Therapeutic Drug Monitoring of Clobazam and Its Metabolite—Impact of Age and Comedication on Pharmacokinetic Variability

Burns, Margrete Larsen; Baftiu, Arton; Opdal, Mimi Stokke; Johannessen, Svein I.; Landmark, Cecilie Johannessen

doi:10.1097/ftd.0000000000000272

Cited by 26 publications

(21 citation statements)

References 35 publications

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“…The table is based on the summary of product characteristics (SPC) and reports from Burns et al . (), Johannessen and Johannessen Landmark (), Johannessen Landmark and Patsalos (), and Johannessen Landmark et al . (b).…”

Section: The Present: 50 Years Of Evolution Of Knowledge Of Pharmacolmentioning

confidence: 99%

“…Comedication with AEDs or other drugs is the most important external factor since many AEDs have a pronounced potential to cause pharmacokinetic interactions, as there are both strong enzyme inhibitors (valproic acid, stiripentol, and felbamate) and inducers (carbamazepine, phenytoin, and phenobarbital), as well as AEDs which are substrates for interactions. Drugs like lamotrigine and clobazam are affected by both inducers and inhibitors and thus pronounced changes in serum concentrations are observed (Bartoli et al ., ; Johannessen Landmark et al ., a; Burns et al ., ). One example is the interaction between lamotrigine and oral contraceptives, in which the serum concentrations of lamotrigine are reduced by 50% on average, as compared to women not using oestradiol‐containing oral contraceptives (Sabers et al ., ).…”

Section: The Present: 50 Years Of Evolution Of Knowledge Of Pharmacolmentioning

confidence: 99%

“…For drugs for which the parent molecule and active metabolite are present at high concentrations ( i.e . clobazam and N‐desmethylclobazam), both can be measured and various metabolite/parent compound ratios used in the interpretation of the results (Burns et al ., ).…”

Section: The Present: 50 Years Of Evolution Of Knowledge Of Pharmacolmentioning

confidence: 99%

“…Complementary pharmacogenetic testing may, however, elucidate the reason for unexpected relationships between dose and serum concentrations of certain AEDs when CYP2C9 and 2C19, and to some extent UGTs, are shown to have polymorphisms that may give rise to a poor metaboliser phenotype. Susceptible AEDs are clobazam, phenytoin, and to a lesser extent, lamotrigine (Lee et al, 2007;Gulcebi et al, 2011;Burns et al, 2016;Reimers et al, 2016). Genetic variability in drug transporters, as a mechanism for pharmacoresistance, is still under debate and needs further research (Löscher et al, 2009).…”

Section: Genetic Factorsmentioning

confidence: 99%

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Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring

Landmark¹,

Johannessen²,

Tomson³

2016

Epileptic Disorders

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This review focuses on the evolution of approaches to dosing of antiepileptic drugs (AEDs) in clinical practice through history. There has been a shift in the view of treatment of epilepsy, from “one dose fits all patients” in the early days to individualisation of treatment. Over the past 50 years, our knowledge of pharmacological variability of AEDs has markedly increased through implementation of therapeutic drug monitoring (TDM). The use of TDM has demonstrated extensive pharmacokinetic variability for AEDs and a need to individualise the treatment for an optimal outcome. Factors that contribute to pharmacokinetic variability include external factors (including food and comedication), physiological factors (gender, age, and pregnancy), pathological conditions (organ dysfunction), and genetic factors (polymorphisms in metabolising enzymes). Patient groups of children, pregnant women, and the elderly, in whom the most extensive pharmacokinetic changes occur, need special attention and close follow‐up of treatment. Patients with complicated and changing combination treatments are also vulnerable. Therapeutic drug monitoring may be particularly helpful in such situations. There are also challenges regarding the use and misuse of therapeutic drug monitoring, such as the use of drug monitoring without a clear indication, misinterpretation of the reference range, and erroneous sampling times.

