Therapeutic Monitoring Of Antiepileptic Drugs Research Articles

Therapeutic monitoring of antiepileptic drugs: Recommendations to improve care of patients with epilepsy in the Palestinian practice

BackgroundTherapeutic drug monitoring (TDM) can play a major role in optimizing pharmacotherapy of epilepsy. This study was conducted to explore views and opinions of clinicians who care for patients with epilepsy (PWE) in Palestine and to develop consensus-based recommendations with regard to importance, justification, technical, and analytical issues of TDM of antiepileptic drugs (AEDs). MethodsThe study was conducted in three phases: (1) the published literature was thoroughly searched for an initial list of items relevant to TDM of AEDs, (2) the list was supplemented by items provided by key experts (n = 8) through semi-structured in-depth interviews, (3) views and opinions of clinicians (n = 20) on TDM of AEDs were explored, and (4) a two-round Delphi technique was followed among a panel of experts (n = 27) to develop consensus-based recommendations to guide TDM of AEDs in Palestine. ResultsConsensus was achieved on items related to importance (8 items) of TDM of AEDs, clinical justifications of TDM of AEDs (19 items), guidelines for optimal TDM of AEDs (11 items), TDM of some AEDs (21 items), TDM practice (24 items), and some technical and analytical issues in TDM of AEDs (13 items). ConclusionConsensus-based recommendations that might be used in guiding TDM of AEDs in Palestine were developed. Future studies are still needed to investigate if these consensus-based recommendations can improve healthcare of PWE in Palestine.

Clinical validation and implications of dried blood spot sampling of carbamazepine, valproic acid and phenytoin in patients with epilepsy.

To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 12.6.1.0 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r = 0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT−1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs.

Development and validation of a bioanalytical LC-UV method with solid-phase extraction for determination of valproic acid in saliva

A bioanalytical HPLC method with UV detection for the determination of the antiepileptic drug valproic acid in human saliva has been developed and validated. Saliva represents an alternative matrix for therapeutic monitoring of antiepileptic drugs due to the increasing interest in free drug concentration. The proposed method involved solid-phase extraction for sample preparation and yielded very good mean recoveries of 99.4 % and 97.9 % for valproic acid and IS, respectively. The calibration function for valproic acid was linear over the concentration range of 1.0-50.0 μg mL⁻¹ (R² = 0.9989). Within-run and between-run precision and accuracy were studied at four concentrations and RSDs were less than 7.3 and 2.2 %, while accuracy values were higher than 96.8 and 97.5 %, respectively. The described method provides sensitivity, linearity, precision, accuracy and is suitable for analyses of valproic acid in saliva samples.

Corrigendum to “Modern management of epilepsy: A practical approach” [Epilepsy Behav 12 (2008) 501–539

On page 518, in Table 5, in the column “Effect of drug on disposition of other AEDs,” the entry “At OXC doses > 900 mg (▾)” should read “No relevant change.” Diurnal lamotrigine plasma level fluctuations: clinical significance and indication of shorter half-life with chronic administrationEpilepsy & BehaviorVol. 13Issue 3PreviewFor therapeutic monitoring of antiepileptic drugs (AEDs), morning trough levels (MTLs) are generally used. For specific questions like verification of breakthrough seizures or reported toxicity, however, other measures such as minimal and maximal concentrations (Cmin, Cmax) can be important and may require daily profiles. For clinical reasons, 20 daily profiles of lamotrigine (LTG) plasma levels were determined in nine patients. The results revealed fluctuations exceeding those expected from its elimination half-life (t1/2) of 22 h as reported in the literature. Full-Text PDF

Diurnal lamotrigine plasma level fluctuations: clinical significance and indication of shorter half-life with chronic administration

For therapeutic monitoring of antiepileptic drugs (AEDs), morning trough levels (MTLs) are generally used. For specific questions like verification of breakthrough seizures or reported toxicity, however, other measures such as minimal and maximal concentrations (C(min), C(max)) can be important and may require daily profiles. For clinical reasons, 20 daily profiles of lamotrigine (LTG) plasma levels were determined in nine patients. The results revealed fluctuations exceeding those expected from its elimination half-life (t(1/2)) of 22h as reported in the literature. Patients on twice-daily regimens without pharmacokinetic interactions exhibited C(min)/C(max) ratios between 0.62 and 0.69. Fluctuations were smaller in those co-medicated with valproate, and reached a ratio of 0.55 in those co-medicated with phenobarbital. The C(max) was as much as 58% above the MTL. Therefore, verification of complaints indicating toxicity requires determination of drug levels when the symptoms are present. Our findings indicate that the t(1/2) of LTG with chronic treatment is shorter than generally assumed, and suggest that a slow-release formulation could be helpful in achieving full seizure control in patients with a narrow individual therapeutic index for LTG.

