Effect of oral contraceptives on lamotrigine levels depends on comedication

Wegner, Ilse; Wilhelm, Abraham J.; Lambrechts, Danielle A.J.E.; Sander, Josemir W.; Lindhout, Dick

doi:10.1111/ane.12197

Cited by 16 publications

(5 citation statements)

References 20 publications

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“…However, if she is on a concomitant hormonal contraceptive that includes an estrogen, then her dose can often be adjusted lower when the hormonal contraceptive is stopped if she is on LTG, VPA, and probably OXC. LTG clearance is increased not only in pregnancy with the endogenous rise in sex steroid hormones, but clearance is also approximately 2-fold higher with exogenous administration of estrogens via combined oral contraceptive pills and other contraceptives that contains estrogens (e.g., patch, vaginal ring) [46][47][48][49][50]. Similar but more modest effects have been shown for VPA [51]; VPA concentrations were 23 % lower in the VPA plus combined oral contraceptive group than the VPA alone group.…”

Section: Establishing Individual Aed Target Concentrationsmentioning

confidence: 63%

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.

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Section: Establishing Individual Aed Target Concentrationsmentioning

confidence: 63%

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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“…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%

“…On the other hand, in patients taking valproic acid, the half‐life of LTG is substantially prolonged [10]. LTG has been extensively evaluated in pregnancy and in women taking oral contraceptives because of the reported decrease in serum LTG concentrations . LTG glucuronidation appears to be induced with estradiol [16].…”

Section: Introductionmentioning

confidence: 99%

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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“…Wang et al [66] developed a statistical population pharmacokinetic model and showed that pharmacogenetic allelic forms and oestrogen levels during pregnancy are important covariates that influence the lamotrigine concentrations during pregnancy. Wegner et al [67] demonstrated in a clinical drug-drug interaction study that oral contraceptives influence the lamotrigine concentrations and proposed that changes in LTG clearance were due to UGT1A4 induction similar to that seen during pregnancy. The PBPK modelling strategy adopted by us includes the effect of oestrogen hormones during pregnancy but currently excludes the PK variability that may occur due to UGT1A4 genetic polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modelling of UGT Substrate Drugs Lamotrigine and Raltegravir during Pregnancy

Berezowska,

Coppola,

Pilla Reddy

et al. 2024

Future Pharmacology

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Pregnancy is associated with various physiological changes that can significantly impact the disposition of drugs. To further the insight into how pregnancy affects the pharmacokinetics of drugs at different stages, clinical studies can be simulated using Physiologically Based Pharmacokinetic modelling. PBPK modelling of drugs metabolised by Phase I enzymes (CYPs) in pregnant population models had been reported in the past, while its use in Phase II (UGTs) is not known. In this study, based on the results of a recent meta-analysis, lamotrigine (UGT1A4) and raltegravir (UGT1A1) were selected as candidate drugs, and pregnancy-specific models were developed for both using the Simcyp v.21 simulator. A middle-out strategy was used where previously published drug parameters were adapted from a minimal to a full PBPK model to allow their application for the pregnancy population models using Simcyp PBPK software. Adapted models were successfully validated against observed clinical data both qualitatively (visual overlay of plasma concentrations on graphs) and quantitatively (calculating the predicted/observed ratios for AUC, Cmax and CL as well as statistical analysis using model prediction power metrics). They were then applied to predict the PKs of both drugs in pregnancy population models. The temporal changes in maternal enzymatic activities during gestation were modelled based on in vitro data reported in literature and default relationships encoded in the Simcyp platform for UGT1A1 and UGT1A4, respectively. Our study demonstrates the successful development and validation of a PBPK model for LTG and RTG in pregnancy population models. Future work with additional UGT1A4 substrate drugs using the proposed changes in UGT1A4 activity may enable validating the pregnancy population model and its subsequent use for the prospective prediction of PK.

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Effect of oral contraceptives on lamotrigine levels depends on comedication

Cited by 16 publications

References 20 publications

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

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

Physiologically Based Pharmacokinetic Modelling of UGT Substrate Drugs Lamotrigine and Raltegravir during Pregnancy

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