Pharmacokinetics Of Antiepileptic Drugs Research Articles

ANTIEPILEPTIC DRUGS

The goal of epilepsy treatment is no seizures and no side effects. Antiepileptic drugs (AEDs) are the mainstay of treatment. Chronic use, however, often leads to serial drug changes over time, exposing patients with epilepsy (PWE) to recurrent risks due to adverse effects (AEs) and drug interactions. Both unwanted acute and chronic AEs may occur that are usually dose-related, suggested by AED pharmacology, and addressed with appropriate use of serum drug concentrations. Idiosyncratic AEs can pose significant health issues for PWE and be lifesaving with early identification. AED pharmacokinetics and pharmacodynamic properties serve as the foundation for anumber of drug interactions. Hepatic enzyme systems may facilitate AED interaction with other coadministered medication through induction or inhibition of drug metabolism and result in AEs or seizures from drug interactions. A working knowledge of AED pharmacology is an essential component of good clinical practice to help clinicians predict potential AEs and DIs in the treatments of PWE.

Prediction of antiepileptic drug efficacy: the use of intracerebral microdialysis to monitor biophase concentrations

Biophase concentrations of antiepileptic drugs can differ significantly from pharmacokinetics in plasma. A crucial determinant in the disposition of antiepileptic drugs to the brain is represented by the blood-brain barrier. There is growing evidence that this barrier can alter the availability of antiepileptic drugs at the target site. The permeability of the blood-brain barrier becomes particularly relevant in epileptic conditions and in drug refractory situations. In vivo, intracerebral microdialysis is a valuable technique to determine biophase drug concentrations as it enables investigation of antiepileptic drug transport and distribution in the brain as a function of time. The present review illustrates that intracerebral microdialysis is an indispensable tool for the assessment of the pharmacokinetics of antiepileptic drugs. In addition, we demonstrate how microdialysis data can be used in conjunction with mechanism-based pharmacokinetic/pharmacodynamic modeling for dose selection and optimization of the therapeutic regimen for novel compounds.

Monitoring Antiepileptic Drugs: A Level-Headed Approach

Despite advances in epilepsy therapeutics, some physicians feel uncomfortable with newer antiepileptic drugs (AEDs) due to difficulty in promptly obtaining blood levels to guide medication adjustment, and even when levels for newer AEDs are obtained, many practitioners feel they are not very useful. Lacking confidence in AEDs whose levels that cannot readily or expeditiously be measured, many clinicians share uncertainty about proper use of the newer AEDs and monitoring AED administration. Similarly, some epilepsy patients inflate the importance of AED blood level monitoring, feeling that blood levels falling within traditionally therapeutic ranges are a fail-safe for seizure control, regardless of their compliance or personal behavior aggravating seizure burden, such as poor sleep or use of illicit substances. This review examines the elusive concept of therapeutic AED blood levels and potential uses and abuses of blood level monitoring, reinforcing appropriate uses for blood levels to ensure compliance and adjust for altered AED pharmacokinetics in the context of aging and disease states, pregnancy, or drug interactions.

Manajemen Epilepsi pada Kehamilan

Epilepsy is recognized as the commonest serious neurological disorder in the world. Women with epilepsy experience several gender-related physical and social problems. They constitute high obstetric risk because of reduced fertility, risk of seizures during pregnancy, and complications of pregnancy. Hormonal and other factors can alter the pharmacokinetics of antiepileptic drugs during pregnancy and puerperium. Antenatal exposure to antiepileptic drugs, particularly at higher dosage and in polytherapy, increases the risk of fetal malformation. Recent reports raise the possibility of selective developmental language deficits and neurocognitive deficits with antenatal exposure to antiepileptic drugs. There are concerns regarding the effect of traces of antiepileptic drugs that pass to the infant during breast-feeding. The pre conception management is the cornerstone for epilepsy care in Women with epilepsy. A careful reappraisal of each case should ascertain the diagnosis, the need for continued antiepileptic drugs therapy, selection of appropriate antiepileptic drugs, optimization of the dosage, and prescription of folic acid. During pregnancy, the fetal status needs to be monitored with estimation of serum a-feto-protein and ultrasound screening for malformations. The dosage of antiepileptic drugs can be adjusted according to clinical requirement and blood levels of antiepileptic drugs. Several institutions recommend oral vitamin K toward the end of pregnancy when enzymeinducing. Key Words : epilepsy, pregnancy, management, complication

