Pharmacokinetics Of Antiepileptic Drugs Research Articles

A prospective, real‐world, clinical pharmacokinetic study to inform lacosamide dosing in critically ill patients undergoing continuous venovenous haemofiltration (PADRE‐02)

Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH). Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre-filter, post-filter and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling time points post-administration. Patient-specific flow rates and clinical measures were also collected simultaneously at the time of sampling. Plasma concentrations were measured using a validated high-performance liquid chromatography with ultraviolet radiation detection (HPLC-UV) bioanalytical method. Non-compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide. The observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5-12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was -2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate-based dosing regimens could be used to individualize lacosamide therapeutics. CVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.

Estrogen profile- and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = −30.899 vs. −20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33–50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33–66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

Pharmacokinetics of antiepileptic drugs and their safety in breastfeeding women

Pharmacokinetics of antiepileptic drugs and their safety in breastfeeding women

Renal transplant recipient seizure practical management

Seizures are not uncommon in renal transplant patients. The common aetiologies are metabolic disturbance associated with renal failure, immunosuppression and associated complications and infections. Their management can be challenging because of altered pharmacokinetics of antiepileptic drugs (AEDs) and their removal by dialysis. A practical approach to the management of seizure in renal transplant patients is discussed. This review highlights the guidelines for use of various AEDs in renal transplants.

Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy.

During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine's active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15-25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.

Genetic polymorphisms of CYP3A5, CHRM2, and ZNF498 and their association with epilepsy susceptibility: a pharmacogenetic and case-control study.

BackgroundA total of 50 million persons were diagnosed worldwide with epilepsy. One-third of them are experiencing debilitating seizures despite optimum anti‐epileptic drugs (AEDs) treatment. Several studies have suggested that CYP3A5, CHRM2, and ZNF498 influence the pharmacokinetics of AEDs. Therefore, the severity of the disease as well as the degree of response to the AEDs could be affected by the genetic polymorphisms within these genes.ObjectivesIn this study, we assessed the effect of certain single nucleotide polymorphisms (SNPs) within CYP3A5, CHRM2, and ZNF498 genes on the susceptibility to develop epilepsy and the responsiveness to AEDs treatment.MethodsA case–control and pharmacogenetic study was conducted on samples of 299 healthy individuals in addition to 296 epileptic patients. Genotypic, allelic, and clinical data association were performed for the selected polymorphisms within the (rs324649, rs420817, rs15524, and rs1859690) in the Jordanian population.ResultsThe analysis revealed no significant association of the investigated SNPs with epilepsy in general, partial and generalized epilepsy as well as drug responsiveness. CYP3A5 and ZNF498 were associated with family history (P=0.003 and P=0.002, respectively) and the classification of epilepsy for the ZNF498 variant (P=0.009). On the other hand, CHRM2 was not linked to either disease severity or treatment responsiveness.ConclusionOur results failed to confirm the association of CYP3A5, ZNF498, and CHRM2 variants with either disease development or treatment response. Clinical pharmacogenetic studies may contribute to treatment personalization, appropriate drug dose selection, minimizing drug adverse reactions, increasing drug efficacy, and reducing the costive burdens.

Update on Antiepileptic Drugs 2019.

This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity.Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug's efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.

Pharmacokinetic considerations for anti-epileptic drugs in children

ABSTRACTIntroduction: Epilepsy is a chronic and debilitating neurological disease, with a peak of incidence in the first years of life. Today, the vast armamentarium of antiepileptic drugs (AEDs) available make even more challenging to select the most appropriate AED and establish the most effective dosing regimen. In fact, AEDs pharmacokinetics is under the influence of important age-related factors which cannot be ignored.Areas covered: Physiological changes occurring during development age (different body composition, immature metabolic patterns, reduced renal activity) can significantly modify the pharmacokinetic profile of AEDs (adsorption, volume of distribution, half-life, clearance), leading to an altered treatment response. We reviewed the main pharmacokinetic characteristics of AEDs used in children, focusing on age-related factors which are of relevance when treating this patient population.Expert opinion: To deal with this pharmacokinetic variability, physicians have at their disposal two tools: 1) therapeutic drug concentration monitoring, which may help to set the optimal therapeutic regimen for each patient and to monitor eventual fluctuation, and 2) the use of extended-release drug formulations, when available. In the next future, the development of ‘ad-hoc’ electronic dashboard systems will represent relevant decision-support tools making the AED therapy even more individualized and precise, especially in children.

