Arne Reimers

Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations.

Summary:  Purpose: To study the interaction between lamotrigine (LTG) and hormonal contraception.

Serum concentration/dose ratio of levetiracetam before, during and after pregnancy

PURPOSE To investigate changes in levetiracetam (LEV) serum concentration/dose ratio (C/D-ratio) in relation to pregnancy. METHODS Altogether 21 consecutive pregnancies in 20 women with epilepsy receiving LEV during gestation were studied retrospectively. The main target variable was the C/D-ratio before and during pregnancy, and in the post partum period. Secondary target variables were changes in LEV dose, concomitant use of other antiepileptic drugs and seizure frequency. Students paired t-test and two-sample t-test for independent samples were used to test for statistically significant changes in C/D-ratio means. RESULTS Mean C/D-ratio in the third trimester was 50% of the mean C/D-ratio at baseline (p<0.001, n=11). Baseline levels were reached within the first weeks after pregnancy. The interindividual variability was pronounced. CONCLUSIONS Serum concentrations of LEV declined significantly in the third trimester of pregnancy and increased rapidly after delivery.

Drug interactions between lamotrigine and psychoactive drugs : Evidence from a therapeutic drug monitoring service

Abstract: We present a systematic study on the interaction potential of lamotrigine, with focus on psychoactive drugs. A review of routine serum concentration measurements of lamotrigine performed in our laboratory yielded a total of 1733 serum samples from 829 patients (530 women, 299 men) suitable for statistical analysis. Main results for the whole study population were (median; interquartile range in parentheses): dose, 200 (100-300) mg; serum concentration, 2.97 (1.82-4.74) μg/mL; Lamotrigine serum concentration-to-dose ratio (LTG-CDR), 14.8 (9.9-24.6) (ng/mL)/(mg/d). A linear mixed model, allowing multiple observations from the same patient, was used to identify and quantitate the effect of factors influencing the LTG-CDR. In addition to age and gender, a total of 35 different comedications (25 drugs used in psychiatry as well as 10 other drugs) were evaluated. With women younger than 70 years as the reference group, factors found to lower the LTG-CDR significantly were: male gender and comedication with carbamazepine, ethinylestradiol, fluoxetine, lithium, phenytoin, phenobarbital, or topiramate. Factors associated with a significantly higher LTG-CDR were: age ≥70 years, and cotreatment with valproate. No antidepressants other than fluoxetine and none of the antipsychotic drugs included were associated with an altered LTG-CDR. Concerning pharmacokinetic drug interactions, we conclude that lamotrigine can be safely combined with most psychotropic drugs.

Seizure control and pharmacokinetics of antiepileptic drugs in pregnant women with epilepsy

The main concerns associated with epilepsy during pregnancy consist of maternal and fetal risks from uncontrolled seizures, and harmful effects of the treatment on the development of the offspring. Although seizure control is maintained in the majority, worsening occurs in a fraction of childbearing women with epilepsy. As multiple factors associated with pregnancy may have a negative impact on epilepsy, a careful analysis of the situation should be performed in those who deteriorate. Emotional and behavioural influence, including insufficient sleep and treatment non-compliance, as well as physical factors, such as emesis and pelvic distortion, should receive attention. The serum concentrations of almost all antiepileptic drugs decrease during pregnancy, particularly those which are metabolised by glucuronidation. The inter-individual variability is pronounced. In highly protein-bound drugs, such as phenytoin and valproate, unbound drug is less affected than total concentrations. Lamotrigine and levetiracetam concentrations may decrease by more than 50% in the course of pregnancy; monohydroxyoxcarbazepine by up to 30-40%. Appropriate clinical follow-up tailored to individual needs and supported by therapeutic drug monitoring should be performed in pregnant women with epilepsy. Education concerning reproductive issues is an essential part of the epilepsy service to fertile women.

Serum concentration/dose ratio of topiramate during pregnancy.

Purpose:  To study the impact of pregnancy on the serum concentration/dose ratio (C/D‐ratio) of topiramate (TPM).

Second-generation antiepileptic drugs and pregnancy: a guide for clinicians

When treating pregnant women with antiepileptic drugs (AEDs), clinicians have to balance potential fetal adverse effects against the risks of uncontrolled maternal disease. Only recently have emerging scientic data provided a rational basis for treatment decisions considering both aspects. The focus of research is currently moving from the first to the second AED generation. Lamotrigine is relatively well studied, and data on other novel AEDs, such as levetiracetam, oxcarbazepine, topiramate, zonisamide, gabapentin and pregabalin, are in progress. Safety issues appear to be favorable for lamotrigine, and preliminary results are also promising for levetiracetam and oxcarbazepine. Drugs metabolized by uridine-diphospate glucuronosyl transferase or excreted unchanged by the kidneys are particularly susceptible to increased body clearance during pregnancy. Lamotrigine is subject to both mechanisms, and therapeutic serum levels may sometimes be difficult to maintain. The authors review the recommendations and clinical research on modern AED treatment during pregnancy, highlighting current experience with second-generation drugs.

