Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy

Objective: To further characterize pregnancy-induced alterations in the pharmacokinetics of lamotrigine (LTG).
Methods: Fifteen women treated with LTG were studied during 17 pregnancies. Complete trough blood samples from all trimesters and baseline > 1 month after delivery were available for 12 pregnancies (Group A), whereas, five contributed with samples only from the third trimester and baseline (Group B). High-performance liquid chromatography (HPLC) was used to determine LTG plasma concentrations, and liquid chromatography-mass spectrometry to assay the main metabolite 2-N-lamotrigine glucuronide (2-N-GLUC) in plasma.
Results: In group A, the mean dose/plasma concentration ratio (D/C) of LTG at baseline after pregnancy was 66.5 ± 17.9 (± SD) L/day and approximately 250% higher in late pregnancy. The mean lamotrigine-2-N-glucuronide/lamotrigine plasma concentration ratio (2-N-GLUC/LTG) was 0.349 ± 0.141 (± SD) at baseline and 147% higher in late pregnancy. Taking group A and B together, the 2-N-GLUC/LTG ratio was 175% higher in the third trimester compared to baseline.
Conclusion: Our study confirms a significant decline in LTG plasma levels during pregnancy in women on monotherapy with LTG. An increased 2-N-GLUC/LTG ratio suggests that this decline may be related to an increased metabolism of LTG by glucuronidation.     

Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation

PURPOSE: To investigate the pharmacokinetics of lamotrigine (LTG) during delivery, during the neonatal period, and lactation. METHODS: High-performance liquid chromatography was used to determine plasma and milk levels of LTG in nine pregnant women with epilepsy treated with LTG, and plasma levels in their 10 infants. Samples were obtained at delivery, the first 3 days postpartum, and at breast-feeding 2-3 weeks after delivery. RESULTS: At delivery, maternal plasma LTG concentrations were similar to those from the umbilical cord, indicating extensive placental transfer of LTG. There was a slow decline in the LTG plasma concentration in the newborn. At 72 h postpartum, median LTG plasma levels in the infants were 75% of the cord plasma levels (range, 50-100%). The median milk/maternal plasma concentration ratio was 0.61 (range, 0.47-0.77) 2-3 weeks after delivery, and the nursed infants maintained LTG plasma concentrations of approximately 30% (median, range 23-50%) of the mother's plasma levels. Maternal plasma LTG concentrations increased significantly during the first 2 weeks after parturition, the median increase in plasma concentration/dose ratio being 170%. CONCLUSIONS: Our data demonstrate a marked change in maternal LTG kinetics after delivery, possibly reflecting a normalization of an induced metabolism of LTG during pregnancy. LTG is excreted in considerable amounts in breast milk (the dose to the infant can be estimated to >/=0.2-1 mg/kg/day 2-3 weeks postpartum), which in combination with a slow elimination in the infants, may result in LTG plasma concentrations comparable to what is reported during active LTG therapy. No adverse effects were observed in the infants, however.     

Effects of pregnancy and contraception on lamotrigine disposition: new insights through analysis of lamotrigine metabolites.

OBJECTIVE: To investigate possible underlying mechanisms for alterations in lamotrigine (LTG) kinetics by gestation and use of contraceptives. METHODS: Plasma concentrations of LTG and its main metabolite lamotrigine-2-N-glucuronide (2-N-GLUC) were measured in 31 women on LTG taking combined oral contraceptives (COC), in 12 with contraceptive intrauterine devices containing levonorgestrel (CIUD), and in 20 on LTG without hormonal contraception (controls). We also measured the levels of LTG and 2-N-GLUC in plasma and urine in eight women during pregnancy, and up to three months postpartum. LTG levels in plasma were measured by high-performance liquid chromatography method (HPLC) and N-2-GLUC in urine and plasma and LTG in urine by liquid chromatography-mass spectrometry (LC/MS). RESULTS: There were no significant differences in LTG dose/concentration (D/C), or N-2-GLUC/LTG ratios between women with CIUD and controls. In contrast, compared to controls, the LTG D/C ratio was 56% higher in women taking COC (mean+/-SD, 83+/-47 versus 53.0+/-24.2; p<0.01) and N-2-GLUC/LTG ratio 82% higher in women taking COC (mean 0.477+/-0.212 SD versus 0.262+/-0.127; p<0.0003. The 2-GLUC/LTG ratios were 154% higher in plasma and 122% higher in urine in late pregnancy compared with baseline 3months postpartum. CONCLUSIONS: Our data indicate that the alterations in LTG kinetics in pregnancy as well as those induced by COC are mainly explained by enzymatic induction of the N-2-glucuronide pathway. In addition we found no evidence for an interaction between LTG and CIUD.     

Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects

PURPOSE: To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure. METHODS: This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m(2). The BMI of the remaining four groups was < or =27 kg/m2. RESULTS: Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated. CONCLUSIONS: TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.     

Lamotrigine versus valproic acid as first-line monotherapy in newly diagnosed typical absence seizures: an open-label, randomized, parallel-group study

PURPOSE: To compare the efficacy of lamotrigine (LTG) and valproic acid (VPA) in newly diagnosed children and adolescents with typical absence seizures. METHODS: A randomized, open-label parallel-group design was used. After undergoing an awake video-EEG recording, which included one to two trials of 3 min of hyperventilation and intermittent photic stimulation, eligible patients were randomized to receive LTG or VPA. LTG was initiated at a daily dose of 0.5 mg/kg for 2 weeks in two divided doses, followed by 1.0 mg/kg/day for an additional 2 weeks. Thereafter, doses were increased in 1-mg/kg/day increments every 5 days until seizures were controlled, intolerable adverse effects occurred, or a maximum dose of 12 mg/kg/day had been reached. VPA was equally uptitrated according to clinical response, starting at 10 mg/kg and increasing by 5 mg/kg/24 h every 3 days, if required, to a maximum of 30 mg/kg/day in three divided doses. Patients were seen in the clinic every month for < or = 12 months.The primary efficacy end point at each visit was seizure freedom, defined as lack of clinically observed seizures since the previous visit and lack of electroclinical seizures during ambulatory 24-h EEG testing and a video-EEG session with hyperventilation. RESULTS: Thirty-eight children (17 boys, 21 girls), aged from 3 to 13 years (mean, 7.5 years), all newly diagnosed with childhood or juvenile typical absence seizures, were enrolled. After 1 month of treatment, 10 (52.6%) of 19 children taking VPA and one (5.3%) of 19 taking LTG were seizure free (p = 0.004). By the 3-month follow-up, 12 (63.1%) children taking VPA and seven (36.8%) taking LTG were controlled (p = 0.19). After 12 months, 13 children taking VPA (dose range, 20-30 mg/kg/day; mean serum level, 76.8 mg/L; range, 51.4-91 mg/L) and 10 taking LTG (dose range, 2-11 mg/kg/day; mean serum level, 8.1 mg/L; range, 1.1-18 mg/L) were seizure free (p = 0.51). Side effects were mostly mild and transient and were recorded in two (10.6%) children treated with VPA and in six (31.8%) treated with LTG. CONCLUSIONS: Both VPA and LTG can be efficacious against absence seizures, although VPA shows a much faster onset of action, at least in part because of its shorter titration schedule.     

The prevalence of valproic-acid-associated hyperammonaemia in patients with intractable epilepsy resident at the Chalfont centre for epilepsy

Valproic acid (VPA)-induced hyperammonaemia, with or without clinical or laboratory evidence of hepatoxicity, is well-documented. This study was designed to assess the prevalance of hyperammonaemia in institutionalised patients treated with VPA chronically and to identify contributing factors. Eight-two refractory patients (60 men and 22 women; mean age, 39 years; mean weight, 70.1 kg), were studied. Ten patients were on VPA monotherapy, and 72 were on antiepileptic drug (AED) polytherapy. Fourteen epileptic patients on AED polytherapy excluding VPA (patient controls) and 10 volunteers (healthy controls) were also evaluated. VPA dose ranged between 7.1 and 71.4 mg/kg/day and was associated with VPA plasma concentrations of 114–753 and 77–1,315 μmol/L pre-and postprandially, respectively. A plasma ammonium (NH₄⁺) concentration of 50 μmol/L is considered the upper normal limit in healthy adult subjects. Pre- and postprandial plasma NH₄⁺ concentrations >50 μmol/L were seen in 20% and 30% of VPA-treated patients, respectively. In contrast, all healthy and patient controls had plasma NH₄⁺ concentrations <50 μmol/L. VPA dose correlated significantly with VPA plasma concentration only in the monotherapy group and with postprandial plasma NH₄⁺ concentration. The highest VPA dose (71.4 mg/kg/day) was associated with the highest (95 μmol/L) plasma NH₄⁺ concentration. There was a significant correlation (r = 0.61; p < 0.02) between plasma NH₄⁺ and VPA concentration postprandially in male patients taking VPA and carbamazepine in combination. It is concluded that, although VPA medication can be associated with elevated plasma NH₄⁺ concentrations that are not clinically significant in many patients, caution is necessary when prescribing VPA.     

