and lamotrigine had no significant influence. Moreover, regression analysis indicated that primidone and methsuximide lowered topiramate concentrations, whereas gabapentin, bromide, and sulthiame did not. In addition to comedication, the patient's age was significantly correlated with topiramate clearance. In accordance with the results of previous studies, these results indicated that infants and children had lower topiramate concentrations than adults receiving the same topiramate dose per body weight. Comedication and age should be considered in adjusting topiramate dosage. Determination of topiramate serum concentrations may be useful, especially when enzyme-inducing drugs are withdrawn or added.     

Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed?

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range.The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured.For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.     

Interactions between antiepileptic drugs and hormonal contraception

An interaction between antiepileptic drugs (AEDs) and the combined oral contraceptive pill was first proposed when the dose of estradiol in the oral contraceptive pill was reduced from 100 to 50 microg. There was a higher incidence of breakthrough bleeding and contraceptive failure among women with epilepsy compared with women in general. Since then, interaction studies have been undertaken to look for possible interactions between AEDs and the combined oral contraceptive pill. Phenobarbital (phenobarbitone), phenytoin, carbamazepine, oxcarbazepine, felbamate and topiramate have been shown to increase the metabolism of ethinylestradiol and progestogens. Therefore, if a women is on one of the AEDs and wishes to take the oral contraceptive pill, she will need to take a preparation containing at least 50 microg of ethinylestradiol. Levonorgestrel implants are contraindicated in women receiving these AEDs because of cases of contraceptive failure. It is recommended that medroxyprogesterone injections be given every 10 rather than 12 weeks to women who are receiving AEDs that induce hepatic microsomal enzymes. There are no interactions between the combined oral contraceptive pill, progesterone-only pill, medroxyprogesterone injections or levonorgestrel implants and the AEDs valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide, ethosuximide and the benzodiazepines. Therefore, normal dose contraceptive preparations can be used in patients receiving these AEDs.     

Clinical pharmacokinetics of levetiracetam

Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs.Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours.The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment.To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward.     

托吡酯治疗成人癫痫部分性发作

目的 :观察托吡酯单药和与不同抗癫痫药(AEDs)合用治疗成人癫痫部分性发作疗效、剂量和不良反应的关系。方法 :A组 (n =31)托吡酯与酶诱导剂AEDs合用 ;B组 (n =19)托吡酯与非酶诱导剂AEDs合用 ;C组 (n =5 1)单用托吡酯。托吡酯剂量为 :开始 12 .5～ 2 5mg·d- 1,每周根据疗效增加12 .5～ 2 5mg·d- 1,分 2次口服 ,共 2 0wk。观察各组疗效、剂量和不良反应。结果 :A组有效率 61%,B组为 68%,C组为 88%,A和B组疗效相似 ,P >0 .0 5 ;C组疗效高于A和B组 ,P <0 .0 5。 3组间有效治疗剂量差异无显著意义。不良反应率A组38%,B组 2 1%,C组 31%,P >0 .0 5 ,2例合用卡马西平出现严重精神症状。结论 :托吡酯是治疗癫痫部分性发作有效药物 ,与不同AEDs合用在疗效、剂量和不良反应方面差异无显著意义。中枢神经系统少见严重不良反应 ,但值得重视。     

Pharmacovigilance in psychiatry: pharmacogenetic tests and therapeutic drug monitoring are promising tools

Contraceptive management in women with epilepsy is critical owing to the potential maternal and fetal risks if contraception or seizure management fails. This article briefly describes the pharmacokinetic interactions between antiepileptic drugs (AEDs) and hormonal contraceptives and the rational strategies that may overcome these risks. Hormonal contraception, including the use of oral contraceptives (OCs), is widely used in many women with epilepsy – there is no strong evidence of seizures worsening with their use. AEDs are the mainstay for seizure control in women with epilepsy. However, there are many factors to consider in the choice of AED therapy and hormonal contraception, since some AEDs can reduce the efficacy of OCs owing to pharmacokinetic interactions. Estrogens and progestogens are metabolized by cytochrome P450 3A4. AEDs, such as phenytoin, phenobarbital, carbamazepine, felbamate, topiramate, oxcarbazepine and primidone, induce cytochrome P450 3A4, leading to enhanced metabolism of either or both the estrogenic and progestogenic component of OCs, thereby reducing their efficacy in preventing pregnancy. OCs can also decrease the concentrations of AEDs such as lamotrigine and, thereby, increase the risk of seizures. Increased awareness of AED interactions may help optimize seizure therapy in women with epilepsy.     

The pharmacokinetics and interactions of new antiepileptic drugs: an overview

In the past decade 10 new antiepileptic drugs (AEDs)have been introduced: felbamate, gabapentin, lamotrigine, levetiracetem, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin,and zonisamide. The pharmacokinetics (PK) of these new AEDs as well as their potential for drug interactions are reviewed in this article.In general, new AEDs have better PK profiles and are less involved in drug interactions than the 4 established AEDs: phenobarbital,phenytoin, carbamazepine, and valproic acid. However, in spite of the large therapeutic arsenal of old and new AEDs, about 30% of epileptic patients are still not seizure-free, and thus, there is a substantial need to develop new AEDs.     

