Effect of UGT1A4, UGT2B7, UGT2B15, UGT2B17 and ABC1B polymorphisms on lamotrigine metabolism in Danish patients.

OBJECTIVE: To evaluate the impact of genetic polymorphisms of UGT enzymes (UGT1A4, UGT2B7, UGT2B15 and UGT 2B17) and the transporter protein ABCB1 on Lamotrigine (LTG) metabolism. METHODS: Single nucleotide polymorphisms UGT1A4*2 (P24T, c.70C>A), UGT1A4*3 (L48V c.142T>G), UGT2B7*2 (H802Y, c.802C>T), UGT2B15*2 (Y85D, c.253G>T), UGT2B17 deletion and transporters ABC 1236C> T and 3435C> T were determined in 337 Caucasian patients with epilepsy treated with LTG in Denmark. The prospectively collected data included LTG dosage, LTG plasma concentration, 2-N-GLU concentration, sex, smoking habits, concomitant medicine, oral contraceptives (OC). RESULTS: The non-smokers with LTG monotherapy and LTG polytherapy with other non-interacting drugs NIAEDs (n = 199) were analyzed separately in univariant analyses. LTG ratios (LTG plasma concentration/ (LTG dose/weight)) in patients carrying wild type UGT1A4*2 C-allele were 22% lower than in heterozygous C-carriers (p = 0.013). Patients with UGT2B7*2 polymorphism TT genotype had 1.2-fold higher LTG ratios (p = 0.0078) and 0.78-fold lower GLU/LTG ratio (p = 0.0275) than patients homozygous for the C allele. The similar significant findings were also seen comparing homozygotes (TT) with heterozygotes patients (CT). Individuals homozygous for the UGT2B15*2 T allele displayed 18% lower LTG ratio concentrations than individuals homozygous for the G allele (p = 0.014),while significant difference in GLU/LTG ratio was only seen comparing wild type with homozygous patients (GG versus TT, p = 0.031). A copy number variation gene deletion polymorphism of UGT2B17 showed that individuals devoid of the gene (del/del) exhibited 1.3-fold higher LTG ratio (p = 0.015). For ABCB1c.1236 C>T and ABC1B1c.3435 C>T no associations with LTG and GLU ratios were found. Sex specific differences in enzyme activity (most prominent effect in women) on LTG metabolism were found for UGT2B15, UGT2B17, UGT1A4 and UGT2B7 polymorphisms. Multiple regression analysis confirmed the significant effect of OC, VPA and UGT1A4 * 2 and UGT2B7 * 2 on LTG metabolism. CONCLUSION: Our study confirms the previous findings that genetic variations in UGT2B7 and UGT1A4 genes are associated with serum LTG concentrations. Furthermore, our results indicate that it is possible that different UGT genotypes may exert larger impact on LTG metabolism in women than in men.

UGT polymorphisms and lamotrigine clearance during pregnancy.

OBJECTIVE: To evaluate the impact of maternal UGT1A4 and UGT2B7 genetic polymorphisms and sex of foetus on gestation-induced changes in lamotrigine (LTG) clearance during pregnancy and post-partum (PP). METHODS: Single nucleotide polymorphisms UGT1A4 142T > G, L48V (*3), UGT1A4 70C > A, P24T (*2) and UGT2B7 802C > T, H268Y (*2) were determined in 40 women (47 pregnancies) with epilepsy treated with LTG. Retrospectively collected data included LTG dosage and LTG plasma levels before pregnancy (T0), and LTG dosage and LTG plasma level changes in the first (T1), second (T2) and third trimester (T3), and post-partum (PP) as well as the sex of the foetus. RESULTS: Reductions in the LTG concentration-to-dose ratio (C/D ratio) during pregnancy were seen in all genotype panels and varied between -53% and -74% in T3. Genetic polymorphism of UGT1A4 T142G (*3) and UGT2B7 C802T (*2) had the most pronounced influence on LTG clearance. Women with UGT1A4 142TG had a lower decrease in the C/D ratio in T3 than those with wild type: -53% (95%CI: -68% to -39%) versus -65% (95%CI: -69% to -60%) (p = 0.04). In homozygous carriers of UGT2B7 802TT the LTG C/D ratio was reduced significantly already in T1 (p = 0.015) as well as in T3 compared to the heterozygous carriers (802CT) (p = 0.04). Multiple regression analysis demonstrated that women who carried a female foetus had a significantly higher reductions in the LTG C/D ratio from T0 to the end of pregnancy than those with a male foetus (p = 0.003). In the univariate analysis the reductions in LTG C/D ratio were -64% in T2 (95%CI: -69% to -59%) and -67% in T3 (95%CI: -71% to -63%) in women who expected a female child compared to whose with a male child -58% in T2 (p = 0.002, 95%CI: -67% to -48%) and -57% in T3 (p < 0.001, 95%CI: -65% to -48%). CONCLUSION: Genetic polymorphism in UGT1A4 and UGT2B7 may play a modest role in LTG clearance changes during pregnancy. In addition, our study indicates that the sex of the foetus influenced significantly the change in LTG clearance.