Lamotrigine clearance during pregnancy

OBJECTIVE: To evaluate changes in lamotrigine (LTG) clearance before, during, and after pregnancy. METHODS: Twelve pregnancies that had complete steady-state data before, during, and after pregnancy were evaluated. Data included weight, LTG dose, and LTG blood levels at preconception, during pregnancy, and postpartum, and concomitant use of other antiepileptic drugs and their dosages. Apparent clearance (L/[kg.day]) of LTG was calculated by dose/level/weight for time points at preconception; during the first trimester, second trimester, and third trimester; and postpartum. Apparent clearance was compared between preconception and each of the three trimesters. Statistical analysis was performed using one-way analysis of variance, the Student-Newman-Keuls test, and the paired Student's t-test. RESULTS: An increase in apparent clearance (>65%) was observed between preconception and the second and third trimesters (p < 0.05). Eleven pregnancies required higher doses of LTG to maintain therapeutic levels during pregnancy. There was no significant change in apparent clearance between each trimester. A decrease in apparent clearance was observed between the last two trimesters and postpartum (p < 0.05). In the postpartum period, apparent clearances returned to the preconception baseline, and LTG doses needed to be reduced. CONCLUSION: Pregnancy increases LTG clearance by >50%. This effect occurs early in pregnancy and reverts quickly after delivery. LTG levels should be monitored before, during, and after pregnancy.     

Tolerability and pharmacokinetics of oral loading with lamotrigine in epilepsy monitoring units

PURPOSE: To investigate the tolerability and pharmacokinetics of oral loading with lamotrigine (LTG) among epilepsy patients after temporary drug discontinuation in an epilepsy monitoring unit. METHODS: We conducted a pilot study among epilepsy patients (18 years or older) receiving maintenance doses of LTG. LTG was discontinued on admission and restarted at the end of epilepsy monitoring. LTG was given as a single oral dose calculated based on the population expected volume of distribution (Vd, 1.0 L/kg) and target blood level on admission. Baseline and serial blood levels of LTG were determined hourly for 10 to 12 h after the loading dose. Outcome measures: (a) frequency of patients with side effects; (b) time to maximum concentration (Tmax), maximum concentration (Cmax), actual volume of distribution, and half-life. RESULTS: Twenty-four patients received a single oral load of LTG (mean, 6.5 +/- 2.7 mg/kg). Overall, LTG loading was well tolerated with no serious adverse events or skin rash observed. Two patients had transient and mild nausea 1 to 2 h after the oral load. The mean estimated pharmacokinetic parameters are as follows: Tmax, 3.1 +/- 2.1 h; Cmax, 8.2 +/- 6.5 mg/L; Vd, 1.1 +/- 1.0 L/kg; clearance, 0.08 +/- 0.08 mg/L/h; half-life, 22 +/- 30 h. All patients reached their target blood levels. CONCLUSIONS: Epilepsy patients temporarily discontinued from LTG can be restarted with a single oral loading dose. This was well tolerated, and therapeutic levels can be achieved within 1 to 3 h.     

Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin

OBJECTIVE: The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers. BACKGROUND: LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process. DESIGN/METHOD: As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl(o)), where LTG Cl(o) was estimated as the dose/concentration ratio. RESULTS: Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl(o) determined prior to withdrawal of the inducers was significantly greater in patients (n=28) on LTG+PHT (160% increase) than in those (n=48) receiving LTG+CBZ (62% increase): 1.77+/-0.77 vs. 1.06+/-0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl(o) occurred only when CBZ plasma concentrations reached approximately 2 microg/ml or PHT plasma concentrations reached zero. CONCLUSIONS: Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.     

