Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs

Piana, Chiara; Antunes, Nilson; Pasqua, Oscar Della

doi:10.1517/17425255.2014.872630

Cited by 18 publications

(24 citation statements)

References 122 publications

(88 reference statements)

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“…Until today, effective management of epilepsy remains challenging in clinical practice . The differences in response to treatment may be caused by many factors, in addition to the variation in patient disease status, individual difference in drug disposition may also result in the failure of seizure treatments.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

et al. 2019

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Summary What is known and objectives Oxcarbazepine (OXC) is a widely used antiepileptic drug whose effect mainly depends on its active metabolite 10‐hydroxycarbazepine (MHD). This study established a population pharmacokinetic (PPK) model of MHD in Chinese children with epilepsy and conducted a dosage simulation in order to provide support for individualized OXC treatment. Methods Ninety‐one plasma sampling points from 88 paediatric patients were retrospective collected. MHD concentrations were detected, and patients’ clinical data were recorded. PPK analysis was performed using a non‐linear, mixed‐effect modelling approach. The goodness‐of‐fit (GOF) plots, bootstrap method, prediction‐corrected visual predictive check (pcVPC) and normalized prediction distribution errors (NPDE) were performed to evaluate the final model. External model validations by an independent group of paediatric patients (10 patients, 10 blood samples) were conducted. The steady‐state trough concentrations of MHD were determined by Monte Carlo simulations for doses ranging from 8 to 60 mg/kg/day. Results A one‐compartment model with first‐order elimination successfully described the data. The typical values for MHD clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka) were 3.25 L/h/70 kg, 151.41 L/70 kg and 0.598 h−1, respectively. The CL/F and V/F of MHD were related to body weight (WT) via an empirical allometric model. Internal and external validations demonstrated a good predictability of the final model. Monte Carlo simulations revealed that for most paediatric patients, a dosing regimen of 20‐30 mg/kg/d bid maybe sufficient to reach MHD therapeutic range. What is new and conclusion A PPK model of MHD in Chinese paediatric patients was successfully established. A priori dosing guideline was proposed considering WT and MHD plasma concentrations, providing a basis for OXC dosage calculations and adjustments in Chinese epileptic children.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

et al. 2019

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“…Such a variation may lead to significant differences in the hepatic clearance of many AEDs [37], with increase or reduction in metabolic capacity resulting in different phenotypes [38]. Similarly, renal clearance can be affected by differences in the expression level of renal transporters [39,40]. While the impact of genetic differences can be accounted for when defining the dose and dosing regimen, genotyping or phenotyping are not used in standard practice when initiating or changing therapy and is most probably not encouraged in children.…”

Section: Clearance: Influence Of Genotype Size and Maturationmentioning

confidence: 99%

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Dijkman

Álvarez-Jiménez

Danhof

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.

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“…Articles are still frequently written on the “promise of pharmacogenetics,” but as yet the concrete benefits are conspicuous by their absence except perhaps in detecting hypersensitivity to individual AEDs, mostly carbamazepine in people from Asia 18, 19, 20, 21, 22, 23, 24. In our view, the complexity and multifactorial nature of success or failure of antiepileptic drug treatment render it unlikely that simple single pharmacogenetic mechanisms, at least as they are currently conceived, do have any major impact on therapy.…”

Section: Today's Theories and Practices Which May Not Withstand The Tmentioning

confidence: 99%

The right and the wrong with epilepsy and her science

Shorvon

Schmidt²

2016

Epilepsia Open

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SummaryThis is a commentary and an opinion paper attempting a critical reassessment of the methods and practices of epilepsy research as we see it. The enormous progress in the field of epilepsy in recent years is a cause of celebration. Advances have been made on most fronts, and the position of patients with epilepsy in society has greatly improved. However, there have also been culs‐de‐sac and dead ends of modern science and clinical practice which are also intriguing. It may be true that we can learn more from our mistakes than from our successes. In this opinion paper, we have listed some of the successes and some of the failures of past epilepsy practice, and also areas of current practice and theory which we feel are likely to prove mistaken. The underlying reasons for misdirected practices and theories include, in our view, the influence of fashion, bad science, and the bureaucracies of practice and academic medicine. As a result, some findings are far from objective. Recognition is the first step to remediation, and hopefully future research will minimize some of the pitfalls mentioned in this article and bring the “End of Epilepsy,” as defined and predicted by Oswei Temkin, closer than it is today.

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Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs

Cited by 18 publications

References 122 publications

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

The right and the wrong with epilepsy and her science

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