Clinical experience with eslicarbazepine acetate in adults with sub-analysis of elderly.

PURPOSE: Eslicarbazepine acetate (ESL) is indicated for treatment of focal epilepsy. Our aim was to evaluate the effect and tolerability of ESL in elderly and younger adults. The primary objective was to measure changes in seizure frequency before and after at least six months of treatment. Secondary objective was to analyse the safety profile. Sub-analysis was performed in patients previously treated with oxcarbamazepine. METHOD: A single-centre, retrospective study of patients with focal epilepsy treated with ESL. Data were collected by reviewing the clinical and laboratory files. Seventy-two patients received ESL, of which 14 were ≥60 years old, and were analysed for adverse effects. Fifty-nine patients received treatment for ≥6 months and were included in the evaluation of seizure frequency; in this group 12 were ≥60 years old. RESULTS: Seizure frequency (n=59) was reduced for both young adults (< 60years) and elderly adults (≥60); both groups achieved better seizure control from an average of 2 to 0.5 (p-value: 0.002) and 3.5 to 0.65 (p-value:<0.05) seizures per month, respectively. Adverse effects leading to treatment discontinuation (n=72) were more frequent in elderly (42.9%) than in young adults (17.2%) (p-value 0.04). There was no significant difference in mild adverse effects between young (15.5%) and elderly adults (14.3%). Most common adverse effects were somnolence, gastrointestinal disturbances and dizziness. CONCLUSIONS: The study indicates that ESL has an advantageous profile in relation to seizure control. The discontinuation rate might be higher in elderly than in younger adults. Further prospective studies are needed to confirm these conclusions.

[Transient epileptic amnesia]. / Transitorisk epileptisk amnesi

Transient epileptic amnesia (TEA) is a presumably underdiagnosed syndrome belonging to the group of temporal lobe epilepsies. It can easily be misdiagnosed as transient global amnesia (TGA), transient ischaemic attack, psychogenic amnesia or even dementia. Many patients complain of loss of autobiographical memory and accelerated long-term forgetting. We present a case to emphasize both the importance of diagnosing TEA and the pitfalls between TEA and TGA syndrome.

Seizure frequency in pregnant women treated with lamotrigine monotherapy.

Previous studies have demonstrated that the pharmacokinetics of the new antiepileptic drug (AED) lamotrigine (LTG) are substantially influenced by pregnancy and are more likely to be associated with seizure deterioration in pregnancy compared to other AEDs. This is of great concern, as LTG has developed into a first-line AED for women of childbearing age. In this study we evaluated the risk of seizure deterioration in a cohort of women treated with LTG monotherapy (n = 42) who were closely monitored with frequent dose adjustments based on monthly routine plasma level determinations. It was demonstrated that with this close monitoring set-up, the risk of increased seizure frequency (19%) was not higher than that reported for other AED treatment regimens.

Seizure deterioration in women treated with oxcarbazepine during pregnancy.

