Pharmacokinetics of lamotrigine in paediatric and young adult epileptic patients—nonlinear mixed effects modelling approach

Brzaković, Branka; Vučićević, Katarina; Kovačević, Sandra Vezmar; Miljković, Branislava; Prostran, Milica; Martinović, Žarko; Pokrajac, M.

doi:10.1007/s00228-013-1606-5

Cited by 19 publications

(22 citation statements)

References 36 publications

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“…On the other hand, LTG CL in patients concomitantly treated with inducers of hepatic metabolism (carbamazepine, phenytoin and phenobarbital) was 55% higher. This is consistent with the previous reports . The current guidelines for LTG dosing account for the clearance alteration in patients when using enzyme inducing or inhibiting drugs .…”

Section: Discussionsupporting

confidence: 92%

“…We confirmed that LTG CL and V depended on patient's body weight. Similar results have been reported by other authors in paediatric and adult populations of epileptic patients . In accordance with the allometric scaling approach the effect of weight on V was more adequately described with the linear model, while a power model was more appropriate for the relationship of weight with CL.…”

Section: Discussionsupporting

confidence: 89%

“…Previous published studies showed that various factors such as weight , age , pregnancy , smoking , blood urea nitrogen : serum creatinine ratio , race , LTG daily dose [31], oral contraceptives and use of concurrent AEDs influence LTG plasma concentrations. Additionally, genetic polymorphisms in genes encoding drug‐metabolizing enzymes UGT1A4 , UGT2B7 and ABCB1 transporter [21] were also suggested to contribute to the IIV of LTG CL.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of lamotrigine and its metabolite N‐2‐glucuronide: Influence of polymorphism of UDP‐glucuronosyltransferases and drug transporters

Milosheska

Lorber

Vovk

et al. 2016

Brit J Clinical Pharma

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AIMSThis study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODSWe included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N-2-glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for UGT1A4, UGT2B7, ABCB1 and SLC22A1. Population pharmacokinetic analysis was performed by non-linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent-metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism. RESULTSWith a base model absorption rate (interindividual variability) was estimated at 1.96 h À1 (72.8%), oral clearance at 2.32 l h À1 (41.4%) and distribution volume at 77.6 l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs. In patients with UGT2B7-161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with UGT2B7 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher). CONCLUSIONSVariability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for UGT2B7 may be useful in various clinical settings. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Interindividual variability in lamotrigine pharmacokinetics is large and therapeutic drug monitoring may be warranted.• Lamotrigine disposition is mediated by UDP-glucuronosyltransferases, mainly by UGT1A4 and UGT2B7. ABCB1 and SLC22A1 transporters appear to be also involved.• Polymorphisms in UGT1A4, UGT2B7, ABCB1 and SLC22A1 genes affect protein activity and expression. WHAT THIS STUDY ADDS• Influences of polymorphisms of UGT2B7, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs on lamotrigine pharmacokinetics were quantified.• No significant association of lamotrigine pharmacokinetics with UGT1A4, SLC22A1 and ABCB1 polymorphisms was observed.• Clearance of lamotrigine-N-2-glucuronide depends on renal function and body weight.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of lamotrigine and its metabolite N‐2‐glucuronide: Influence of polymorphism of UDP‐glucuronosyltransferases and drug transporters

Milosheska

Lorber

Vovk

et al. 2016

Brit J Clinical Pharma

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“…LTG exhibits first-order linear pharmacokinetics with rapid and complete absorption when administered orally and is bio-transformed mainly through uridine diphosphate glucuronosyltransferase (UGT) (Chan et al, 2001), whose metabolism is significantly influenced by patient comedications. The co-administration of enzyme inhibitors [such as valproic acid (VPA) (Rivas et al, 2008; Brzakovic et al, 2014; Zhang et al, 2017; van Dijkman et al, 2018)] prolongs the LTG half-life by two-fold (van Dijkman et al, 2018), whereas the half-life is substantially shortened by coadministration of enzyme inducers [such as phenytoin (PHT) (Rivas et al, 2008; Brzakovic et al, 2014; Milosheska et al, 2016; Zhang et al, 2017; van Dijkman et al, 2018)].…”

Section: Introductionmentioning

confidence: 99%

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

et al. 2019

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Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1 -1222AA carriers. Patients with the ABCG2 -34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1 -2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13–65 years of age.

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“…The absorption was modelled as a zero‐order process following a short delay, reflecting the in vitro dissolution profile. The disposition was one compartment distribution with first‐order elimination, based on extensive previous experience . Other structure models, and a range of between‐subject variability and residual models were explored and found less suitable.…”

Section: Methodsmentioning

confidence: 99%

Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel‐group study of lamotrigine

Yang

Bullman

et al. 2019

Brit J Clinical Pharma

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A new strength of lamotrigine extended-release formulation unexpectedly failed to show bioequivalence with the existing strengths at the same dose in a parallel-group study. We report the post-hoc analyses conducted to identify the cause and propose an approach for future evaluations in similar situations. METHODSA seemingly bimodal distribution of the half-life among the study participants prompted the use of terminal-phase-rate-constantadjusted area under the concentration curve as the endpoint for bioequivalence assessment. Population pharmacokinetic modelling was also performed to assess the bimodal distribution of apparent clearance and the potential treatment effects on bioavailability. RESULTSThe cause for failing to achieve bioequivalence appeared to be a biased representation of a bimodal clearance distribution between the groups. The pharmacokinetic modelling with a mixture routine identified two subpopulations: 88% had a mean clearance of 1.99 l h À1 ; 12% had a mean clearance of 0.64 l h À1 . The low-clearance population was unequally represented by 13% and 4% of subjects in the reference and test groups, respectively, and treatment appeared to have no significant effect on oral bioavailability. The bioequivalence comparison using the adjusted area concluded with a 90% confidence interval of 0.91-1.06, suggesting that treatment had no significant effect on bioavailability and the formulations would meet regulatory criteria for bioequivalence. CONCLUSIONSThe adjustment of the area under the concentration curve adjusted by terminal-phase rate constant should be considered for situational application in bioequivalence assessment when there are multiple clearance subpopulations in a parallel-group study.• Standard formulation bioequivalence tests investigate bioavailability differences between formulations by assuming equivalent drug clearance between the treatments. WHAT THIS STUDY ADDS• We illustrate the utility of a terminal-phase-rate-adjustment method for bioequivalence tests when clearance distribution is different for test and reference groups in a case study.Terminal-phase-rate-adjusted AUC for bioequivalence analysis Br J Clin Pharmacol (2019) 85 563-569 569

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Pharmacokinetics of lamotrigine in paediatric and young adult epileptic patients—nonlinear mixed effects modelling approach

Abstract: The LTG population pharmacokinetic model developed in this study may be a reliable method for individualising the LTG dosing regimen in paediatric and young adult patients on combination therapy during therapeutic drug monitoring.

Cited by 19 publications

References 36 publications

Pharmacokinetics of lamotrigine and its metabolite N‐2‐glucuronide: Influence of polymorphism of UDP‐glucuronosyltransferases and drug transporters

Pharmacokinetics of lamotrigine and its metabolite N‐2‐glucuronide: Influence of polymorphism of UDP‐glucuronosyltransferases and drug transporters

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel‐group study of lamotrigine

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