Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Teratogenic effects of antiepileptic drugs.

The use of older generation antiepileptic drugs (AEDs) during pregnancy is known to be associated with a two- to threefold increased risk of birth defects in the offspring and possible also other adverse outcomes in the exposed infant. Much less has been known about newer generation AEDs in this respect. Recent studies based on national registries as well as specific epilepsy and pregnancy registries are beginning to provide information on comparative teratogenic effects of different AEDs. Hence, the prevalence of birth defects appears to be higher with exposure to valproate compared with carbamazepine and possibly also in comparison with lamotrigine. Further studies based on larger cohorts are needed to compare AEDs at different dosages and to analyse the possible impact of confounding factors. Furthermore, data is insufficient to assess the human teratogenic potential of other newer generation AEDs than lamotrigine. Retrospective and a few small prospective studies suggest that exposure to valproate also might be associated with a lower verbal IQ at school age, but further prospective studies are needed to draw firm conclusions.     

Postictal serum levels of antiepileptic drugs for detection of noncompliance

Medication noncompliance (NC) is thought to be a major cause of insufficient seizure control. In an explorative study we investigated whether postictal serum levels (PISLs) of antiepileptic drugs (AEDs) are a reliable indicator of NC. Young adults with epilepsy on a stable AED regimen were asked to contact medical service as soon as possible when a seizure occurred to obtain serum levels of their AEDs. PISLs were compared with the mean value of two routine serum levels of the same medication. PISLs lower than 50% of the individual reference value were regarded as an indicator of NC. PISL samples in 61 seizures of 52 patients treated mainly with carbamazepine, valproic acid, or lamotrigine were evaluated. A drop in serum levels >50% indicating NC was noted in 44.3% of the seizures. Determination of PISLs seems to be a simple and useful method for detecting or ruling out irregular intake patterns as a cause of "breakthrough" seizures.     

A comparison of four antiepileptic drugs in status epilepticus: experience from India

Purpose: We report the efficacy and safety of lorazepam (LOR), phenytoin (PHT), valproate (VPA) and levetiracetam (LEV) as first and second choice antiepileptic drug (AED) in status epilepticus (SE) and their combinations in preventing refractory SE. Materials and methods: The results of our two earlier trials on SE were compared; one evaluated VPA versus PHT (group I) and the other LOR versus LEV (group II). In group I, additional patients were recruited in addition to published data. The primary outcome was cessation of SE after first and second AEDs and secondary outcome was mortality and side effects. The efficacy of these four drugs as first and second choice was compared. The frequency of refractory seizure in groups I and II and their contributing factors were analyzed. Results: One hundred and seventeen patients were in group I and 79 in group II. The baseline characteristics of the patients were similar in LOR, LEV, VPA and PHT groups. As a first choice, LOR controlled SE in 75.1%, LEV in 76.3%, VPA in 55.4% and PHT in 44.2% patients. As a second choice, LEV was effective in 88.9%, LOR in 70%, VPA in 74.1% and PHT in 25% patients. Refractory SE was more frequent in group I than group II (29.9% versus 10.5%), however, complications and mortality were higher in group II. Conclusion: LOR and LEV combination was superior in reducing refractory SE but at the cost of higher complications and death.     

Measuring the efficacy of antiepileptic drugs.

Clinical trials of new antiepileptic drugs (AEDs) include regulatory studies aimed at demonstrating efficacy and reasonable safety, post-marketing open-open label studies and longer term outcome studies. Regulatory trials involve a carefully selected population of patients and are conducted under rigorously standardised conditions. Data from such studies cannot often be translated into clinical practice. Pragmatic post-marketing studies using flexible dosing schedules allow clinicians to better judge the utility of the new drug in a wider population of patients with epilepsy and decide the most appropriate dosing schedules. This paper discusses some of the issues surrounding the measurement of efficacy of new AEDs in both pre- and post-marketing phases of their development. All of the newer AEDs are initially used in patients with refractory partial seizures as adjunctive treatment. These trials are generally parallel-group studies although cross-over designs have been employed. The use of placebo-control is uncontroversial in this type of study. Efficacy endpoints are generally manipulations of seizure frequency on study drug compared to control. Global outcome measures and health related quality of life scores can also be used to measure efficacy. As the standard AEDs are associated with a high rate of seizure remission in patients who receive them as monotherapy, demonstration of superior efficacy of a new agent in a comparative trial will require large numbers of patients in a design that takes into account the natural history of treated epilepsy. Comparing investigational agents to a standard AED in an 'active-control' study with demonstration of equivalent efficacy would seem to be an acceptable way of assessing efficacy of new AEDs in this population. Some regulators, however, do not accept equivalence as proof of efficacy and insist on demonstration of superiority compared to a control. The use of placebo alone in the control group is ethically dubious. Several innovative study designs have, therefore, been used to satisfy regulatory requirements, while maintaining patient safety including withdrawal to monotherapy using high versus low dose comparators. Observational outcome studies provide the best opportunity of exploring the long-term utility of individual AEDs. Such studies largely follow standard clinical practice and need considerable time and resources. They can, however, yield valuable information about the effectiveness of AEDs in everyday clinical practice. Data from regulatory trials should be complemented by postmarketing studies and longer term studies of outcome to help clinicians decide the best way of utilising new AEDs and establishing their role in the therapeutic armamentarium.     