Lamotrigine and its N2-glucuronide during pregnancy: The significance of renal clearance and estradiol

PURPOSE To investigate the physiological mechanisms behind the pronounced decline of lamotrigine (LTG) serum concentrations during pregnancy. METHODS Serum and urine concentrations of LTG and its main metabolite, LTG-N2-glucuronide (LTG-GLUC), were measured monthly in 21 pregnancies of 19 women using LTG. Simultaneously, a panel of biochemical variables was monitored to evaluate liver and kidney function and possible hemodilution effects. Pharmacokinetic parameters were calculated once at baseline and once in gestational month 8. RESULTS Initially, LTG and LTG-GLUC serum concentrations fell simultaneously by 27% and 38%, respectively (gestational month 2). Subsequently, the ratio of the LTG-GLUC/LTG serum concentrations increased gradually, correlating strongly with rising serum estradiol concentrations. In gestational month 8, the ratio was 164% higher than at baseline. At that time, LTG total clearance had increased by 118%, and the amount of unchanged LTG in urine had dropped by 40% while the amount of LTG-GLUC had increased by a corresponding 37%. CONCLUSIONS The simultaneous decline of LTG and LTG-GLUC serum concentrations in early pregnancy suggests that in this phase, increased renal blood flow is the major cause. After gestational month 2, estradiol-induced glucuronidation of LTG becomes more important, leading to a further fall of LTG serum concentrations and a gradual rise of the LTG-GLUC/LTG-ratio through the remaining pregnancy. An expanded volume of distribution may also contribute to reduced LTG serum concentrations in pregnancy.

Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations

Antiepileptic drugs (AEDs) and hormonal contraceptives may affect each others metabolism and clinical efficacy. Loss of seizure control and unplanned pregnancy may occur when these compounds are used concomitantly. Although a large number of available preparations yield a plethora of possible drug combinations, most of these drug interactions are predictable and, thus, avoidable. Unfortunately, there is a substantial lack of data regarding the newer AEDs. Detailed understanding of these issues is necessary for those who prescribe AEDs and/or hormonal contraception to women with epilepsy, as well as for those who provide comprehensive care, education and counseling to them, in order to reduce the unacceptably high number of unplanned pregnancies among women with epilepsy.

Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine.

The gene encoding uridine diphosphate glucuronosyltransferase (UGT) 1A4 shows considerable polymorphism. Several common drugs are metabolised by UGT1A4, among them lamotrigine (LTG). Experimental and clinical studies suggest that certain variants of UGT1A4 are associated with altered enzyme activity. However, results are conflicting. This clinical study aimed to investigate the frequencies of two common UGT1A4 variants, *2 (P24T) and *3 (L48V), and their potential effects on serum concentrations of LTG. The *2 variant was associated with a trend towards higher serum concentrations, while the *3 variant was associated with significantly lower serum concentrations of LTG. The calculated allele frequencies were in the same range as in earlier studies on Caucasian populations. To our knowledge, this is the first study suggesting a clinical effect of UGT1A4*2. Further study is needed to confirm this finding.

New antiepileptic drugs and women

Since 1990, sixteen new antiepileptic drugs (AEDs) have been introduced. Most of these new AEDs have only been insufficiently studied with respect to women-specific aspects such as endogenous sex hormones, hormonal contraception, pregnancy, breastfeeding, or menopause. This is of concern because it has been shown for some of the new AEDs that these factors may have a clinically significant impact on their pharmacokinetics and seizure control. Also, new AEDs may affect hormone homeostasis and pass over into breast milk. The best studied of the new AEDs are lamotrigine, levetiracetam and oxcarbazepine. Although gabapentin and pregabalin are even more frequently used (due to their therapeutic effects in nonepileptic conditions), our understanding of these two drugs in relation to womens issues is surprisingly poor. Little to nothing is known about zonisamide, retigabine/ezogabine, lacosamide, perampanel and the other new AEDs. Nevertheless, many small studies and case series have been published on new AEDs and women-specific aspects. This review gives an overview on what is known today.