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Section: The Present: 50 Years Of Evolution Of Knowledge Of Pharmacolmentioning

confidence: 99%

Section: The Present: 50 Years Of Evolution Of Knowledge Of Pharmacolmentioning

confidence: 99%

Section: The Present: 50 Years Of Evolution Of Knowledge Of Pharmacolmentioning

confidence: 99%

Section: Genetic Factorsmentioning

confidence: 99%

See 2 more Smart Citations

Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring

Landmark¹,

Johannessen²,

Tomson³

2016

Epileptic Disorders

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“…inhibitors has not yet been studied. Inducers act at various steps during the metabolism of CBD, CYP3A4, 2C19 and UGTs (carbamazepine, phenytoin), and inhibitors during the metabolism of CYP2C19 and UGTs (stiripentol, felbamate, valproate, and the mixed inducer/inhibitor oxcarbazepine) Patsalos, 2013a;Burns et al, 2016).…”

Section: What We Do Not Know?mentioning

confidence: 99%

Pharmacology and drug interactions of cannabinoids

Landmark

Brandl

2020

Epileptic Disorders

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Cannabinoids include a variety of substances, of which cannabidiol (CBD) is the main substance investigated for the treatment of epilepsy, and this will be the focus in the present review. CBD preparations exist in various forms. There are significant differences in quality control regarding content and reproducibility for an approved drug versus herbal preparations. Cannabidiol has challenging pharmacological properties, and pharmaceutical and pharmacokinetic aspects will depend on the formulation or preparation of a certain product. This article will focus on the characteristics, pharmacokinetic challenges, and interactions of standardised CBD‐containing drugs based on evidence from clinical and pharmacokinetic studies.

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A retrospective review of changes and challenges in the use of antiseizure medicines in Dravet syndrome in Norway

et al. 2020

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Objective Dravet syndrome is a developmental and epileptic encephalopathy characterized by severe and drug‐resistant seizures in early childhood, followed by developmental delay. The purpose of this study was to investigate aspects of pharmacological treatment of Norwegian patients with Dravet syndrome, focusing on the use of antiseizure medicines (ASMs) and identifying treatment challenges. Methods Patients were identified through medical registries at the National Center for Epilepsy in Norway and National Center for Rare Epilepsy Related Disorders during 2008‐2018. Additional clinical data were obtained from medical records and laboratory request forms. Results We identified 53 patients with Dravet syndrome, 30/23 males/females, aged 2‐50 years. The majority of patients with known seizure frequency experienced frequent seizures, 80% (n = 35/44). Only two patients were seizure‐free. Valproate (n = 48), clobazam (n = 45), levetiracetam (n = 30), and stiripentol (n = 38) were most commonly used, previous or current use. More than one‐third (n = 20) had tried sodium channel blockers (including lamotrigine), but these drugs were used less during the last decade. Polytherapy was common, 81% (n = 43) used two or more ASMs, and eight of these patients used 4‐5 drugs (15%). Several challenges were identified: high seizure frequency, comorbidities, treatment changes with a wide range of ASMs, common use of oral gastro‐tubes, extensive polypharmacy, and drug interactions. Significance The use of ASMs has changed over the last decade, in accordance with updated international recommendations. Various treatment challenges were identified. This vulnerable group of patients needs close follow‐up for an optimal treatment outcome.

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Therapeutic Drug Monitoring of Clobazam and Its Metabolite—Impact of Age and Comedication on Pharmacokinetic Variability

Abstract: The pharmacokinetic variability of CLB and its metabolite NCLB in clinical practice is extensive, and is influenced by drug-drug interactions, age, and pharmacogenetics. Therapeutic drug monitoring of CLB and NCLB is therefore valuable in patient management.

Cited by 26 publications

References 35 publications

Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring

Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring

Pharmacology and drug interactions of cannabinoids

A retrospective review of changes and challenges in the use of antiseizure medicines in Dravet syndrome in Norway

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