Life-threatening adverse events of antiepileptic drugs.

Treating a patient with antiepileptic drugs (AEDs) may give rise to unexpected life-threatening adverse events. Despite extensive experimental and clinical testing to ensure safety, most AEDs on the market have been associated with cases of severe cutaneous reactions, serious hematological disorders, or hepatic failure. Most of these disorders emerge as idiosyncratic immune-mediated disease or are related to toxic metabolic products of the AEDs. Early diagnosis is the only means of reducing the harmful, potentially fatal effects of these reactions. A high degree of suspicion, knowledge of risk factors, and close physician-patient contact increases the likelihood of early diagnosis and treatment. When diagnosed, severe reactions must be fully documented and reported to health authorities. The very rare occurrence of life threatening events should not, in general, limit treatment decision-making. Future epidemiological, chemical, and genetic research might provide methods for ascertaining which patients are at risk, so undue exposure can be avoided.     

Pharmacokinetic interactions between contraceptives and antiepileptic drugs.

The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un-intended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs (carbamazepine, phenytoin and phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased the risk of contraceptive failure. In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible.     

A comparison of four new antiepileptic medications.

In order to select a new medication for a patient with epilepsy, it would be helpful to have an idea of which drug might have the greatest overall chance for success. Since epilepsy is a chronic disorder, the long-term effectiveness and tolerability of the medications are very important. Here, we compared gabapentin, lamotrigine, topiramate and vigabatrin using Kaplan-Meier survival analysis to see how long patients chose to stay on each drug and if they stopped, why they stopped. The results seem to suggest the type of responses to be expected in a hospital seizure clinic.     

Pharmacokinetics of antiepileptic drugs

ABSTRACT The rational use of antiepileptic drugs requires the consideration of their pharmacokinetics, which may be influenced by the physiological and pathological factors. Pharmacokinetic intractions between antiepileptic drugs may lead to considerable fluctuation in plasma drug concentration, and monotherapy is often preferable.
The absorption of phenytoin depends on pharmaceutical formulation. Phenytoin is highly bound to plasma proteins, thus the changes in the unbound fraction are of clinical significance. The saturation kinetics of its metabolism and drug interactions have further consequences. Carbamazepine is well absorbed and largely metabolized. Due to the autoinduction its half-life shortens in chronic administration. Valproate is highly, but variably bound to plasma proteins. It is eliminated mainly by metabolism. Due to the long half-life of phenobarbital its plasma concentrations change slowly, and time to the steady-state may be up to 30 days, if no loading dose is given. Primidone is partly metabolized to phenobarbital, and at steady-state plasma concentration of phenobarbital often exceeds that of primidone. Diazepam, clonazepam and nitrazepam are largely bound to plasma proteins and extensively metabolized with the half-lives of 20 to 60 hours.     

Discovery of antiepileptic drugs

Since 1993, the Anticonvulsant Drug Development Program has contributed to the successful development of nine clinically effective drugs for the symptomatic treatment of epilepsy. These include felbamate (1993), gabapentin (1994), lamotrigine (1994), fosphenytoin (1996), topiramate (1996), tiagabine (1997), levetiracetam (1999), zonisamide (2000), and oxcarbazepine (2000). Despite the apparent success of the current discovery process, a significant need persists for more efficacious and less toxic antiepileptic drugs (AEDs). This is particularly true for patients whose seizures remain refractory to the currently available AEDs. This chapter will review the current process for AED discovery employed by the Anticonvulsant Drug Development Program at the University of Utah and other laboratories working toward the common goal of discovering better therapeutic options for patients living with epilepsy. It will discuss some of the inherent advantages and limitations of the primary animal models employed, while offering insight into potential future directions as we seek to better understand the pathophysiology underlying acquired epilepsy, therapy resistance, and epileptogenesis.     