Therapeutic monitoring of antiepileptic drugs for epilepsy

The aim of drug treatment for epilepsy is to prevent seizures without causing adverse effects. To achieve this, drug dosages need to be individualised. Measuring antiepileptic drug levels in body fluids (therapeutic drug monitoring) is frequently used to optimise drug dosage for individual patients. To review the evidence regarding the effects of therapeutic drug monitoring upon outcomes in epilepsy. We searched the Cochrane Epilepsy Group Specialised Register (September 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4), MEDLINE (January 1966 to April 2005) and EMBASE (1974 to May 2005). No language restrictions were imposed. We checked the reference lists of retrieved articles for additional reports of relevant studies. Randomised controlled trials comparing the outcomes of antiepileptic drug monotherapy guided by therapeutic drug monitoring with drug treatment without the aid of therapeutic drug monitoring. We based this review on published aggregate data. The main outcomes measured were the proportions of patients achieving a 12-month remission from seizures, reporting adverse effects, and being withdrawn from the treatment they had been randomised to receive. Only one study met the inclusion criteria for the review. In this open study, 180 patients with newly-diagnosed, untreated epilepsy were randomised to treatment with the antiepileptic drug selected by their physician either with or without therapeutic drug serum level monitoring as an aid to dosage adjustments. The antiepileptic drugs used were carbamazepine, valproate, phenytoin, phenobarbital and primidone. A 12-month remission from seizures was achieved by 60% of the patients randomised to therapeutic drug monitoring (intervention group) and by 61% in the control group. A total of 56% in the intervention group and 58% in the control group were seizure free during the last 12 months of follow up. Adverse effects were reported by 48% in the intervention group and 47% of the control group patients. Of those randomised to therapeutic drug monitoring, 62% completed the two-year follow up compared with 67% of the control group. We found no clear evidence to support routine antiepileptic drug serum concentration measurement with the aim of reaching predefined target ranges for the optimisation of treatment of patients with newly-diagnosed epilepsy with antiepileptic drug monotherapy. However, this does not exclude the possible usefulness of therapeutic drug monitoring of specific antiepileptic drugs during polytherapy, in special situations or in selected patients, although evidence is lacking.

Therapeutic Monitoring of Antiepileptic Drugs: A Comparison Between a Czech and a Swedish University Hospital

Plasma concentrations obtained during routine therapeutic monitoring of antiepileptic drugs (AED) (N03A ATC group) were compared in patients treated with one or several AED in the University Hospitals in Ostrava, Czech Republic and Huddinge, Sweden. Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of mean plasma concentrations (PC). The study included 2,824 adult out- and inpatients in Huddinge treated from 1995 to 1999 and 1,268 outpatients treated in Ostrava from 1993 to 2004. PC of valproic acid in Huddinge and all AED except clonazepam in Ostrava were analyzed with gas-liquid chromatography. Plasma concentrations of clonazepam in Ostrava and all AED except valproic acid in Huddinge were analyzed by HPLC. The differences in PC were tested by Student's t-test. Chi(2) method was used for the differences in the distribution of PC relative to the therapeutic window. The mean plasma concentrations generally reached the apparent therapeutic ranges but were below the range in the cases of phenytoin monotherapy in both hospitals, and clonazepam, phenobarbital and phenytoin in polytherapy in Ostrava. In monotherapy 33% of the analyses showed sub-therapeutic concentrations in Huddinge, compared to 38% in Ostrava. Eight percent of the analyses showed potentially toxic concentrations in Huddinge, but only 3% in Ostrava. The highest number of sub-therapeutic concentrations was detected for phenytoin in both hospitals: 59% in Huddinge, 78% in Ostrava. In polytherapy only slight differences between the hospitals were found. PC/dose ratios were significantly lower in polytherapy than in monotherapy for carbamazepine and valproic acid in both hospitals. In contrast a higher PC/dose ratio was found in polytherapy for phenytoin in both cohorts and for lamotrigine in Ostrava. Drug treatment of epilepsy in our two hospitals is surprisingly similar in terms of achieved plasma concentrations, in spite of socioeconomic and cultural differences between our two countries. This may be explained by the long experience with TDM in both hospitals, which has the inherent capacity to promote evidence based drug therapy.