TREATMENT OF EPILEPSY IN PATIENTS OF “VU LNERABLE” AGE: THE ADOLESCENTS AND THE ELDERLY

The incidence of epilepsy is highest in children and in elderly people (over 60 years of age). In about 75% of cases, the first seizures occur before the age of 16 with the maximal occurrence observed before the age of 10 [1]. The problems of diagnosis and treatment of epilepsy in patients of the “transitional” age – adolescents, as well as elderly people – need more attention because these two groups go through the most vulnerable periods of their lives, both psychologically and physiologically. These problems should be approached in the way specific for each age group. For example, there are difficulties in diagnosing a particular form of epilepsy in adolescents; therefore the diagnoses of “unspecified epilepsies” are made. In these cases, the use of wide spectrum antiepileptic agents is recommended. In elderly patients, we often see symptomatic forms of epilepsy in combination with a number of concomitant disorders. Given the age-related changes in pharmacokinetics of antiepileptic drugs, the treatment options for the elderly are quite limited. Here, the medical records of 420 patients (from 3 to 79 years old) diagnosed with various forms of epilepsy were studied. We were interested in patients with “unspecified” forms of epilepsy and the treatments they received. In 17% of cases, the form of epilepsy could not be identified. Levetiracetam and valproate were used most often; as a result of the therapeutic optimization, the volume of carbamazepine-based therapy declined. Among other agents, topiramate, zonisamide, lamotrigine and lacosamide were also in use. In 75% of the studied cases, the treatment with broad-spectrum drugs allowed to control seizures in patients with “unspecified” forms of epilepsy, which indicated the correct choice of therapy.

Farmakologija protiepileptičnih zdravil v obdobju novorojenčka in dojenčka

Te aim of this review article is to elucidate the profound effect of developmental characteristics of newborns and infants on the dosing regimen of antiepileptic drugs (AEDs). AEDs have different mechanisms of action that can broadly be grouped in three categories. Te pharmacokinetics of AEDs are largely affected by developmental changes in absorption, distribution, metabolism and excretion. Te cytochrome P450 enzymes represent an important component of the drug metabolism and vary widely with the child’s development and genetics. In the light of this, an important path is paved by a new science–pharmacogenetics, the study of drug response in relation to specifc genes, which is becoming increasingly important in adjusting the drug dosage. Some recommendations regarding the genetic profle have already been approved but are not yet implemented into daily clinical practice. Considering both, the developmental changes and AED characteristics, an optimal dosage with minimal adverse effects may be achieved.

Antiepileptic Drugs

Treatment of epilepsy starts with antiepileptic drug (AED) monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. Older-generation AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer-generation AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, and, more recently, zonisamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer-generation AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.

Pharmacokinetic characteristics of antiepileptic drugs (AEDs).

Antiepileptic drugs (AEDs) are routinely prescribed for the management of a variety of neurologic and psychiatric conditions, including epilepsy and epilepsy syndromes. Physiologic changes due to aging, pregnancy, nutritional status, drug interactions, and diseases (ie, those involving liver and kidney function) can affect pharmacokinetics of AEDs. This review discusses foundational pharmacokinetic characteristics of AEDs currently available in the United States, including clobazam but excluding the other benzodiazepines. Commonalities of pharmacokinetic properties of AEDs are discussed in detail. Important differences among AEDs and clinically relevant pharmacokinetic interactions in absorption, distribution, metabolism, and/or elimination associated with AEDs are highlighted. In general, newer AEDs have more predictable kinetics and lower risks for drug interactions. This is because many are minimally or not bound to serum proteins, are primarily renally cleared or metabolized by non–cytochrome P450 isoenzymes, and/or have lower potential to induce/inhibit various hepatic enzyme systems. A clear understanding of the pharmacokinetic properties of individual AEDs is essential in creating a safe and effective treatment plan for a patient.

Management of epilepsy during pregnancy: an update.

The clinical management of women with epilepsy on antiepileptic drugs (AEDs) during pregnancy presents unique challenges. The goal of treatment is optimal seizure control with minimal in utero fetal exposure to AEDs in an effort to reduce the risk of structural and neurodevelopmental teratogenic effects. This paper reviews the following key issues pertaining to women with epilepsy during pregnancy: AED pharmacokinetics; clinical management of AEDs; seizure frequency; major congenital malformation; neurodevelopmental outcomes; perinatal complications; and breast feeding.

Influence of MPEP (a selective mGluR5 antagonist) on the anticonvulsant action of novel antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)pyridine (MPEP — a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients.

ANÁLISE DE INFORMAÇÕES TÉCNICO-CIENTÍFICAS EM BULAS DE MEDICAMENTOS ANTICONVULSIVANTES UTILIZADOS NA GRAVIDEZ

O objetivo deste trabalho foi analisar as informações técnico-científicas contidas nas bulas de medicamentos anticonvulsivantes, quanto a possíveis riscos e alterações farmacológicas durante a gravidez. Foram analisadas informações, sobre os processos farmacológicos e possíveis riscos de quatro fármacos (ácido valpróico, carbamazepina, diazepam e fenitoína) usados como anticonvulsivantes, confrontando os dados obtidos nas bulas de medicamentos com as informações científicas difundidas na literatura pesquisada e na legislação de bulas vigente. A coleta de dados foi efetuada com a investigação das seções Informações ao Paciente e Informações aos Profissionais de Saúde das bulas obtidas em dicionários de especialidades farmacêuticas (DEF), em sites oficiais dos próprios fabricantes ou de instituições que exercem atividades na área da saúde. Das bulas analisadas, 100% apresentaram ausência do item alterações na farmacocinética das drogas antiepilépticas durante a gravidez; regulação das doses para gestantes e classificação da droga quanto à categoria de risco para mulheres grávidas. No item, advertências e riscos na gravidez e lactação, 40% das bulas analisadas foram consideradas incompletas por não apresentarem os possíveis riscos teratogênicos ao feto. Os riscos da automedicação e interrupção do tratamento estavam ausentes em cerca de 33% das bulas analisadas e, cerca de 40% destas, apresentavam informações sobre interações medicamentosas com contraceptivos. Portanto, as informações presentes nas seções Informações ao Paciente e Informações ao Profissional da Saúde (ou Informações Técnicas), em sua maioria, foram insatisfatórias como material informativo para as gestantes, segundo os critérios considerados.

