Pharmacokinetic Properties of New Antiepileptic Drugs

Eight new antiepileptic drugs (AEDs) have been approved for use within the United States within the past decade. They are felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide. These afford clinicians with more options to increase efficacy and tolerability in the treatment of patients with epilepsy. Pharmacokinetic properties and drug interactions with other AEDs and other medications taken for comorbidities are individually discussed for each of these new agents. Drug concentrations are not routinely monitored for these newer agents, and there have been few studies designed to investigate their concentration-effect relationships. For most of these medications, the concentrations observed in responders and nonresponders overlap considerably and levels associated with efficacy are often associated with adverse events, complicating the definition of target ranges. Also, epilepsy manifests itself sporadically causing difficulty in clinically monitoring efficacy of medications. Therapeutic drug monitoring provides for the individualization of treatment for these agents, which is important because they demonstrate significant variability in inter- and intraindividual pharmaco-kinetic properties. Therapeutic drug monitoring also allows for identification of noncompliance, drug interactions, and toxicity. Current knowledge of the relationships between efficacy, toxicity, and drug concentrations is discussed.

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Optimum Use of Therapeutic Drug Monitoring and Pharmacokinetics-Pharmacodynamics in the NICU

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-14.2.66 ◽

2009 ◽

Vol 14 (2) ◽

pp. 66-74

Author(s):

Peter Gal

Keyword(s):

Drug Therapy ◽

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Therapeutic Range ◽

Drug Monitoring ◽

Population Based ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Patient Response ◽

Drug Concentrations

Therapeutic drug monitoring is increasingly giving way to dosing drugs based on population-based pharmacokinetic parameters, even when pharmacokinetic values vary quite a bit in individual patients. Further, drug concentrations are often considered appropriate if they are within a defined therapeutic range, even if the patient response is suboptimal. This lecture discusses the limitations of therapeutic ranges in neonates, and proposes greater emphasis on pharmacodynamic curves to individualize drug therapy. Examples are provided using methylxanthines, indomethacin, antiepileptic drugs and aminoglycosides. The potential to use pharmacokinetic findings to describe physiologic changes and occasionally assist with diagnosis is also discussed.

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Therapeutic drug monitoring of old and newer anti-epileptic drugs

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2004.245 ◽

2004 ◽

Vol 42 (11) ◽

Cited By ~ 100

Author(s):

Hugo M. Neels ◽

Ann C. Sierens ◽

Kristine Naelaerts ◽

Simon L. Scharpé ◽

George M. Hatfield ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Interactions ◽

Drug Monitoring ◽

Seizure Control ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Potential Value ◽

Pharmacokinetic Properties ◽

New Generation ◽

The Relationship

AbstractThe aim of the present paper is to provide information concerning the setting up and interpretation of therapeutic drug monitoring (TDM) for anti-epileptic drugs. The potential value of TDM for these drugs (including carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pheneturide, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide) is discussed in relation to their mode of action, drug interactions and their pharmacokinetic properties. The review is based upon available literature data and on observations from our clinical practice. Up until approximately 15 years ago anti-epileptic therapeutics were restricted to a very few drugs that were developed in the first half of the 20th century. Unfortunately, many patients were refractory to these drugs and a new generation of drugs has been developed, mostly as add-on therapy. Although the efficacy of the newer drugs is no better, there is an apparent improvement in drug tolerance, combined with a diminished potential for adverse drug interactions. All new anticonvulsant drugs have undergone extensive clinical studies, but information on the relationship between plasma concentrations and effects is scarce for many of these drugs. Wide ranges in concentrations have been published for seizure control and toxicity. Few studies have been undertaken to establish the concentration-effect relationship. This review shows that TDM may be helpful for a number of these newer drugs.