Therapeutic Monitoring of Antiepileptic Drugs during Pregnancy and in the Postpartum Period

As in all patient populations, epilepsy is common in pregnant women. Consequently, approximately 1 in 200 pregnancies is exposed to antiepileptic drugs (AEDs). Although exposure to AEDs in utero has been associated with an increased risk of major fetal malformations, most women with epilepsy require medication throughout pregnancy, since seizures themselves may be potentially harmful not only for the mother but also for the developing fetus. Physiological changes during pregnancy result in a reduction in the serum concentrations of most AEDs, particularly in late pregnancy. Changes in protein binding lead to a greater reduction in total than free (active) drug concentrations. Pharmacokinetic changes in pregnancy show interindividual variability and are not well understood for most newer AEDs. However, recent studies have shown that changes in lamotrigine clearance are particularly marked, with increases in each trimester and a significant fall in plasma concentrations, leading to consequent breakthrough seizures in some women. Concentrations may then rise precipitously after delivery, leading to symptoms of lamotrigine toxicity. Therapeutic drug monitoring could theoretically guide adjustment of AED dosage to achieve good seizure control while minimising fetal exposure, although there are several limitations to such monitoring. Firstly, there are wide interindividual variations in serum drug concentrations, with seizure control often correlating poorly with a given therapeutic range. Secondly, therapeutic ranges have not been well defined for newer AEDs and their measurement is often not always available. Thirdly, for highly protein-bound drugs, although measurement of free drug concentrations may more accurately reflect drug availability during pregnancy than total drug concentrations, assays for this are not always available and may be unreliable. Thus, it may be useful, prior to pregnancy, to establish the total and free drug concentrations required to achieve optimal seizure control in a given individual. Regular monitoring of AEDs has been advocated in each trimester and shortly after delivery, with adjustment of dosage to avoid seizure precipitation during pregnancy or symptoms of toxicity after birth. More frequent monitoring has been recommended for lamotrigine. However, aggressive drug monitoring of any AED has yet to be proven to be effective in improving seizure control or care. Furthermore, higher doses may be associated with a greater potential for teratogenicity and it is not yet known whether longer term adverse effects may be related to in utero exposure in the latter half of pregnancy. There is limited evidence about the relationship of maternal serum drug concentrations and teratogenicity. While there is a theoretical role for therapeutic drug monitoring in improving the risk-to-benefit ratio of AED therapy during pregnancy, there are many practical limitations. Future work is needed to clarify its role in improving seizure control during pregnancy and identifying serum drug concentrations that may be considered safe for fetal exposure.

Laboratory controls and therapeutic antiepileptic drug monitoring during the treatment of children with epilepsy – sense or nonsense – Contra

A singular laboratory control of blood parameters (i.e. red and white count, chemistry and coagulation) is necessary to perform at the beginning of antiepileptic treatment as a screening of body functions and basal determination before possible complications later on. Regular controls lack evidence based studies and are a waste of ressources in many cases. Instead genuine medical attitude should focus on well being and symptoms of the patient with epilepsy. In the guidelines for therapeutic monitoring of antiepileptic drugs (TMA) of the International League Against Epilepsy (ILAE) it is stated, that regular TMA is redundant in such cases, if the patient is free of seizures and/or no side effects can be detected. Accordingly, it is even dangerous to change antiepileptic drug (AED) dosages because the AED blood level is not in the "therapeutic range". Two categories of clinical situations are cited in which TMA might be considered: 1. Regular TMA due to theoretical considerations (after begin of AED treatment, once or twice annually for surveillance of compliance, after every change of AED or concomittant medication) and 2. tailored TMA (in cases of side effects, in situations lacking therapeutic success despite adequate medication, in cases with metabolic, hepatic and renal diseases, during pregnancies, during polytherapy). There should always be a good clinical reason for venipuncture and laboratory expense, that means the gain of knowledge of such a blood value should be of therapeutic relevance otherwise not achievable. In a recently published randomised, controlled multicenter study (2000) on the clinical importance of TMA it was shown, that the vast majority of patients with epilepsy can be treated successfully without TMA. The experience with the application of some AED without common TMA (e.g. benzodiazepines, topiramate, felbamatem acetacolamide) teaches that good AED tretament is possible without TMA. The patient with epilepsy, not the epilepsy and at least the blood values should be treated.

Therapeutic Monitoring of Antiepileptic Drugs: Efficacy, Safety, and Drug Interactions

Therapeutic Monitoring of Antiepileptic Drugs: Efficacy, Safety, and Drug Interactions

Semi-automated continuous-flow enzyme immunoassay for antiepileptic drugs in serum.

We have developed a semi-automated method for measuring five kinds of antiepileptic drugs in serum by successfully adapting commercial competitive-binding enzyme immunoassay kits (MARKIT; Dainippon) for use with a continuous-flow analyzer (Technicon AutoAnalyzer II equipped with a dialyzer). The free enzyme-labeled drug is automatically separated by a microfilter from the competitive immunoreaction mixture between labeled and unlabeled drug for anti-drug immunoglobulin coupled to bacterial cell walls. The concentrations of the antiepileptic drugs in serum samples can be determined by automated measurement of enzyme activity of the enzyme-labeled drugs. Results of the semi-automated method correlated well with those obtained by manual enzyme immunoassay, gas-liquid chromatography, and "high-pressure" liquid chromatography. The correlation coefficients were all greater than 0.95, showing the practicality of this method for therapeutic monitoring of antiepileptic drugs.