Managing antiepileptic drugs during pregnancy and lactation

This review discusses data on the pharmacokinetics of antiepileptic drugs (AEDs) in pregnancy and lactation, and the clinical consequences thereof, thus providing a basis for a rational management of AEDs during pregnancy and lactation. Studies have confirmed that the elimination of lamotrigine and the active metabolite of oxcarbazepine is enhanced during pregnancy. It has been established that the increased clearance of lamotrigine is caused by induction of glucuronidation. Also, the plasma concentrations of levetiracetam decline in pregnancy but the mechanism for this effect is yet to be explored. Lamotrigine is eliminated slowly in breast-fed infants, but although lamotrigine concentrations in the infant can reach pharmacological levels, no studies have reported clinically relevant adverse effects caused by lactation. Knowledge of the pharmacokinetics of AEDs in pregnancy and during lactation is important to enable optimal treatment. Gestation induced alterations in pharmacokinetics vary with the AED but also between patients and are difficult to predict. Therapeutic drug monitoring is, therefore, advisable during pregnancy and the use of the individual patient's optimal prepregnancy drug level is recommended as reference. Breastfeeding is in general safe but needs appropriate observation of the nursing infant.

Serum concentration/dose ratio of topiramate during pregnancy

To study the impact of pregnancy on the serum concentration/dose ratio (C/D-ratio) of topiramate (TPM). Twelve women with epilepsy using TPM during pregnancy, and 15 pregnancies were studied. The main target variable was the C/D-ratio at baseline and during pregnancy. Additional variables were changes in TPM dose, concomitant use of other antiepileptic drugs, seizure frequency, and pregnancy outcome. Clinical and pharmacological data were obtained from the women's medical records. The average C/D-ratios in the second and third trimester were 30% (p = 0.002, n = 11) and 34% (p = 0.001, n = 8) lower than the baseline values, respectively. The interindividual variability was pronounced. Increased seizure frequency was common in pregnant women using TPM, but a correlation to the decline in TPM C/D-ratio could not be established from our data. Dose-corrected serum concentrations of TPM appear to decline gradually throughout pregnancy. The underlying mechanisms are not known. Increased glomerular filtration may play a major role. During pregnancy, therapeutic drug monitoring of TPM may be useful.

Treating seizures in renal and hepatic failure

INTRODUCTION: Renal and hepatic diseases cause seizures and patients with epilepsy may suffer from such diseases which change antiepileptic drugs (AEDs) metabolism. OBJECTIVES: To revise how seizures may be caused by metabolic disturbances due to renal or hepatic diseases, by their treatment or by comorbidities and how AEDs choice might be influenced by these conditions. RESULTS: Seizures arise in renal failure due to toxins accumulation and to complications like sepsis, hemorrhage, malignant hypertension, pH and hydroelectrolytic disturbances. Hemodialysis leads to acute dysequilibrium syndrome and to dementia. Peritoneal dialysis may cause hyperosmolar non-ketotic coma. Post-renal transplant immunosupression is neurotoxic and cause posterior leukoencephalopathy, cerebral lymphoma and infections. Some antibiotics decrease convulsive thresholds, risking status epilepticus. Most commonly used AEDs in uremia are benzodiazepines, ethosuximide, phenytoin and phenobarbital. When treating epilepsy in renal failure, the choice of AED remains linked to seizure type, but doses should be adjusted especially in the case of hydrosoluble, low-molecular-weight, low-protein-bound, low apparent distribution volume AEDs. Hepatic failure leads to encephalopathy and seizures treated by ammonium levels and intestinal bacterial activity reductions, reversal of cerebral edema and intracranial hypertension. Phenytoin and benzodiazepines are usually ineffective. Seizures caused by post-hepatic immunosupression can be treated by phenytoin or levetiracetam. Seizures in Wilson's disease may result from D-penicillamine dependent piridoxine deficiency. Porphyria seizures may be treated with gabapentin, oxcarbazepine and levetiracetam. Hepatic disease changes AEDs pharmacokinetics and needs doses readjustments. Little liver-metabolized AEDs as gabapentin, oxcarbazepine and levetiracetam are theoretically more adequate. CONCLUSIONS: Efficient seizures treatment in renal and hepatic diseases requires adequate diagnosis of these disturbances and their comorbidities besides good knowledge on AEDs metabolism, their pharmacokinetic changes in such diseases, careful use of concomitant medications and AEDs serum levels monitoring.