(R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: Evaluation in a rat epilepsy model

Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy.Brain uptake of (R)-[11C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders.In rats with drug-sensitive epilepsy, (R)-[11C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups.Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.

Pregnancy and epilepsy

The main goal of this review is to provide some answers about the best therapy of pregnant women with epilepsy and/or women with epilepsy taking oral contraception. We have collected information’s concerning the problems that may arise before and after a pregnancy, involving the best therapeutically options for a pregnant woman. Women with epilepsy have frequent menstrual disorders, reproductive endocrinological disturbances, ovulatory dysfunction and infertility, presenting a risk of contraceptive failure associated with some antiepileptic. Antiepileptic drugs have some side effects on pregnancy by increasing the rate of abortion, preterm labor and vaginal bleeding, especially in polytherapy. Pregnancy can affect the pharmacokinetics of antiepileptic drugs at any level from absorption, distribution, metabolism, and therefore we have showed a list of the most used antiepileptic and how they can affect a future pregnancy from conceiving until delivery and after. Epilepsy represents a sensible field in relationship with pregnancy that involves contraception, heredity and teratology, especially if we consider that the risk of a convulsive seizure to mother and child is frequently over weighted by a continued therapy. <br/><a href=

Antiepileptic drug treatment in pregnancy: Changes in drug disposition and their clinical implications

Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference.

A Systematic Review of the Pharmacokinetics of Antiepileptic Drugs in Neonates With Refractory Seizures

Neonatal seizures are associated with neurological sequelae and an increased risk of epilepsy later in life. Phenobarbital and phenytoin remain the antiepileptic drugs (AEDs) most commonly used to treat neonatal seizures, despite their suboptimal effectiveness and safety. As a result, other AEDs, such as levetiracetam and topiramate, are often used in neonates with refractory seizures, despite limited data and off-label use. To systematically review published pharmacokinetic data for second-line AEDs used in neonates with seizures and to provide dosing recommendations for these agents in the neonatal population. A literature search was conducted in PubMed (1949-May 2012), Medline (1950-May 2012), and Embase (1980-May 2012). Each study was ranked according to the quality of evidence it provided, based on the classification system developed by the US Preventive Services Task Force. Information extracted from each study included study design, number of subjects, gestational and postnatal age, AED dosage regimen, pharmacokinetic parameters, pharmacokinetic model, AED serum concentrations, and sampling times. Nineteen relevant pharmacokinetic studies involving a total of 8 different drugs were identified. No prospective, randomized, controlled studies (level I evidence) or nonrandomized controlled studies (level II-I evidence) were identified; 2 studies were prospective, nonrandomized, uncontrolled (cohort) studies (level II-2 evidence), 11 studies obtained evidence from multiple time series (level II-3 evidence), and 6 studies were case reports or descriptive studies (level III evidence). There are limited pharmacokinetic data for the use of carbamazepine, levetiracetam, lidocaine, paraldehyde, topiramate, valproic acid, and vigabatrin for neonates with seizures refractory to treatment with first-line antiepileptic agents. Further research is needed to elucidate target AED serum concentrations (if any) required to optimize effectiveness and minimize dose-related adverse effects in neonates.

Pregabalin effect on steady‐state pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine

By reducing neuronal excitability through selective binding to the α(2)δ subunit of voltage-dependent calcium channels, pregabalin effectively treats epilepsy, chronic pain, and anxiety disorders. To evaluate if pregabalin coadministration affects pharmacokinetics of other antiepileptic drugs, population pharmacokinetic analyses using NONMEM software were performed on data from three epilepsy trials involving seven antiepileptic drugs with pregabalin as add-on therapy. Results demonstrated that pregabalin did not alter the steady-state plasma concentrations of carbamazepine, lamotrigine, phenobarbital, phenytoin, tiagabine, topiramate, and valproate. Furthermore, the small percent change in the population estimate of antiepileptic drug plasma clearance values (-2% to +7%) suggests that pregabalin coadministration exerted no significant effect on the pharmacokinetics of these antiepileptic drugs, with the possible exception of tiagabine (+34.9%). These findings are in agreement with those of previously published reports. A further clarification study is necessary for tiagabine. In conclusion, it appears that pregabalin can be coadministered with other antiepileptic drugs without concern for significantly altering their pharmacokinetic profiles.