Development and clinical applications of the dried blood spot method for therapeutic drug monitoring of anti‐epileptic drugs

Anti‐epileptic drugs (AEDs) have various pharmacokinetic profiles, inter‐individual variabilities, high possibilities of drug‐drug interactions and narrow therapeutic indices. To provide optimal treatment for patients, therapeutic drug monitoring (TDM) is necessary. However, TDM requires sufficient quantities of blood samples to measure drug concentrations. Therefore, TDM could be a burden, particularly in paediatric cases. A good alternative that overcomes these disadvantages is the dried blood spot (DBS) method, which is simple, convenient to use and less invasive, requiring a lower quantity of blood than traditional blood sampling methods. However, the DBS method is affected by haematocrit (Hct) levels to varying extents depending on the drug properties. In addition, different papers with varying characteristics are available for use when applying the DBS method. Therefore, it has not yet been applied to TDM in clinical practice. To achieve this, several steps are required, including method development, method validation and clinical validation. Currently, the development status of the DBS method is different for each AED and unclear. Therefore, we assessed the development status of the following 19 AEDs in 26 studies: lamotrigine, valproic acid, levetiracetam, phenytoin, topiramate, carbamazepine, carbamazepine epoxide, gabapentin, phenobarbital, pregabalin, clobazam, clonazepam, ethosuximide, felbamate, monohydroxycarbamazepine, nitrazepam, rufinamide, vigabatrin and zonisamide. Among them, carbamazepine, lamotrigine, topiramate and valproic acid have been developed such that they are nearly available for TDM. In addition, Whatman 903 Protein Saver Cards and concentration analysis by liquid chromatography with triple quadrupole mass spectrometer were used most often.     

Treatment of epilepsy in women of reproductive age: pharmacokinetic considerations

Although epilepsy affects men and women equally, there are many women's health issues in epilepsy, especially for women of childbearing age. These issues, which include menstrual cycle influences on seizure activity (catamenial epilepsy), interactions of contraceptives with antiepileptic drugs (AEDs), pharmacokinetic changes during pregnancy, teratogenicity and the safety of breastfeeding, challenge both the woman with epilepsy and the many healthcare providers involved in her care. Although the information in the literature on women's issues in epilepsy has grown steeply in recent years, there are many examples showing that much work is yet to be done. The purpose of this article is to review these issues and describe practical considerations for women of childbearing age with epilepsy. The article addresses the established or "first-generation" AEDs (phenobarbital, phenytoin, primidone, carbamazepine, ethosuximide and valproic acid) and the "second-generation" AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). Although a relationship between hormones and seizure activity is present in many women, good treatment options for catamenial epilepsy remain elusive. Drug interactions between enzyme-inducing AEDs and contraceptives are well documented. Higher dosages of oral contraceptives or a second contraceptive method are suggested if women use an enzyme-inducing AED. Planned pregnancy and counselling before conception is crucial. This counselling should include, but is not limited to, folic acid supplementation, medication adherence, the risk of teratogenicity and the importance of prenatal care. AED dosage adjustments may be necessary during pregnancy and should be based on clinical symptoms, not entirely on serum drug concentrations. Many groups have turned their attention to women's issues in epilepsy and have developed clinical practice guidelines. Although the future holds promise in this area, many questions and the need for progress remain.     

Fosinopril and zofenopril, two angiotensin-converting enzyme (ACE) inhibitors, potentiate the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice

The renin-angiotensin system (RAS) exists in the brain and it may be involved in pathogenesis of neurological and psychiatric disorders including seizures. The aim of the present research was to evaluate the effects of some angiotensin-converting enzyme inhibitors (ACEi; captopril, enalapril, fosinopril and zofenopril), commonly used as antihypertensive agents, in the DBA/2 mice animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive interactions in the same model. All ACEi were able to decrease the severity of audiogenic seizures with the exception of enalapril up to the dose of 100mg/kg, the rank order of activity was as follows: fosinopril>zofenopril>captopril. The co-administration of ineffective doses of all ACE inhibitors with AEDs, generally increased the potency of the latter. Fosinopril was the most active in potentiating the activity of AEDs and the combination of ACEi with lamotrigine and valproate was the most favorable, whereas, the co-administrations with diazepam and phenobarbital seemed to be neutral. The increase in potency was generally associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of AEDs with ACEi was predominantly more favorable than control. ACEi administration did not influence plasma and brain concentrations of the AEDs studied excluding pharmacokinetic interactions and concluding that it is of pharmacodynamic nature. In conclusion, fosinopril, zofenopril, enalapril and captopril showed an additive anticonvulsant effect when co-administered with some AEDs, most notably carbamazepine, felbamate, lamotrigine, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.     

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.     