Topiramate in older patients with partial‐onset seizures: A pilot double‐blind, dose‐comparison study

Pharmacokinetics of antiepileptic drugs (AEDs) can be altered by age-related changes in physiology, thereby altering clinical effects, especially tolerability, in older adults. We compared two dosages of topiramate (TPM) in a pilot study of patients >or=60 years of age with partial-onset seizures. In this 24-week, double-blind, randomized, parallel-group study, patients with one or more seizures in previous 6 months were randomized to treatment with 50 or 200 mg/day TPM. TPM was initiated as monotherapy or added to one AED and titrated by 25 mg/day per week to target or maximum tolerated dose as the concomitant AED, if any, was withdrawn. Thirty-eight patients were randomized to the 50 mg/day TPM (mean age, 68 years) and 39-200 mg/day TPM (69 years). Seizure control was similar with the two dosages when TPM could be used as monotherapy, whereas 200 mg TPM was more effective than 50 mg in patients requiring adjunctive therapy. The overall incidence of adverse events was similar for the two dosages--66% with 50 mg and 62% with 200 mg TPM. Most common adverse events were somnolence (TPM 50, 13%; TPM 200, 8%), dizziness (13% vs. 8%), and headache (13% vs. 5%). Of 10 (13%) patients reporting a cognitive-related adverse event, six patients were assigned to the 50-mg group. A total of 14 patients (18%; seven in each group) discontinued TPM due to adverse events. This pilot study supports the practice of using low-to-moderate dosages of AEDs in older adults.

Epilepsy in older women

Women suffering from epilepsy require special attention throughout their life. In this review, management of epilepsy during the periods of perimenopause, menopause and late maturity is discussed. The effect of epilepsy on age at menopause, changes in seizure frequency during perimenopause and menopause, and the risks of hormone replacement therapy are also presented. Altered antiepileptic drug pharmacokinetics with increasing age and the management of this vulnerable population is also discussed.

Pharmacokinetics of antiepileptic drugs in pregnancy

A substantial proportion of women with epilepsy experience seizure deterioration during pregnancy. This is most likely explained by a drop in plasma levels of antiepileptic drugs (AEDs) as a consequence of altered drug pharmacokinetics. It has been known for many years that gestation induces the elimination of standard AEDs (phenytoin, barbiturates, carbamazepine and valproate). In general, newer AEDs have more simple pharmacokinetic properties and it should, therefore, be expected that the pharmacokinetics of these drugs are influenced in a simpler manner by physiological changes, such as pregnancy. However, within the last few years it has been established that the elimination of several newer AEDs is significantly accelerated during pregnancy. This is particularly the case for glucuronidated AEDs (i.e., lamotrigine) and the pharmacological active metabolite of oxcarbazepine (metabolite 10-hydroxycarbazepine). Recent observations show it is probable that the elimination of levetiracetam is also increased during pregnancy. Pharmacokinetic alterations during pregnancy show wide interindividual variability and the effects on the plasma levels are mostly unpredictable. Regular routine drug monitoring during pregnancy is therefore recommended. The future perspective involves the development of pharmacogenetic charting, which may assist in providing an individualized treatment strategy and refine preconceptional therapeutic planning to ensure the best possible health for the mother and developing child.

