Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

He, Dongyi; Wang, Li; Qin, Jiong; Zhang, Shen; Lu, Wei; Li, Ling; Zhang, Jianming; Bao, Wei-Qun; Song, Xiaoqing; Liu, Haitao

doi:10.1038/aps.2012.118

Cited by 21 publications

(30 citation statements)

References 32 publications

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“…Models describing the PK of carbamazepine (CBZ) , clobazam (CLBZ) , clonazepam (CLNZ) , lamotrigine (LMT) , levetiracetam (LVT) , oxcarbazepine (OXC) , phenobarbital (PHB) , phenytoin (PHT) , topiramate (TPM) , valproic acid (VPA) and zonisamide (ZNS) were collected from the published literature. Given the primary objective of our analysis, models were selected if covariate effects were identified for one or more AEDs and study population included >50 patients.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children

Dijkman

Rauwé

Danhof

et al. 2017

Brit J Clinical Pharma

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AIMSPopulation pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment. METHODSModels describing the pharmacokinetics of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid and zonisamide in adult and paediatric patients were collected from the published literature and implemented in NONMEM v7.2. Taking current clinical practice into account, we explore simulation scenarios to characterize AED exposure in virtual patients receiving mono-and polytherapy. Steady-state, maximum and minimum concentrations were selected as parameters of interest for this analysis. RESULTSOur simulations show that DDIs can cause major changes in AED concentrations both in adults and children. When more than one AED is used, even larger changes are observed in the concentrations of the primary drug, leading to significant differences in steady-state concentration between mono-and polytherapy for most AEDs. These results suggest that currently recommended dosing algorithms and titration procedures do not ensure attainment of appropriate therapeutic concentrations. CONCLUSIONSThe effect of DDIs on AED exposure cannot be overlooked. Clinical guidelines must consider such covariate effects and ensure appropriate dosing recommendations for adult and paediatric patients who require combination therapy. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• First-line and alternative first line antiepileptic drugs (AEDs) are often used in combination with second-line line drugs (i.e. add-on).• Many AED combinations lead to pharmacokinetic drug-drug interactions (DDIs), which may result in large variation in drug exposure.• The implications of such DDIs have not been considered in existing clinical guidelines. WHAT THIS STUDY ADDS• We evaluate how demographic and clinical factors, including comedications (polytherapy), affect systemic exposure to AEDs in the target patient population. In addition, we demonstrate that AED dosing regimens can be optimized to ensure drug concentrations are maintained within a reference therapeutic range.• DDIs can lead to significant changes in systemic exposure and potentially alter the efficacy and safety profile of AEDs in adult and paediatric patients.• These results form the basis for a comprehensive review of clinical guidelines for the use of first and second line AEDs, including novel algorithms for dose adjustment.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children

Dijkman

Rauwé

Danhof

et al. 2017

Brit J Clinical Pharma

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“…Models describing the adult and pediatric PK of carbamazepine (CBZ), clobazam (CLBZ), clonazepam (CLNZ), lamotrigine (LMT), levetiracetam (LVT), oxcarbazepine (OXC), phenobarbital (PHB), phenytoin (PHT), topiramate (TPM), valproic acid (VPA), and zonisamide (ZNS) were collected from the published literature. Models were transcribed into the appropriate format in R v. 3.1.1, along with the parameter estimates and combined with analytical solutions of the mathematical equations describing the concentration over time profiles (Eqs.…”

Section: Methodsmentioning

confidence: 99%

Individualized Dosing Algorithms and Therapeutic Monitoring for Antiepileptic Drugs

Dijkman

Wicha

Danhof

et al. 2017

Clin Pharma and Therapeutics

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Pharmacokinetic (PK) models exist for most antiepileptic drugs (AEDs). Yet their use in clinical practice to assess interindividual differences and derive individualized doses has been limited. Here we show how model-based dosing algorithms can be used to ensure attainment of target exposure and improve treatment response in patients. Using simulations, different treatment scenarios were explored for 11 commonly used AEDs. For each drug, five scenarios were considered: 1) all patients receive the same dose. 2) Individual clearance (CL), as predicted by population PK models, is used to personalize treatment. 3-5) Individual CL, obtained by therapeutic drug monitoring (TDM) according to different sampling schemes, is used to personalize treatment. Attainment of steady-state target exposure was used as the performance criterion to rank each scenario. In contrast to current clinical guidelines, our results show that patient demographic and clinical characteristics should be used in conjunction with TDM to personalize the treatment of seizures.

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“…Salem et al [16] reviewed 145 reports of drug interactions and suggested that interactions were more severe in children under 2 years old than in adults. Unfortunately, there have only been a few investigations of the pharmacokinetics of LTG in pediatric patients [1,3,6,7,10,14] and its plasma concentration profile in children less than 3 years old is unknown.…”

Section: Introductionmentioning

confidence: 99%

Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy

Yamamoto

Takahashi

Imai

et al. 2015

Drug Metabolism and Pharmacokinetics

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Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

Cited by 21 publications

References 32 publications

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children

Individualized Dosing Algorithms and Therapeutic Monitoring for Antiepileptic Drugs

Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy

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