Pre-Congress Symposium



100 Years of Antiepileptic Drugs: The Role of TDM in Optimizing Patient Care


David J. Berry, Consultant Clinical Scientist, Therapeutic Drug Monitoring Unit, Chalfont Centre for Epilepsy, UK

Philip N. Patsalos, Professor of Clinical Pharmacology, Therapeutic Drug Monitoring Unit, Chalfont Centre for Epilepsy, UK

0800-0840   Registration

0840-0850   Introduction

0850-0930   Therapeutic Drug Monitoring (TDM) of New Antiepileptic Drugs Undergoing Development

Dan Kaufmann, Anticonvulsant Drug Development (ADD) Program Pharmacology and Toxicology Department, University of Utah, USA

This will cover AED measurements/pharmacokinetics in pre-clinical (animal) models and clinical (Phase I, II and III) studies in healthy volunteers and patients with epilepsy.


At the end of this session the participants will be able to:

  • Identify the novel AEDs in preclinical and clinical trials.
  • Describe the potency and efficacy of the novel AEDs in animal seizure models.
  • Describe the clinical studies done in healthy volunteers and epileptic patients with the novel AEDs.
  • Gain an insight into the toxicological, pharmacokinetic and mechanistic studies of the novel AEDs in development.

In the last two decades sixteen new antiepileptic drugs (AEDs) have been introduced to the market. Compared to the late 1960s the number of patients with refractory epilepsy has not been significantly reduced. In addition to efficacy current pharmacotherapy suffers from adverse effect and drug-drug interactions. This enables the development of novel more efficacious and better tolerated AEDs. The presentation will cover the novel antiepileptic drugs currently in different developmental stages in preclinical and clinical trials. The following novel drugs will be discussed: brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel, tonabersat, sec-propylbutylacetamide (SPD), VX-765. This presentation will also provide a status update on the clinical studies in both healthy volunteers and epilepsy patients with an emphasis on tolerability, pharmacokinetics and side effect profile.

0930-1010   Alternative Approaches to TDM of AEDs

David J. Berry, Consultant Clinical Scientist, Therapeutic Drug Monitoring Unit, Chalfont Centre for Epilepsy, UK

This will entail discussion of the usefulness of various matrices (e.g. serum/plasma, blood spots, saliva and hair) their advantages and disadvantages and of practice guidelines.


At the end of this session the participants will be able to:

  • To understand that AEDs can transfer from blood into alternative biological matrices.
  • To appreciate the potential for TDM of AEDs in various biological matrices.
  • To learn about practical issues associated with TDM of AEDs in the alternative matrices.

The measurement of antiepileptic drugs (AEDs) in plasma/serum has proved to be a valuable adjunct to the management of individual patients with epilepsy for the past 40 years or more. This presentation will review and discuss the value of undertaking AED measurements in some alternative biological matrices e.g. saliva, blood spots and hair, compared with serum/plasma. The added value of each biomatix will be compared and disadvantages reviewed together with some practical approaches to the use of alternative biological specimens for AED dose individualisation.

1010-1040   Refreshment Break

1040-1120   AED TDM in Children, Adolescents and Teenagers

Professor Frank Besag, Consultant Neuropsychiatrist, South Essex Partnership University NHS Foundation Trust and Visiting Clinical Professor, School of Pharmacy, University of London, UK

This will cover the special need of AED TDM in this population which is associated with significant pharmacokinetic variability and constantly changing metabolic capacity.


At the end of this session the participants will be able to:

  • Demonstrate the clinical importance of therapeutic drug monitoring in young people with epilepsy.
  • Indicate the value of tracking blood levels to reveal unsuspected drug interactions.
  • Provide examples of the clinical importance of therapeutic drug monitoring in managing and preventing drug toxicity.
  • Illustrate how therapeutic drug monitoring can be used to guide the management of both pharmacokinetic and pharmacodynamic drug interactions in young people with epilepsy.

Compliance (adherence, concordance) with medication depends not only on efficacy but also on tolerability. Therapeutic drug monitoring of antiepileptic medication children and teenagers can be of benefit with regard to both efficacy and tolerability, especially at a time when not only metabolic parameters are changing but the manifestations of the epilepsy are also liable to undergo major change. In this session, specific clinical examples will be given of how therapeutic monitoring of antiepileptic medication has been of value in practice and how therapeutic drug monitoring research has informed the clinician. Determining blood levels of antiepileptic medication can be of major value when managing certain particular antiepileptic drugs. A case is made for specifically-targeted therapeutic drug monitoring, where it is most likely to be of clinical benefit.

1120-1200   AED TDM in Women of Child Bearing Potential and in Pregnancy

Page B. Pennell, Director of Research, Epilepsy Division, Department of Neurology, Brigham and Women’s Hospital, USA

This will cover the use of TDM to manage the pharmacokinetic variability due to interactions with oral contraception and the substantial pharmacokinetic changes associated with pregnancy.


