Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations

Patsalos, Philip N.; Zugman, Miguel; Lake, Charlotte; James, Anthony; Ratnaraj, Neville; Sander, Josemir W.

doi:10.1111/epi.13802

Cited by 101 publications

(106 citation statements)

References 36 publications

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“…The L‐amino acid transport system 2 (LAT2) activity is involved in GAB absorption and the saturation of the transporter explains the dose‐dependent oral bioavailability . GAB does not bind to plasma proteins, is not metabolised and is eliminated unchanged in urine . Renal function showed a positive correlation with GAB renal clearance, since GAB is mainly eliminated by glomerular filtration .…”

Section: Introductionmentioning

confidence: 99%

“…8,[11][12][13][14] GAB does not bind to plasma proteins, is not metabolised and is eliminated unchanged in urine. [15][16][17] Renal function showed a positive correlation with GAB renal clearance, since GAB is mainly eliminated by glomerular filtration. [18][19][20] However, studies suggested the activity of the organic cation transporters OCT2 and OCTN1 in the renal excretion of GAB.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Yamamoto

Benzi

Azeredo

et al. 2018

Basic Clin Pharma Tox

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Gabapentin (GAB) is eliminated unchanged in urine, and organic cation transporters (OCT2 and OCTN1) have been shown to play a role in GAB renal excretion. This prospective clinical study aimed to evaluate the genetic polymorphisms effect on GAB pharmacokinetic (PK) variability using a population pharmacokinetic approach. Data were collected from 53 patients with chronic pain receiving multiple doses of GAB. Patients were genotyped for SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms. Both polymorphisms' distribution followed the Hardy-Weinberg equilibrium. An one-compartment model with first-order absorption and linear elimination best described the data. The absorption rate constant, volume of distribution, and clearance estimated were 0.44 h , 86 L, and 17.3 × (estimated glomerular filtration ratio/89.58) L/h, respectively. The genetic polymorphism SLC22A4 c.1507C>T did not have a significant influence on GAB absorption, distribution or elimination. Due to the low minor allelic frequency of SLC22A2 c.808G>T, further studies require higher number of participants to confirm its effect on GAB renal elimination. In conclusion, GAB clinical pharmacokinetics are strongly influenced by renal function and absorption process, but not by the OCTN1 (SLC22A4 c.1507C>T) polymorphism.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Yamamoto

Benzi

Azeredo

et al. 2018

Basic Clin Pharma Tox

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“…In addition, anticonvulsants such as Valproic acid, and Clonazepam are greater than 88% protein bound so they do not cross the blood brain barrier well and therefore provide little if any medication to the targeted areas. In addition, Valproic acid and similar drugs demonstrate serum protein saturable binding which can impact other medications when given simultaneously [62]. Newer anticonvulsants such as ethosuximide and topirimate are more promising, yet the disease is far from controlled.…”

Section: Clinical Relevance and Conclusionmentioning

confidence: 99%

Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction

Sizemore

Lucke‐Wold²,

Rosen³

et al. 2018

obm neurobiol

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The brain is an integrated network of multiple variables that when compromised create a diseased state. The neuropathology of temporal lobe epilepsy (TLE), stroke, and traumatic brain injury (TBI) demonstrate both similarity and complexity that reflects this integrated variability; TLE with its live human tissue resection provides opportunity for translational science to demonstrate scale equivalent experimentation between the macroscopic world of clinical disease and the microscopic world of basic science. The extended value of this research is that the neuroinflammatory abnormalities that occur throughout astrocytes with hippocampal sclerosis and damaged or even reversed signaling pathways (inhibition to excitation such as with gaba-aminobutyric acid) are similar to those seen in post-stroke and TBI models. In evaluation of the epilepsy population this interconnectedness of pathology warrants further evaluation with collaborative efforts. This review summarizes patterns that could shift experimentation closer to the macro level of humanity, but still represent the micro world of genetics, epigenetics, and neuro-injury across etiologies of physiologic dysfunction such as TLE, stroke, and TBI with evaluation of cell function using electrophysiology. In conclusion we demonstrate the plausibility of electrophysiologic voltage and current measurement of brain tissue by patch clamp analysis to specify actual electrophysiologic function for comparison to electroencephalography in order to aid neurologic evaluation. Finally, we discuss the opportunity with multiscale modeling to display integration of the hyperpolarization cyclic-nucleotide gated channel, the depolarized calcium channels, and sodium-potassium-chloride-one/potassium-chloride-two co-transporter channels as potential mechanisms utilized as tri-coordinate biomarkers with these three forms of neurologic disease at a molecular scale of electrophysiologic pathology.

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“…9 Gabapentin has variable absorption and nonlinear pharmacokinetics, which leads to large interindividual differences in doseto-plasma concentrations and makes it an excellent candidate for therapeutic drug monitoring (TDM). 10,12 The interaction potential is therefore seen as low, even though interactions with some antacids and analgesics have been reported. 10,12 The interaction potential is therefore seen as low, even though interactions with some antacids and analgesics have been reported.…”

mentioning

confidence: 99%

“…7,10,11 It is not protein bound or metabolized, but rather cleared entirely by renal elimination, with an elimination half-life of 5-7 hours in healthy subjects. 10,12 The interaction potential is therefore seen as low, even though interactions with some antacids and analgesics have been reported. 13,14 Therapeutic drug monitoring is a commonly used tool to optimize treatment of epilepsy 7 and has been used as a part of the comprehensive care approach in epilepsy for 50 years.…”

mentioning

confidence: 99%

Therapeutic drug monitoring of gabapentin in various indications

et al. 2019

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Objectives Gabapentin has been increasingly used in various indications in recent years. Despite variable pharmacokinetics, therapeutic drug monitoring (TDM) is scarcely described in other indications than epilepsy. The aim of the study was to investigate the use and pharmacokinetic variability of gabapentin in epilepsy and non‐epilepsy indications and to further evaluate the use of TDM in patients with restless legs syndrome (RLS). Materials & Methods Population‐based data from the Norwegian Prescription Database, retrospective TDM data from the section for Clinical Pharmacology, the National Center for Epilepsy, Norway, and prospective observational data on patients with RLS were used. Results The use of gabapentin increased by 30% from 2014 to 2017 (32 181 to 42 675 users). TDM data from 120 patients showed a 22‐fold pharmacokinetic variability in concentration/dose ratios, and this ratio was elevated in elderly patients (≥65 years). The majority of elderly used gabapentin for non‐epilepsy indications. In patients with RLS, intake in the evening/night only was common due to nocturnal symptoms, in contrast to regular dosing regimens in epilepsy. Thus, drug fasting concentrations do not reflect concentrations at the time of required therapeutic effect. TDM was still found useful in most patients to support dosage increase or evaluate adverse effects. Conclusion Due to extensive pharmacokinetic variability, TDM can benefit patients using gabapentin. Challenges with applying TDM in new indications such as RLS include different dosage regimens and consequently different interpretation of serum concentrations. Thus, TDM should be requested on clear clinical grounds and the service tailored according to the therapeutic indication.

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Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations

Abstract: These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine-epoxide and N-desmethyl-clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.

Cited by 101 publications

References 36 publications

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction

Therapeutic drug monitoring of gabapentin in various indications

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