Thirteen pregnancies in ten women on oxcarbazepine (OXC) monotherapy and one pregnancy in a woman on OXC and topiramate therapy were retrospectively analyzed. A significant decrease of ratio plasma concentration of 10-monohydroxy derivate (MHD) of oxcarbazepine to dosage was found by 26.2% during first trimester, by 36.5% during second trimester and by 38.2% during third trimester when compared to pre-pregnant levels. Eight patients experienced seizure deterioration during the pregnancy, five of which had been seizure-free before the pregnancy. In seven pregnancies (50%) the seizure frequency was at least doubled during pregnancy compared to a pre-pregnancy baseline. There was a trend toward a correlation between seizure deterioration and decrease in plasma concentration of MHD.

Pharmacokinetics of antiepileptic drugs in pregnancy.

A substantial proportion of women with epilepsy experience seizure deterioration during pregnancy. This is most likely explained by a drop in plasma levels of antiepileptic drugs (AEDs) as a consequence of altered drug pharmacokinetics. It has been known for many years that gestation induces the elimination of standard AEDs (phenytoin, barbiturates, carbamazepine and valproate). In general, newer AEDs have more simple pharmacokinetic properties and it should, therefore, be expected that the pharmacokinetics of these drugs are influenced in a simpler manner by physiological changes, such as pregnancy. However, within the last few years it has been established that the elimination of several newer AEDs is significantly accelerated during pregnancy. This is particularly the case for glucuronidated AEDs (i.e., lamotrigine) and the pharmacological active metabolite of oxcarbazepine (metabolite 10-hydroxycarbazepine). Recent observations show it is probable that the elimination of levetiracetam is also increased during pregnancy. Pharmacokinetic alterations during pregnancy show wide interindividual variability and the effects on the plasma levels are mostly unpredictable. Regular routine drug monitoring during pregnancy is therefore recommended. The future perspective involves the development of pharmacogenetic charting, which may assist in providing an individualized treatment strategy and refine preconceptional therapeutic planning to ensure the best possible health for the mother and developing child.

Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial.

PURPOSE: This study evaluates the effect of oral contraceptives on lamotrigine (LTG) plasma concentrations and urine excretion of LTG metabolites in a double-blind, placebo-controlled, crossover study in patients with epilepsy. METHODS: Women with epilepsy, treated with LTG in monotherapy and taking combination-type oral contraceptives, were randomized to treatment with placebo or a standard combination-type contraceptive pill. The dose-corrected trough plasma concentration of LTG and the ratio of N-2-glucuronide/unchanged LTG on urine after 21 days of concomitant placebo treatment was analyzed versus those after 21 days of concomitant treatment with the oral contraceptive pill. RESULTS: The mean dose-corrected LTG concentration after placebo treatment was 84%[95% confidence interval (CI), 45-134%] higher than after oral contraceptives, signifying an almost doubling of the concentration after cessation of oral contraceptives. Most of this increase took place within the first week after oral contraceptives were stopped. The N-2-glucuronide/LTG ratio in the urine was decreased by 31% (95% CI, -20-61%) when shifting from oral contraceptives to placebo. CONCLUSIONS: Cessation of oral contraceptives leads to an 84% increase in the concentration of LTG. In parallel, the excretion of the N-2-glucuronide was decreased, indicating that the changes are caused by altered LTG glucuronidation. The change in LTG concentrations was observed within 1 week of the shift of treatment, suggesting that induction and deinduction of LTG glucuronidation is faster than that seen for other metabolic pathways (e.g., cytochrome P450).

Individual changes in lamotrigine plasma concentrations during pregnancy.

Eleven pregnant women on lamotrigine (LTG) monotherapy were retrospectively reviewed. A significant decrease in the ratio of plasma LTG concentration-to-dose by 65.1% was observed during the second trimester (TM2) (p=0.0058) and by 65.8% during TM3 (p=0.0045) compared to pre-pregnancy values. Five patients experienced seizure deterioration during pregnancy. The pharmacokinetic changes display marked inter-patient variation, which stresses the importance of evaluating each woman individually by closely monitoring LTG concentrations until term.