At the end of this session the participants will be able to:

  • Appreciate the bidirectional interactions that occur between hormonal contraceptive agents and antiepileptic drugs, as well as the clinical implications.
  • Identify which AEDs undergo substantial increased clearance with contraceptive hormones and/or pregnancy and to what degree.
  • Have a basic understanding of how TDM can be used during preconception, pregnancy and postpartum phases to achieve better maternal and child outcomes.

Optimal treatment of women with epilepsy during the child bearing years requires an understanding of the complex bidirectional interactions between AEDs and sex steroid hormones. A planned pregnancy with good seizure control is the most important factor in achieving healthy maternal and child outcomes. However, many AEDs lower efficacy of hormonal contraceptives via induction of the hepatic cytochrome P-450 system and /or glucuronidation. This commonly allows ovulation and a high proportion of unplanned pregnancies. Conversely, most hormonal contraceptive agents enhance glucuronidation and cause increased clearance of some AEDs, which can result in break-through seizures.

During pregnancy, achieving an optimal balance between seizure control and fetal AED exposure is especially important to lower teratogenic risks. During pregnancy, AED levels decline substantially due to a variety of pharmacokinetic changes, but the degree and time course of change varies by AED and between individuals. Therapeutic drug monitoring to maintain the individual’s target concentration during pregnancy can lower the risk for seizure worsening and lower the risk to the developing fetus. Management of postpartum AED pharmacokinetic changes will also be discussed in the context of possible breastfeeding with continued infant AED exposure.

1200-1300   Lunch Break

1300-1340   AED Polytherapy and Concurrent Pathologies: The Role of Therapeutic Drug Monitoring

Philip N. Patsalos, Professor of Clinical Pharmacology, Therapeutic Drug Monitoring Unit, Chalfont Centre for Epilepsy, UK

This will cover how AED TDM can be usefully employed to manage patients prescribed polytherapy AEDs and polytherapy with other non-AED drugs. The impact of pathologies such as malnutrition, burns and surgery on AED PK and how these can be managed by TDM will also be discussed.


At the end of this session the participants will be able to:

  • To understand the importance of antiepileptic drug (AED) interactions in the management of patients with epilepsy.
  • To learn how TDM can be used to manage AED pharmacokinetic interactions.
  • To learn how concurrent pathologies impact on AED TDM.

The mainstay of epilepsy treatment involves antiepileptic drugs (AEDs). Monotherapy AED treatment typically results in approximately 60-70% of newly diagnosed patients having their seizures controlled effectively whilst switching to an alternative AED monotherapy will result in effective seizure control in 50% of the remaining 30-40% of patients. For the remaining patients, polytherapy AEDs are prescribed in an attempt to control their seizures more effectively. However, these patients can experience problematic adverse pharmacokinetic and pharmacodynamic interactions and these interactions can be exacerbated by concomitant drugs that may be used to treat concomitant or intercurrent comorbidities. As a therapeutic class of drugs, the AEDS are associated with more drug interactions than any other drug class and the purpose of this session is to highlight various pharmacokinetic interactions, how they can be identified, characterised and quantified, and how via the use of TDM they can be managed effectively in the clinical setting.
Illnesses, including hepatic or renal failure, infections, burns, stroke, cardiac failure, and other conditions can markedly affect the pharmacokinetics of AEDs and AED TDM should be undertaken in these situations. Furthermore, because protein binding due to hypoalbuminemia typically occurs, measurement of unbound drug concentrations is essential for highly protein bound AEDs (e.g. phenytoin, valproate). Although specific guidelines for extent of TDM are not available, the monitoring of serum AED concentrations is valuable in helping the clinician to identify these pharmacokinetic changes and enabling him or her to make dose adjustments whenever appropriate.

1340-1420   AED TDM in the Elderly and the Frail

Ilo Leppik, Professor, Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, USA

The elderly are therapeutically vulnerable in that not only is there a decline in metabolic capacity but additionally they are more sensitive to AED adverse effects. Also they are prescribed polytherapy which can result in complicated PK interactions and also increases the risk of non-compliance.


At the end of this session the participants will be able to:

  • Understand that epilepsy is common in nursing homes.
  • Understand that AED levels may not be stable.
  • Understand that genetic factors may be more important than age.

Elderly patients need to be segregated into groups on the basis of their health status those with epilepsy who are healthy, those who have multiple medical problems in addition to epilepsy, and those who are frail. Elderly people living in nursing homes need to be managed differently than community dwelling elderly people because they are more frail and have more comorbid conditions. Pharmaceutical treatment of elderly people carries greater risks than does that of younger people. Age-related changes in gastrointestinal tract functioning, hepatic enzyme capacity, protein binding, and kidney function can lead to drug pharmacokinetics that are different in elderly patients compared with younger adults. Cytochrome P450 enzyme content is thought to decrease with age. Findings from one study using IV stable labeled phenytoin showed that advancing age affected phenytoin clearance, but by only a small amount. The person’s genotype for the CYP 2C9 or 2C19 isoenzyme was more predictive of clearance than was age.