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A Rapid LC–MS-MS Method for the Quantitation of Antiepileptic Drugs in Urine

Journal of Analytical Toxicology ◽

10.1093/jat/bkaa095 ◽

2020 ◽

Vol 44 (7) ◽

pp. 688-696

Author(s):

Sheng Feng ◽

Brandi Bridgewater ◽

Erin C Strickland ◽

Gregory McIntire

Keyword(s):

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Drug Monitoring ◽

Method Development ◽

Therapeutic Drug ◽

Reference Ranges ◽

Concentration Data ◽

Drug Concentrations ◽

Repeat Rate ◽

Analytical Range

Abstract Epilepsy is a common neurologic disease that requires treatment with one or more medications. Due to the polypharmaceutical treatments, potential side effects, and drug-drug interactions associated with these medications, therapeutic drug monitoring is important. Therapeutic drug monitoring is typically performed in blood due to established clinical ranges. While blood provides the benefit of determining clinical ranges, urine requires a less invasive collection method, which is attractive for medication monitoring. As urine does not typically have established clinical ranges, it has not become a preferred specimen for monitoring medication adherence. Thus, large urine clinical data sets are rarely published, making method development that addresses reasonable concentration ranges difficult. An initial method developed and validated in-house utilized a universal analytical range of 50–5,000 ng/mL for all antiepileptic drugs and metabolites of interest in this work, namely carbamazepine, carbamazepine-10,11-epoxide, eslicarbazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, 4-hydroxyphenytoin, and topiramate. This upper limit of the analytical range was too low leading to a repeat rate of 11.59% due to concentrations >5,000 ng/mL. Therefore, a new, fast liquid chromatography–tandem mass spectrometry (LC–MS-MS) method with a run time under 4 minutes was developed and validated for the simultaneous quantification of the previously mentioned nine antiepileptic drugs and their metabolites. Urine samples were prepared by solid-phase extraction and analyzed using a Phenomenex Phenyl-Hexyl column with an Agilent 6460 LC–MS-MS instrument system. During method development and validation, the analytical range was optimized for each drug to reduce repeat analysis due to concentrations above the linear range and for carryover. This reduced the average daily repeat rate for antiepileptic testing from 11.59% to 4.82%. After validation, this method was used to test and analyze patient specimens over the course of approximately one year. The resulting concentration data were curated to eliminate specimens that could indicate an individual was noncompliant with their therapy (i.e., positive for illicit drugs) and yielded between 20 and 1,700 concentration points from the patient specimens, depending on the analyte. The resulting raw quantitative urine data set is presented as preliminary reference ranges to assist with interpreting urine drug concentrations for the nine aforementioned antiepileptic medications and metabolites.

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Rapid point-of-care anti-infliximab antibodies detection in clinical practice: comparison with ELISA and potential for improving therapeutic drug monitoring in IBD patients

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284821999902 ◽

2021 ◽

Vol 14 ◽

pp. 175628482199990

Author(s):

Sonia Facchin ◽

Andrea Buda ◽

Romilda Cardin ◽

Nada Agbariah ◽

Fabiana Zingone ◽

...

Keyword(s):

Clinical Practice ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Point Of Care ◽

Drug Clearance ◽

Elisa Test ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Drug ◽

Drug Concentrations ◽

Inflammatory Bowel

Anti-drug antibodies can interfere with the activity of anti-tumor necrosis factor (TNF) agents by increasing drug clearance via direct neutralization. The presence of anti-drug antibodies is clinically relevant when trough drug concentrations are undetectable or sub-therapeutic. However, traditional immunoassay is not easily and rapidly accessible, making the translation of the results into treatment adjustment difficult. The availability of a point-of-care (POC) test for therapeutic drug monitoring (TDM) might represent an important step forward for improving the management of inflammatory bowel disease (IBD) patients in clinical practice. In this pilot study, we compared the results obtained with POC tests with those obtained by enzyme-linked immunosorbent assay (ELISA) in a group of IBD patients treated with Infliximab (IFX). We showed that POC test can reliably detect presence of antibody-to-IFX with 100% of specificity and 76% sensitivity, in strong agreement with the ELISA test ( k-coefficient = 0.84).

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Feasibility of Using Oral Fluid for Therapeutic Drug Monitoring of Antiepileptic Drugs

European Journal of Drug Metabolism and Pharmacokinetics ◽

10.1007/s13318-020-00661-1 ◽

2021 ◽

Author(s):

Morgan Patrick ◽

Samuel Parmiter ◽

Sherif Hanafy Mahmoud

Keyword(s):

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Drug Monitoring ◽

Oral Fluid ◽

Therapeutic Drug

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Therapeutic Drug Monitoring of Antiepileptic Drugs in a Tertiary Care Hospital in India

Clinical Neuropharmacology ◽

10.1097/wnf.0000000000000057 ◽

2015 ◽

Vol 38 (1) ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Natarajan Harivenkatesh ◽