Monosialoganglioside GM1 blood levels in maternal and newborn umbilical cord blood at birth

Blood levels of the monosialoganglioside GM₁ (nomenclature according to Svennerholm) were tested at birth in the umbilical cord of 37 neonates and their mothers. Comparisons were made based on gestational age and modality of delivery. GM₁ blood levels at birth were significantly higher in mothers than in newborns (373.66±56.83 ng/ml vs 217.95±21.24 ng/ml; P<0.01). Newborns delivered by cesarian section showed levels of GM₁ significantly higher than those delivered vaginally (298.97±38.55 ng/ml vs 169.62±12.62 ng/ml; P<0.01). and preterm newborns had significantly higher levels of GM₁ than full-term newborns (253.50±40.83 ng/ml vs 193.71±21.74 ng/ml; P<0.01). No differences in blood levels of GM₁ were observed in the mothers in relation to length of pregnancy or modality of delivery. The higher levels of GM₁ observed in preterm newborns indicate an increased turnover and/or enhanced bioavailability of the monosialoganglioside GM₁ for the developing central nervous system. Further data are required to evaluate the significance of the increased cord levels of GM₁ in neonates after cesarian section.     

Frequency of antiepileptic drugs and response change in pediatric patients receiving 2 or more antiepileptic drugs

Objectives:To investigate the frequency of changes in antiepileptic drugs (AEDs) use, as well as concomitant changes in the degree of seizure control in pediatric patients, who are receiving 2 or more AEDs.Methods:A prospective follow-up study at Jordan University Hospital’s pediatric neurology clinics was conducted on epileptic pediatric patients receiving at least 2 AEDs between December 2013 and April 2014. Patients were followed for 12 months.Results:A total of 82 patients were included, with a mean age of 7.2±4.7 years. The mean number of AEDs received by patients at enrollment was 2.4±0.6, and 2.5±0.7 after follow-up. Most patients (63.4%) experienced no change in seizure control, and the majority reported at least one adverse drug reaction. Most patients received lower doses than recommended, both at the beginning and end of the study. During the year, only 3 patients (4%) were eligible for dose tapering, which would then be converted to monotherapy. Follow-up appointments average was 4.2±2.9 visits/patients in one year. The frequency of medication changes and dose adjustment was very low, about one-third (29.3%) of patients requiring no change in AEDs during any follow-up visits.Conclusion:During the one year follow-up study, most patients on polytherapy maintained their level of response to the AEDs, with minimal changes in their regimen despite frequent follow-up visits. Only a small percent could be converted to AEDs monotherapy.

Epilepsy is the most common neurological disorder in children.1 Despite the increase in the number of antiepileptic drugs (AEDs), about one third of patients with childhood epilepsy continue to have seizures.2 Successful management of epilepsy depends on many factors, including the cause of epilepsy, type of epilepsy, and AED-related issues, such as: dosing, compliance, side effects, monitoring, and pharmacokinetics.3,4 Most AEDs have a suboptimal patient tolerability profile (with a wide range of side effects); the second-generation AEDs may be better tolerated than the traditional AEDs, but are not actually more effective.5Due to the complexity of classifying seizures, as well as the difficulty in choosing the most appropriate AED, many patients must deal with drug therapy changes over the course of their treatment/management.5-7 It has been estimated that approximately 50% of patients who are newly diagnosed with epilepsy become seizure-free for at least 12 months on their first AED.7 However, about one-third receive 2 or more AEDs, while continuing to experience seizures.5 In general, patients requiring multiple AEDs to manage their epilepsy represent the more resistant group of patients. This group must be closely followed to optimize their AED regimen;8 as the change in drug therapy might be more likely, but improvement is expected to be limited. Cited reasons for lack of improvement include incorrect diagnosis, inappropriate choice of AED and/or dose, in addition to lack of adherence. Data regarding follow-up studies of pediatric patients on AED polytherapy is scarce.9,10 The aim of the current study is to conduct a short-term (12 months) follow-up study of the change in AEDs, as well as the response in a subgroup of pediatric epileptic patients receiving AED polytherapy.