Interactions with other drugs, herbal remedies, and food can occur with AEDs. Knowledge of the metabolic pathways of the AEDs and the other substances is necessary to make appropriate treatment decisions. Interactions between antipsychotic drugs and AEDs are of particular concern because they involve bothpharmacokinetic and pharmacodynamic mechanisms. Under steady state dosing conditions, concentrations of drugs are assumed to be stable. In younger adults (age <65 years), the variability of AED concentrations over time was low, about 20% in compliant patients. Compliant elderly patients were assumed to also have low variability of AED concentrations over time. However, in a study of people who were cared for in nursing homes, phenytoin concentrations fluctuated by as much as two to three times over several months among three more samples in people who had no change in dose, formulation, or interfering cotreatments. However, in some people in the same study concentrations were more stable. Similar variations have been reported for carbamazepine and valproic acid. The causes of this variability are not known, but might be related to age-related gut changes.

1420-1450   Refreshment Break

1450-1530   PK/PD Modeling of AEDs and Its Application to TDM

Alexander A. Vinks, Professor and Division Director Division of Clinical Pharmacology, Cincinnati Children’s Hospital and Medical Center, USA

This will include the use of software to model patient outcome based on TDM data. Also, the use of population data from clinical trials and population data from TDM services to inform on AED PK characteristics and potential PK interactions.


At the end of this session the participants will be able to:

  • Appreciate the potential of the application of population model-based approached to to AED therapeutics.
  • Appreciate the importance of informative experimental design in PK studies.
  • Describe model based Bayesian adaptive control as an attractive strategy for AED dose individualization.

This presentation will review the application of population PK/PD model-based dose optimization of AE drugs. It will review the use of clinical software to predict drug exposure and drug-drug interactions based on sparse TDM data. Examples of how modeling and simulation can help in the design of informative studies and individualized treatment will be discussed.

1530-1610   Modern Day Analysis of AEDs

William Clarke PhD, MBA, DABCC, Associate Professor of Pathology, Johns Hopkins University School of Medicine, USA

This will include the various analytical methodologies (e.g. LC/MS, immunoassays particularly for new AEDs, etc.); the need to participate in QA schemes and to “recommend” as to what should be expected from a modern AED TDM Laboratory service.


At the end of this session the participants will be able to:

  • Discuss the benefits and limitations of immunoassays for AED TDM
  • Discuss the benefits and limitations of LC-MS methods for AED TDM
  • Describe technology developments in high resolution mass spectrometry and alternative calibration strategies in LC-MS and their potential impact on AED TDM
  • Recognize the importance of robust EQA programs in harmonization of AED TDM methods.

This session will discuss various analytical approaches to measurement of AEDs in blood and other matrices. Particular focus will be given to LC-MS and immunoassay methodologies. Additional focus will center around the need for clinical laboratory method harmonization and participation in external QA and proficiency testing schemes.

1610-1640   TDM of Newly Licensed AEDs and the Future of AED TDM

Svein I. Johannessen, Senior Researcher, The National Center for Epilepsy and Department of Pharmacology, Oslo University Hospital, Norway

This will cover the evidence for the usefulness of TDM for the new third-generation AEDs (lacosamide, retigabine, eslicarbazepine acetate and perampanel) and the new orphan AEDs (stiripentol, rufinamide) and to discuss what the future holds for AED TDM (e.g. pharmacogenetics).


At the end of this session the participants will be able to:

  • Appreciate why TDM is important in optimizing therapy also for newer AEDs.
  • Appreciate that pharmacokinetics are quite variable among individuals.
  • Appreciate that TDM is important even if a “reference range” is not yet defined.

This presentation will review therapeutic drug monitoring (TDM) as a valuable tool also for newer AEDs to overcome challenges related to e.g. pharmacokinetic interactions, poor compliance, adverse drug effects, and individualization of drug treatment. It would be more appropriate to focus on the concept of ”individualized reference concentrations” rather than ”therapeutic ranges”, aiming at identifying the optimal concentration at which each patient shows the best response. Then, TDM would be relevant for new as well as old AEDs.

The usefulness of TDM for the new third generation AEDs, including lacosamide, retigabine, eslicarbazepine acetate and perampanel and the new orphan AEDs stiripentol and rufinamide, will be discussed, as well as the future holds for AED TDM (e.g. pharmacogenetics).

1640-1655   Panel Discussion

1655-1700   Concluding Remarks

1700-1730   Break

1730-1830   Opening Ceremonies