Natarajan Haribalaji ◽

Darling Chellathai David ◽

C. M. Prabu Kumar

Keyword(s):

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Drug Monitoring ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Therapeutic Drug ◽

Care Hospital

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Immunosuppressant quantification in intravenous microdialysate – towards novel quasi-continuous therapeutic drug monitoring in transplanted patients

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-1542 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Susanne Weber ◽

Sara Tombelli ◽

Ambra Giannetti ◽

Cosimo Trono ◽

Mark O’Connell ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Real Time ◽

Drug Monitoring ◽

Time Course ◽

Drug Dosage ◽

Immunosuppressive Drug ◽

Therapeutic Drug ◽

Continuous Sampling ◽

Real Time Analysis ◽

Drug Concentrations

AbstractObjectivesTherapeutic drug monitoring (TDM) plays a crucial role in personalized medicine. It helps clinicians to tailor drug dosage for optimized therapy through understanding the underlying complex pharmacokinetics and pharmacodynamics. Conventional, non-continuous TDM fails to provide real-time information, which is particularly important for the initial phase of immunosuppressant therapy, e.g., with cyclosporine (CsA) and mycophenolic acid (MPA).MethodsWe analyzed the time course over 8 h of total and free of immunosuppressive drug (CsA and MPA) concentrations measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 16 kidney transplant patients. Besides repeated blood sampling, intravenous microdialysis was used for continuous sampling. Free drug concentrations were determined from ultracentrifuged EDTA-plasma (UC) and compared with the drug concentrations in the respective microdialysate (µD). µDs were additionally analyzed for free CsA using a novel immunosensor chip integrated into a fluorescence detection platform. The potential of microdialysis coupled with an optical immunosensor for the TDM of immunosuppressants was assessed.ResultsUsing LC-MS/MS, the free concentrations of CsA (fCsA) and MPA (fMPA) were detectable and the time courses of total and free CsA comparable. fCsA and fMPA and area-under-the-curves (AUCs) in µDs correlated well with those determined in UCs (r≥0.79 and r≥0.88, respectively). Moreover, fCsA in µDs measured with the immunosensor correlated clearly with those determined by LC-MS/MS (r=0.82).ConclusionsThe new microdialysis-supported immunosensor allows real-time analysis of immunosuppressants and tailor-made dosing according to the AUC concept. It readily lends itself to future applications as minimally invasive and continuous near-patient TDM.

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Therapeutic Drug Monitoring of Second- and Third-Generation Antiepileptic Drugs: Insights From a College of American Pathologists Proficiency Testing Survey

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2020-0562-cp ◽

2021 ◽

Author(s):

Matthew D. Krasowski ◽

Thomas A. Long ◽

Christine L. H. Snozek ◽

Annabel Dizon ◽

Barbarajean Magnani ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Proficiency Testing ◽

Drug Monitoring ◽

First Generation ◽

Therapeutic Drug ◽

Third Generation ◽

Enzyme Immunoassays ◽

Steady Growth ◽

Survey Results

Context.— Therapeutic drug monitoring has traditionally been widely used for first-generation antiepileptic drugs (AEDs) such as carbamazepine and phenytoin. The last 2 decades have seen the introduction of second- and third-generation AEDs (eg, lamotrigine, levetiracetam, and topiramate) into clinical practice. Objective.— To use data from the College of American Pathologists Therapeutic Drug Monitoring, Extended proficiency testing survey to determine the performance of assays used for therapeutic drug monitoring of newer AEDs, including comparison of enzyme immunoassay and chromatographic techniques. Design.— Six years of proficiency testing surveys were reviewed (2013–2018). Results.— Steady growth was seen in participant volumes for newer AEDs. The analytical performance of automated enzyme immunoassays for lamotrigine, levetiracetam, and topiramate was similar to that of chromatographic methods, consistent with published literature using patient samples for comparisons. The majority of participating laboratories now use enzyme immunoassays to measure levetiracetam. Conclusions.— Survey results reflect steadily growing interest in therapeutic drug monitoring of newer AEDs. The increasing availability of robust immunoassays for new AEDs should facilitate their clinical utility, especially for clinical laboratories that do not perform chromatographic assays for therapeutic drug monitoring.

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