Methsuximide lowers lamotrigine blood levels: A pharmacokinetic antiepileptic drug interaction

PURPOSE: To determine whether methsuximide (MSM) affects lamotrigine (LTG) blood levels and whether any change is of clinical significance. METHODS: LTG serum levels in 16 patients taking MSM were compared with those before starting or after stopping the MSM. The 16 patients, (11 boys, five girls) were young people (mean age, 15.5 years; range, 9-19 years) with a variety of seizure types and syndromes. In six cases, LTG levels were available both before MSM was started and after it was stopped. RESULTS: The mean LTG serum concentration before starting or after stopping MSM was 13.4 mg/L, and the mean level while taking MSM was 6.3 mg/L. This difference was highly significant (p < 0.0005, paired t test). MSM lowered the LTG serum concentration in every case, with a mean decrease of 53% (range, 36-72%). In some patients this led to a deterioration in seizure control when MSM was added or an improvement in seizure control after MSM was stopped. CONCLUSIONS: Although MSM is a valuable add-on, broad-spectrum drug when used in combination with LTG, adjustment of the LTG dose may be necessary when MSM is started or stopped, to allow for the fact that MSM lowers LTG blood levels.     

Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients

PURPOSE: To determine at steady state (in the same group of patients): (a) the pharmacokinetics (PK) of lamotrigine (LTG) with LTG monotherapy, (b) the PK of LTG concomitantly administered with topiramate (TPM) at three escalating TPM doses (100, 200, and 400 mg/day), (c) the PK of TPM at three escalating TPM doses while receiving fixed-dose LTG therapy, and (d) the PK of TPM with TPM monotherapy. METHODS: This was an open-label, sequential, single-group, dose-escalating PK study in which 13 patients with epilepsy not optimally controlled with LTG received stable-dose LTG monotherapy for 2 weeks, followed by stable-dose LTG therapy combined with escalating doses of TPM for 相似文献   

Utility of the Lethargic (lh/lh) Mouse Model of Absence Seizures in Predicting the Effects of Lamotrigine,Vigabatrin, Tiagabine,Gabapentin, and Topiramate Against Human Absence Seizures

Summary: Purpose: Traditional methods of preclinical screening have predicted the effects of a putative antiepi-leptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pen-tylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: noneffi-cacy); (b) lamotrigine (LTG) (PTZ nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ efficacy; human: possibleproabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lWZh model for LTG, VGB, TGB, GBP, and TPM. Methods: Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8–week-old male lWZh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding lfi-min epochs of the 150–min period after administration. Results: LTG (4.8–144 μmol/kg) significantly (p < 0.04) reduced seizure frequency (by 6.5%) compared with vehicle. In contrast, VGB (0.35–11 mmol/kg) and TGB (0.27–27 μmol/kg) significantly increased seizure frequency (300– 700%) and seizure duration (1,700–1,800%; p ≤ 0.001). GBP (18μmol/kg to 1.8 mmol/kg) and TPM (8.9–29.5 pmol/kg) had no significant effect on seizure frequency. Conclusions: In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lWlh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.     

No effect of oral contraceptives on the metabolism of levetiracetam

The effect on clearance of levetiracetam (LEV) was estimated in women with epilepsy of childbearing potential using oral contraceptives (OCs). The estimated clearance (plasma concentration/daily dose) was 39 nmol/L/mg (range 14-88 nmol/L/mg) among women who did not use OC (n=30) and 38 nmol/L/mg (range 18-103 nmol/L/mg) among OC users (n=23) (p=0.8). In conclusion, combing LEV and OCs seems safe from a pharmacokinetic perspective.     