Management of epilepsy in the elderly

Epilepsy among the elderly is a frequently occurring pathology, differing in etiology, clinical presentation and prognosis from those of young people. In addition, beyond a certain age, physiological modifications are produced in the metabolism which alter the pharmacokinetics of antiepileptic drugs (AEDs), increasing the risk of pharmacological interactions, already greater in these patients due to the frequency of polypharmacy. Furthermore, elderly patients are particularly sensitive to certain secondary effects of AEDs, as for example, cognitive disturbances, osteoporosis or weight increase. Given that the efficacy of the major AEDs is a priori quite similar, and that the epilepsies occurring in this age-group generally have a good prognosis, the selection of an AED will depend more upon its pharmacokinetics and ability to induce certain secondary effects than on its efficacy. In this respect, levetiracetam and pregabalin, followed by oxcarbazepine and lamotrigine have the most favorable pharmocokinetical profile. Moreover, on the whole these drugs have very few cognitive effects, do not induce osteoporosis and, with the exception of pregabalin, do not affect weight, making them the first selection for use in the treatment of epilepsy in the elderly.

Seizure control and pharmacokinetics of antiepileptic drugs in pregnant women with epilepsy

The main concerns associated with epilepsy during pregnancy consist of maternal and fetal risks from uncontrolled seizures, and harmful effects of the treatment on the development of the offspring. Although seizure control is maintained in the majority, worsening occurs in a fraction of childbearing women with epilepsy. As multiple factors associated with pregnancy may have a negative impact on epilepsy, a careful analysis of the situation should be performed in those who deteriorate. Emotional and behavioural influence, including insufficient sleep and treatment non-compliance, as well as physical factors, such as emesis and pelvic distortion, should receive attention. The serum concentrations of almost all antiepileptic drugs decrease during pregnancy, particularly those which are metabolised by glucuronidation. The inter-individual variability is pronounced. In highly protein-bound drugs, such as phenytoin and valproate, unbound drug is less affected than total concentrations. Lamotrigine and levetiracetam concentrations may decrease by more than 50% in the course of pregnancy; monohydroxyoxcarbazepine by up to 30-40%. Appropriate clinical follow-up tailored to individual needs and supported by therapeutic drug monitoring should be performed in pregnant women with epilepsy. Education concerning reproductive issues is an essential part of the epilepsy service to fertile women.

Importance of monotherapy in women across the reproductive cycle

Special treatment considerations are warranted in women with epilepsy, particularly those of childbearing age. Treatment guidelines generally recommend the use of antiepileptic drug (AED) monotherapy at the lowest dose possible during pregnancy. The UK Epilepsy and Pregnancy Register reported that the risk for major congenital malformations is higher with AED polytherapy than with monotherapy (6.0% vs 3.7%, respectively) and that valproate carries the highest individual risk. The AEDs that induce hepatic cytochrome CYP450 enzymes carry particular concern both before and after pregnancy. Hepatic enzyme inducers alter steroid metabolism in women receiving oral contraceptives, increase the risk for contraceptive failure, and interfere with calcium absorption and vitamin D metabolism, thus increasing the risk for osteoporosis and fractures. Vitamin K deficiency is another potential consequence of treatment with a hepatic enzyme-inducing AED, increasing the risk for coagulopathy and neonatal intraparenchymal and intracerebral hemorrhage during the first 24 hours of life. Supplemental vitamin K therapy during the last month of pregnancy is warranted. Preconceptional and gestational folate supplementation may also be warranted to prevent neural tube malformation related to AED treatment. Because AED pharmacokinetics may be altered during pregnancy, plasma AED concentrations should be measured before conception and monthly during pregnancy to prevent seizure breakthrough.

