Pharmacokinetic characteristics of antiepileptic drugs (AEDs)

Marvanová, Markéta

doi:10.9740/mhc.2015.01.008

Cited by 44 publications

(70 citation statements)

References 35 publications

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“…Given that many epilepsy patients require life-long treatment, take more than one AED and may take contraceptives or other drugs for diseases related or unrelated to epilepsy, it is important to minimize the risk of pharmacokinetic interactions when selecting AEDs. Pharmacokinetic interactions may alter plasma concentrations of AEDs and other drugs by affecting absorption, transport, distribution (plasma protein binding), metabolism and/or renal elimination [70][71][72]. This may result in reduced efficacy or tolerability.…”

Section: Pharmacokinetic Properties and Pharmacokinetic Interaction Pmentioning

confidence: 99%

“…Several newer AEDs (particularly brivaracetam, gabapentin, lacosamide and levetiracetam, Table 1) have a lower propensity of interactions because they do not induce or inhibit liver enzymes. The older AEDs, particularly hepatic enzyme inducers (e.g., carbamazepine, phenobarbital, phenytoin and primidone) and inhibitors (e.g., valproate) have a higher propensity for pharmacokinetic interactions (Table 1) [70][71][72].…”

Section: Pharmacokinetic Properties and Pharmacokinetic Interaction Pmentioning

confidence: 99%

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Recommendations for the treatment of epilepsy in adult and pediatric patients in Belgium: 2020 update

et al. 2020

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To guide health care professionals in Belgium in selecting the appropriate antiepileptic drugs (AEDs) for their epilepsy patients, a group of Belgian epilepsy experts developed recommendations for AED treatment in adults and children (initial recommendations in 2008, updated in 2012). As new drugs have become available, others have been withdrawn, new indications have been approved and recommendations for pregnant women have changed, a new update was pertinent. A group of Belgian epilepsy experts (partly overlapping with the group in charge of the 2008/2012 recommendations) evaluated the most recent international guidelines and relevant literature for their applicability to the Belgian situation (registration status, reimbursement, clinical practice) and updated the recommendations for initial monotherapy in adults and children and add-on treatment in adults. Recommendations for add-on treatment in children were also included (not covered in the 2008/2012 publications). Like the 2008/2012 publications, the current update also covers other important aspects related to the management of epilepsy, including the importance of early referral in drug-resistant epilepsy, pharmacokinetic properties and tolerability of AEDs, comorbidities, specific considerations in elderly and pregnant patients, generic substitution and the rapidly evolving field of precision medicine.

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Section: Pharmacokinetic Properties and Pharmacokinetic Interaction Pmentioning

confidence: 99%

Section: Pharmacokinetic Properties and Pharmacokinetic Interaction Pmentioning

confidence: 99%

Recommendations for the treatment of epilepsy in adult and pediatric patients in Belgium: 2020 update

et al. 2020

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“…To reduce the risk of adverse effects and drug interactions, therapeutic drug monitoring (TDM) to evaluate plasma levels of ASMs is strongly advisable [ 17 , 18 ]. This clinical practice, which involves the measurement of ASMs concentration at designated time intervals to maintain a constant value in the patient bloodstream, helps to prevent seizures, minimize adverse effects, and optimize individual dosage regimens [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

et al. 2021

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Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM). However, many decisions in TDM are based on the determination of the total drug concentration although measurement of the free fraction, which is not bound to plasma proteins, is becoming of ever-increasing importance since it correlates better with pharmacological and toxicological effects. Aim of this work has been to review methodological aspects concerning the evaluation of the free plasmatic fraction of some ASMs, focusing on the effect and the clinical significance that drug-protein binding has in the case of widely used drugs such as valproic acid, phenytoin, perampanel and carbamazepine. Although several validated methodologies are currently available which are effective in separating and quantifying the different forms of a drug, prospective validation studies are undoubtedly needed to better correlate, in real-world clinical contexts, pharmacokinetic monitoring to clinical outcomes.

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“…The CYP2C9/19-mediated oxidation of phenytoin is usually saturated at the typical phenytoin plasma concentrations observed clinically, leading to non-linear (i.e., Michaelis–Menten) elimination [ 6 , 10 ]. Moreover, phenytoin is a broad spectrum inducer of metabolism enzymes [ 11 , 12 ], which can increase the intrinsic clearance of coadministered drugs.…”

Section: Introductionmentioning

confidence: 99%

Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling

et al. 2020

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Background and objective Phenytoin is extensively protein bound with a narrow therapeutic range. The unbound phenytoin is pharmacologically active, but total concentrations are routinely measured in clinical practice. The relationship between free and total phenytoin has been described by various binding models with inconsistent findings. Systematic comparison of these binding models in a single experimental setting is warranted to determine the optimal binding behaviors. Methods Non-linear mixed-effects modeling was conducted on retrospectively collected data (n = 37 adults receiving oral or intravenous phenytoin) using a stochastic approximation expectation-maximization algorithm in MonolixSuite-2019R2. The optimal base structural model was initially developed and utilized to compare four binding models: Winter-Tozer, linear binding, non-linear single-binding site, and non-linear multiple-binding site. Each binding model was subjected to error and covariate modeling. The final model was evaluated using relative standard errors (RSEs), goodness-of-fit plots, visual predictive check, and bootstrapping. Results A one-compartment, first-order absorption, Michaelis-Menten elimination, and linear protein-binding model best described the population pharmacokinetics of free phenytoin at typical clinical concentrations. The non-linear single-bindingsite model also adequately described phenytoin binding but generated larger RSEs. The non-linear multiple-binding-site model performed the worst, with no identified covariates. The optimal linear binding model suggested a relatively high binding capacity using a single albumin site. Covariate modeling indicated a positive relationship between albumin concentration and the binding proportionality constant. Conclusions The linear binding model best described the population pharmacokinetics of unbound phenytoin in adult subjects and may be used to improve the prediction of free phenytoin concentrations.

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Pharmacokinetic characteristics of antiepileptic drugs (AEDs)

Cited by 44 publications

References 35 publications

Recommendations for the treatment of epilepsy in adult and pediatric patients in Belgium: 2020 update

Recommendations for the treatment of epilepsy in adult and pediatric patients in Belgium: 2020 update

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling

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