A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways

The use of oral contraceptives (OC) causes disturbances of the procoagulant, anticoagulant and fibrinolytic pathways of blood coagulation which may contribute to the increased risk of venous thrombosis associated with OC therapy. Here we report the results of a cycle-controlled randomized cross-over study, in which we determined the effects of so-called second and third generation OC's on a number of anticoagulant parameters. In this study, 28 non-OC using women were randomly prescribed either a second generation (150 microg levonorgestrel/30 microg ethinylestradiol) or a third generation OC (150 microg desogestrel/30 microg ethinylestradiol) and who switched to the other OC after a two month wash out period. The anticoagulant parameters determined were: antithrombin (AT), alpha2-macroglobulin (alpha2-M), alpha1-antitrypsin, protein C inhibitor (PCI), protein C, total and free protein S and activated protein C sensitivity ratios (APC-sr) measured with two functional APC resistance tests which quantify the effect of APC on either the activated partial thromboplastin time (aPTT) or on the endogenous thrombin potential (ETP). During the use of desogestrel-containing OC the plasma levels of alpha2-M, alpha1-antitrypsin, PCI and protein C significantly increased, whereas AT and protein S significantly decreased. Similar trends were observed with levonorgestrel-containing OC, although on this kind of OC the changes in AT, PCI and protein S (which was even slightly increased) did not reach significance. Compared with levonorgestrel, desogestrel-containing OC caused a significant decrease of total (p <0.005) as well as free protein S (p <0.0001) and more pronounced APC resistance in both the aPTT (p = 0.02) and ETP-based (p <0.0001) APC resistance tests. These observations indicate that the activity of the anticoagulant pathways in plasma from users of desogestrel-containing OC is more extensively impaired than in plasma from users of levonorgestrel-containing OC.     

Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: A randomized,double‐blind,placebo‐controlled study

This randomized, double‐blind, placebo‐controlled, two‐way crossover study aimed to assess the pharmacokinetic interactions between brivaracetam 100 mg/day and a combination oral contraceptive (OC) containing 30 μg ethinylestradiol and 150 μg levonorgestrel. The study was performed in 28 healthy women over five 28‐day menstrual cycles: baseline (OC only), two treatment cycles with brivaracetam (50 mg b.i.d.) or placebo coadministered with OC separated by a wash‐out cycle (OC only), and a follow‐up cycle (OC only). The OC was administered on days 1–21 of each cycle, and brivaracetam or placebo on days 1–28 of the treatment cycles. Pharmacokinetics of ethinylestradiol and levonorgestrel were determined on day 20; brivaracetam morning trough levels on days 20 (with OC) and 29 (without OC) were compared. C_max (maximum plasma concentration) and AUC (area under the plasma concentration versus time curve) ratios for brivaracetam versus placebo (90% confidence interval [CI]) were 0.96 (0.88–1.04) and 0.90 (0.86–0.95) for ethinylestradiol, and 0.95 (0.91–0.99) and 0.92 (0.88–0.97) for levonorgestrel, within predefined bioequivalence limits (0.80–1.25). Brivaracetam trough levels were similar on days 20 and 29 (ratio 1.08; 90% CI 0.98–1.18). No differences in breakthrough bleeding were seen across the five cycles. It was concluded that there were no interactions between brivaracetam 100 mg/day and the OC. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy

PURPOSE: to describe the population pharmacokinetics of lamotrigine (LTG) in developmentally disabled (DD) patients with epilepsy and (2) to determine if there is an effect of valproate (VPA) concentration on the extent of the pharmacokinetic interaction between VPA and LTG. METHOD: a NONMEM population analysis of steady-state LTG serum concentrations was conducted in patients receiving LTG either as mono or polytherapy with either an enzyme inducer (IND)-carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) or an inhibitor (VPA). RESULTS: sixty-two patients (33.6+/-11.3 years, 47+/-9.9 kg) receiving LTG monotherapy (n=19) or polytherapy with VPA (n=15), inducer(s) (n=32) or both (n=5) were evaluated. LTG dose of 369+/-236 mg per day (8.1+/-5.9 mg/kg per day) achieved LTG plasma concentrations of 6.8+/-3.3 microg/ml. The observed LTG monotherapy, LTG+IND, and LTG+VPA oral clearance (Cl/F) were 0. 69+/-0.2, 1.60+/-0.65 and 0.2+/-0.05 ml/kg per min, respectively. The final LTG Cl/F model was dependent on body weight, concomitant VPA, and either single or multiple inducers. Including the serum concentrations of CBZ, PHT, or VPA in the model, did not significantly improve estimates of Cl/F. CONCLUSION: LTG Cl/F in DD patients is similar to literature values for ambulatory adult patients; however, low weight adult patients have higher elimination rates, as well as an increased response to enzyme induction. VPA inhibition of LTG Cl/F is maximal within the usually accepted therapeutic range for VPA.     