The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of Epilepsy

Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy.

Various Pharmacogenetic Aspects of Antiepileptic Drug Therapy

Pharmacogenetics concerns the influence of an individual's genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Much of the pharmacogenetic data in the field of epilepsy deals with the pharmacokinetics of antiepileptic drugs (AEDs). In particular, two polymorphisms of cytochrome P450 2C9 are known to slow down the metabolism of phenytoin to a degree that increases the risk of the neurotoxic adverse effects of this drug among carriers of these polymorphisms. A significant number of patients with epilepsy do not respond to AEDs and such pharmacoresistance is a major, largely unsolved, problem that is likely to be multifactorial in nature. In this regard, genetic factors may influence transmembrane drug transporter proteins, thereby modifying the intracerebral penetration of AEDs. Monogenic idiopathic epilepsies are rare and frequently associated with ion channel mutations; however, to date, a consistent relationship between changes in channel properties and clinical phenotype has not been established nor has any association between genotype and response to specific treatment options. Polymorphisms of drug targets may represent another genetic facet in epilepsy: a recent study demonstrated for the first time a polymorphism of a drug target (the alpha-subunit of a voltage-gated sodium channel) associated in clinical practice with differing response to two classic AEDs. Adverse drug reactions and teratogenicity of AEDs remain a major concern. Whole-genome single nucleotide polymorphism profiling might in the future help to determine genetic predisposing factors for adverse drug reactions. Recently, in Han Chinese treated with carbamazepine and presenting with Stevens-Johnson syndrome, a strong association was found with HLA B*1502. If genetically targeted drug development becomes more affordable/cost efficient in the near future, the development of new drugs for relatively rare diseases could become economically viable for the pharmaceutical industry. The synergy of lower trial costs and efficacy-based prescribing may reduce the cost of medical treatment for a particular disease. This hypothetical advantage of the practical use of pharmacogenetics is, however, counterbalanced by several possible dangers, including illicit data mining and the development of a human 'genetic underclass' with the risk of exclusion from, for example employment or health insurance, because of an 'unfavourable' genetic profile.

Optimizing therapy of seizures in patients with renal or hepatic dysfunction

Patients with epilepsy may suffer from renal or hepatic diseases that interfere with their antiepileptic drug (AED) treatment. Furthermore, such diseases may themselves cause seizures. Reduced renal function and hypoalbuminemia lead to accumulation of renally excreted AEDs, such as gabapentin, vigabatrin, topiramate, levetiracetam, and phenytoin. Valproate, lamotrigine, and benzodiazepines are less affected. Low protein-bound AEDs are extensively removed by hemodialysis and supplemental doses are required for dialysis patients. Uremia and related conditions, including intracranial hemorrhage, glucose and electrolyte imbalances, and concomitant drug use, can cause seizures, as can dialysis encephalopathy, primary cerebral lymphoma, fungal infections, and immunosuppressant toxicity in renal transplant recipients. Hepatic dysfunction reduces enzymatic metabolism of AEDs and causes hypoalbuminemia. Gabapentin, topiramate, and levetiracetam are preferred in these conditions, whereas conversely valproate and felbamate are potentially hepatotoxic and should be avoided. Seizures related to hepatic encephalopathy are controlled by oral lactulose or neomycin. Porphyria sufferers may benefit from gabapentin, oxcarbazepine, or levetiracetam. Seizures in Wilson's disease may derive from d-penicillamine-induced pyridoxine deficiency. Effective treatment of seizures in renal and hepatic diseases requires attention to changes in AED pharmacokinetics and adequate care of the underlying illnesses. Monitoring of free drug concentrations is a valuable aid to therapy.