The pharmacokinetic characteristics of levetiracetam

Levetiracetam is the latest in a series of nine new antiepileptic drugs (AEDs) to be licensed for clinical use. Its present license is for use as adjunctive therapy for the treatment of patients with partial seizures with or without secondary generalization that are refractory to other established first line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in patients of all ages with epilepsy, and in certain special populations. Results of these studies indicate that levetiracetam has a very favorable pharmacokinetic profile, characterized by excellent oral absorption and bioavailability (> 95%) and a mean elimination half-life in adults, children and the elderly of 7, 6 and 10.5 h, respectively. Levetiracetam is not bound to plasma proteins and is not metabolized in the liver, so it is not expected to be associated with significant pharmacokinetic interactions. Indeed, to the best of the author's knowledge, no clinically relevant pharmacokinetic interactions with levetiracetam have yet been identified. However, pharmacodynamic interactions with carbamazepine and topiramate have been highlighted. As levetiracetam is primarily excreted unchanged in urine, dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Overall, the pharmacokinetic characteristics of levetiracetam can be considered highly desirable.     

Pharmacologic management of epilepsy in the elderly

OBJECTIVE: To review the epidemiology and pharmacologic management of epilepsy in elderly patients. DATA SOURCES: Controlled trials, case studies, and review articles identified via MEDLINE using the search terms epilepsy, seizures, elderly, phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Recently published standard textbooks on epilepsy were also consulted. DATA SYNTHESIS: Epilepsy is a common neurologic disorder in the elderly. Cerebrovascular and neurodegenerative diseases are the most common causes of new-onset seizures in these patients. Alterations in protein binding, distribution, elimination, and increased sensitivity to the pharmacodynamic effects of antiepileptic drugs (AEDs) are relatively frequent, and these factors should be assessed at the initiation, and during adjustment, of treatment. Drug-drug interactions are also an important issue in elderly patients, because multiple drug use is common and AEDs are susceptible to many interactions. In addition to understanding age-related changes in the pharmacokinetics and pharmacodynamics of AEDs, clinicians should know the common seizure types in the elderly and the spectrum of AED activity for these seizure types. AEDs with activity against both partial-onset and generalized seizures include felbamate, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide. Other AEDs discussed in this review (carbamazepine, gabapentin, phenobarbital, phenytoin, primidone, and tiagabine) are most useful for partial-onset seizures. CONCLUSION: The provision of safe and effective drug therapy to elderly patients requires an understanding of the unique age-related changes' in the pharmacokinetics and pharmacodynamics of AEDs as well as an appreciation of common seizure types and the drugs that are effective for the specific types seen in the elderly.     

The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications

Several different factors, including pharmacogenetics, contribute to interindividual variability in drug response. Like most other agents, many antiepileptic drugs (AEDs) are metabolised by a variety of enzymatic reactions, and the cytochrome P450 (CYP) superfamily has attracted considerable attention. Some of those CYPs exist in the form of genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure (area under the plasma concentration-time curve [AUC]) of AEDs. With regard to the metabolism of AEDs, the polymorphic CYP2C9 and CYP2C19 are of interest. This review summarises the evidence as to whether such polymorphisms affect the clinical action of AEDs. In the case of mephenytoin, defects in its metabolism may be attributable to >10 mutated alleles (designated as *2, *3 and others) of the gene expressing CYP2C19. Consequently, poor metabolisers (PMs) and extensive metabolisers (EMs) could be differentiated, whose frequencies vary among ethnic populations. CYP2C19 contributes to the metabolism of diazepam and phenytoin, the latter drug also representing a substrate of CYP2C9, with its predominant variants being defined as *2 and *3. For both AEDs, there is maximally a 2-fold difference in the hepatic elimination rate (e.g. clearance) or the AUC between the extremes of EMs and PMs which, in the case of phenytoin (an AED with a narrow 'therapeutic window'), would suggest a dosage reduction only for patients who are carriers of mutated alleles of both CYP2C19 and CYP2C9, a subgroup that is very rare among Caucasians (about 1% of the population) but more frequent in Asians (about 10%). The minor contribution of CYP2C19 to the metabolism of phenobarbital (phenobarbitone) can be overlooked. In rare cases, valproic acid can be metabolised to the reactive (hepatotoxic) metabolite, 4-ene-valproic acid. It is not yet clear whether genetic variants of the involved enzyme (CYP2C9) are responsible for this problem. Likewise, the active metabolite of carbamazepine, carbamazepine-10,11-epoxide, is transformed by the microsomal epoxide hydrolase, an enzyme that is also highly polymorphic, but the pharmacokinetic and clinical consequences still need to be evaluated.Pharmacogenetic investigations have increased our general knowledge of drug disposition and action. As for old and especially new AEDs the pharmacogenetic influence on their metabolism is not very striking, it is not surprising that there are no treatment guidelines taking pharmacogenetic data into account. Therefore, the traditional and validated therapeutic drug monitoring approach, representing a direct 'phenotype' assessment, still remains the method of choice when an individualised dosing regimen is anticipated. Nevertheless, pharmacogenetics and pharmacogenomics can offer some novel contributions when attempts are made to maximise drug efficacy and enhance drug safety.