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Ask the Expert: Therapeutic Drug Monitoring of AEDs

Provided by the American Epilepsy Society

Therapeutic drug monitoring (TDM) is the clinical practice of measuring specific drugs at specific intervals to maintain a constant concentration in a patient's bloodstream, thereby achieving effective therapeutic levels. TDM is typically used for monitoring medications with narrow therapeutic ranges, drugs whose concentrations are difficult to monitor, a high degree of pharmacokinetic variability, and drugs that can cause adverse effects.
TDM is based on the assumption that there is a definable relationship between dose and plasma or blood drug concentration, and between blood drug concentration and therapeutic effects. TDM should begin when the drug is first prescribed, and involves determining an initial dosage regimen appropriate for the clinical condition and patient characteristics (age, weight, other medications, etc.). The goal of TDM is to monitor concentrations of medications in order to optimize clinical outcomes in patients.
In pharmacokinetics, steady state is reached 4 to 5 times the half-life for a drug after regular dosing is started. Variability in the time of measurement and Anti-Epileptic Drug (AED) co-therapy influences AED blood levels. Morning trough levels are most clinically useful, but obtaining morning trough levels can be logistically challenging.
Monitoring AEDs can be challenging as, for example, a subtherapeutic level is one patient may control seizures while near-toxic levels in another does not. The table below delineates common pitfalls in AED blood level monitoring when the AED dosage is adjusted based on the level blindly, without regard to clinical efficacy or toxicity. Breakthrough seizures, inappropriate alterations in effective therapy, therapeutic complacency, and toxic side effects may result if the clinical considerations of efficacy and adverse effects are not given priority in adjustments to AED dosage.
Table 1. Common Pitfalls in AED Blood Level Monitoring and Dosing

AED Levels Blind, Reactive AED Adjustment to Level Patient’s Clinical Efficacy Patient’s Clinical Side Effects Resultant Pitfall

Supratherapeutic
Lower dose; move to new/next AED trial
Seizure-free

None
Breakthrough seizures; needless loss of ideal efficacy
Therapeutic No Intractable None Underdosing, therapeutic complacency
Subtherapeutic Raise dose Seizure-free None/toxic Toxic side effects possible

Monitoring of newer AEDs can be challenging because they often have wider therapeutic ranges, and for some, reference ranges are not yet well established.
Physicians and their healthcare team need to be knowledgeable regarding the basic of Therapeutic Drug Monitoring (TDM). They also need to aware of the appropriate role of TDM in managing both the older and the newer AEDs, inclusive of brand names and generics. Physicians and their healthcare teams need to be able to develop appropriate TDM plans when treating people with epilepsy with AEDs. They also need to be aware of the continuing importance of clinical evaluation in combination with TDM.
References:
Kang J-S, Lee M-H. Overview of Therapeutic Drug Monitoring. The Korean Journal of Internal Medicine. 2009;24(1):1-10. doi:10.3904/kjim.2009.24.1.1.
Krasowski MD. Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications. Pharmaceuticals. 2010;3(6):1909-1935. doi:10.3390/ph3061908.
St. Louis EK. Monitoring Antiepileptic Drugs: A Level-Headed Approach. Current Neuropharmacology. 2009;7(2):115-119. doi:10.2174/157015909788848938.

Target Audience
Epileptologists, neurologists, pharmacologists, advanced practice providers, nurses

Learning Objectives


Following participation in this activity, the learner should be able to:
  • Discuss the basics of Therapeutic Drug Monitoring (TDM).
  • Delineate the appropriate role of TDM for older and newer AEDs, inclusive of generics.
  • Prepare an appropriate TDM plan for people with epilepsy being treated with AEDs.
  • Restate the importance of clinical assessment in conjunction with TDM.

Faculty


Moderator & Planner 
Dennis J. Dlugos, MD, Childrens Hospital of Philadelphia, Philadelphia, PA
Chair, AES Education and Professional Development Committee


Presenter
Timothy E. Welty, M.A., Pharm.D, FCCP, Drake University College of Pharmacy and Health Sciences, Des Moines, IA


Accreditation


The American Epilepsy Society is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians

AMA Credit Designation
The American Epilepsy Society designates this live internet activity for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity
International Credits: The American Medical Association has determined that non-US. Licensed physicians who participate in this CME activity are eligible for AMA PRA Category 1 Credits™.
Physician Assistants: AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credits™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category 1 credit for completing this program.

Conflict of Interest & Disclosures

Disclosure Policy
It is the policy of the American Epilepsy Society to ensure balance, independence, objectivity and scientific rigor. All individuals involved in the selection, development and presentation of content are required to disclose any real or apparent conflicts of interest. Conflicts of interest will be resolved by AES prior to an educational activity being delivered to learners.

Faculty, Planning Committee, Reviewers’ Disclosures of Financial Relationships
In accordance with the ACCME Standards for Commercial Support, the AES requires that any person who is in a position to control content of a CME activity must disclose all relevant financial relationships that they have with a commercial interest. The following individuals contributed to this activity’s content.

Faculty & Planners
Dennis Dlugos, MD, Childrens Hospital of Philadelphia, Philadelphia, PA
Dr. Dlugos receives research funding from the NIH, the Pennsylvania Department of Health, and the Epilepsy Study Consortium. He has also given expert testimony in medico-legal cases.

Timothy E. Welty, M.A., Pharm.D, FCCP, Drake University College of Pharmacy and Health Sciences, Des Moines, IA
Dr. Welty has disclosed the following financial relationships relevant to this activity:
  • Consultant: Upsher-Smith Laboratories, Eisai, Sunovian;
  • Co-investigator: Food and Drug Administration-Equigen

CME Reviewer
Ignacio Valencia, MD, St. Christopher's Hospital for Children, Philadelphia, PA
Dr. Valencia has indicated he has no financial relationships to disclose relevant to this activity.

American Epilepsy Society Staff Planners
Jessica A. Daniels, MNA
Debra L. Gist, MPH, FACEHP

Ms. Daniels and Ms. Gist have indicated they have no financial relationships with commercial interests to disclose.

RESOLUTION OF CONFLICTS OF INTEREST

It is the policy of the American Epilepsy Society to ensure balance, independence, objectivity and scientific rigor. All persons involved in the selection, development and presentation of content are required to disclose any real or apparent conflicts of interest. In accordance with the ACCME Standards for Commercial Support of CME, the AES implemented the mechanisms of prospective peer review of this CME activity, to identify and resolve any conflicts. Additionally, the content of this activity is based on the best available evidence.

UNAPPROVED USE DISCLOSURE
The American Epilepsy Society requires CME faculty/authors to disclose to learners when products or procedures being discussed are off-label, unlabeled, experimental, and/or investigational (not FDA approved); and any limitations on the information that is presented, such as data that are preliminary or that represent ongoing research, interim analyses, and/or unsupported opinion.This information is intended solely for continuing medical education and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information. Information about pharmaceutical agents/devices that is outside of U.S. Food and Drug Administration approved labeling may be contained in this activity.

DISCLAIMER
This CME activity is for educational purposes only and does not constitute the opinion or endorsement of, or promotion by, the American Epilepsy Society. Reasonable efforts have been taken to present educational subject matter in a balanced, unbiased fashion, and in compliance with regulatory requirements. However, each activity participant must always use his or her own personal and professional judgment when considering further application of this information, particularly as it may relate to patient diagnostic or treatment decisions including, without limitation, FDA-approved uses and any off-label, investigational and/or experimental uses.