Gender Aspects of Pharmacokinetics of New and Old AEDs

Alterations in drug disposition in pregnancy and drug transfer into breast milk during lactation are the most important gender-related aspects of the pharmacokinetics of antiepileptic drugs(AEDs). The effect of pregnancy on drug disposition has been fairly well characterized for the old AEDs. Total and unbound plasma concentrations of phenobarbital decline up to 50%. Total phenytoin levels may drop to approximately 40% of prepregnancy concentrations,but unbound concentrations considerably less. Unbound valproate levels remain unchanged despite a fairly marked decrease in total concentrations, and changes in unbound and total plasma concentrations of carbamazepine are minor. In contrast, pregnancy has a pronounced effect on lamotrigine, with a 300% increase in apparent clearance in the third trimester. Much less is known about the kinetics of other new AEDs during pregnancy. Umbilical cord/maternal plasma concentration ratios close to unity suggest free transplacental passage of most AEDs,whereas higher ratios indicate fetal accumulation of valproate and gabapentin. Milk/maternal plasma concentration ratios close to 1 demonstrate extensive transfer to breast milk of many AEDs including ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Plasma levels are, however, in general low in the nursed infant, although pharmacological concentrations have been reported occasionally for carbamazepine, ethosuximide, lamotrigine, and phenobarbital. For most of the new-generation AEDs, there is an urgent need for further kinetic data from pregnancy and breast-feeding.

Pharmacokinetics of antiepileptic drugs during pregnancy/lactation

Pharmacokinetics of antiepileptic drugs during pregnancy/lactation

Antiepileptic drug pharmacokinetics during pregnancy and lactation.

The ideal management of women with epilepsy during pregnancy and the postpartum period involves achieving an optimal balance between minimizing fetal and neonatal exposure to the deleterious influences both of antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiologic changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Noncompliance can also be a major factor. The majority of AEDs are characterized by significant increases in clearance during pregnancy. Lamotrigine (LTG) clearance markedly increases throughout pregnancy, to an extent greater than with the older AEDs. Studies during and after birth in mothers taking the older AEDs indicate extensive transplacental transfer and low to moderate excretion into breast milk. Limited studies of the newer AEDs indicate similar extensive transplacental transfer [LTG, oxcarbazepine, topiramate (TPM), zonisamide (ZNS)], and breast milk/maternal plasma concentration ratios less than 1 (LTG, TPM, ZNS). Especially high excretion of levetiracetam into breast milk may occur. Current published guidelines recommend that the ideal AED concentration should be established for each patient before conception and that monitoring of AED concentrations should be performed during each trimester and in the last month of pregnancy. Free concentrations should be measured for phenobarbital, phenytoin, carbamazepine, valproic acid, and primidone. Some authors recommend at least monthly monitoring of AED concentrations, especially for LTG. Future studies of formal pharmacokinetic modeling of AEDs during pregnancy and the postpartum period could provide an important step toward achieving effective drug dosing to maintain therapeutic objectives for the mother but, at the same time, to minimize fetal drug exposure.

The interface of preclinical evaluation with clinical testing of antiepileptic drugs: role of pharmacogenomics and pharmacogenetics

Despite the release of eight antiepileptic drugs (AEDs) during the last decade, the incidence of pharmacoresistant epilepsy has changed relatively little. Predicting efficacy and safety of AEDs in people with epilepsy from acute seizure models in rodents is difficult and risky. It is becoming increasingly clear that genetic polymorphisms play an integral role in variability in both antiepileptic drug pharmacokinetics and pharmacodynamics. The publication of the human genome and increasing sophisticated and powerful genetic tools offers new methods for screening drugs and predicting deadly idiosyncratic side effects. In this review the use of pharmacogenomic and pharmacokinetic techniques in the development and monitoring of antiepileptic drug therapy is reviewed. Genetic techniques have the potential of identifying novel drug targets, predicting drug response, and identifying individuals at risk for serious idosyncratic reactions.