Measurement of levetiracetam drug levels to assist with seizure control and monitoring of drug interactions with other anti-epileptic medications (AEMs)

PurposeLevetiracetam (LEV) therapeutic range (20–40 mg/L) and potential drug interactions were assessed in people with epilepsy (PWE).MethodFifty-two PWE had LEV and concomitant medications [carbamazepine (CBZ); valproate (VPA); lamotrigine (LTG)] blood levels measured and compared to seizure activity. Lacosamide (LCM) levels were unavailable. Adopted therapeutic ranges were: 20–40 mg/L – LEV; 25–50 μmol/L – total CBZ; 6–13 μmol/L – free CBZ; 300–750 μmol/L – total VPA; 30–75 μmol/L – free VPA; and 40–60 μmol/L – LTG. Seizure-freedom was assessed and patients followed for almost two years.Results23 of 52 PWE (44%) used LEV monotherapy and 16/23 (70%) had ‘therapeutic’ LEV with 13/16 (81%) seizure-free. 29 of 52 (56%) used polytherapy and 16/29 (55%) had ‘therapeutic’ LEV with 7/16 (44%) seizure-free. 11 of 29 (38%) used CBZ: 4/11 (36%) had therapeutic mean LEV levels and 7/11 (64%) were seizure-free. Fourteen (48%) used VPA: 9/14 (64%) had therapeutic mean LEV levels and 8/14 (57%) were seizure-free. 13 of 29 (45%) used LTG: 8/13 (62%) had therapeutic mean LEV levels and 5/13 (38%) were seizure-free. LEV did not alter CBZ, but CBZ affected LEV. LEV elevated VPA free levels but not VPA total levels. Dosage/concentration was lowered with polytherapy.ConclusionLEV range (20–40 mg/L) assisted epilepsy management and anti-epileptic medication interactions were suggested with polytherapy thus possibly explaining the impaired efficacy of LEV with polytherapy.     

Effects of Pregnancy on the Pharmacokinetics of Lamotrigine in Dogs

PURPOSE: This study was designed to evaluate the effects of pregnancy on the kinetics of lamotrigine (LTG). METHODS: Five pregnant dogs were given a daily dose of LTG (100 mg) for a period of 1 week. Two months after parturition, the same subjects were given the LTG dose (100 mg) over the same period. On both occasions, plasma LTG concentrations were determined by a sensitive, high-performance liquid chromatographic (HPLC) method, over a 30-h period after the last dose. RESULTS: The mean maximum plasma concentration (Cmax), volume of distribution (Vd/F), and oral body clearance (Cl/F) for LTG (+/- SD) during pregnancy were 7.63+/-2.46 microg/ml 1.74+/-0.29 L/kg, and 0.19+/-0.04 L/h/kg, respectively. After pregnancy, the same variables were 6.12+/-2.24 microg/ml, 2.36+/-1.10 L/kg, and 0.30+/-0.13 L/h/kg, respectively. None of these pharmacokinetic parameters was found to be significantly different between the two groups. CONCLUSIONS: The apparent lack of change in the relevant pharmacokinetic parameters of LTG during pregnancy may indicate that pregnancy has little or no effect on glucuronidation; the principal pathway for the drug's elimination.     

Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry

The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs (P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy (n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses >1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control.     

Antiepileptic drugs and brain maturation: fetal exposure to lamotrigine generates cortical malformations in rats

Intake of antiepileptic drugs (AEDs) during pregnancy can provoke severe and subtle fetal malformations associated with deleterious sequelae, reflecting the need for experimental investigations on the comparative teratogenic potential of these agents. We recently reported that prenatal exposure to vigabatrin and valproate, two AEDs which act through GABAergic mechanisms, induces hippocampal and cortical dysplasias in rodents. We have now investigated the effects of phenobarbital (PB, 30 mg/kg day) i.p.), a drug also endowed with GABAergic effects, and the new generation AEDs lamotrigine (LTG, 5-20mg/kg/day i.p.), topiramate (TPM, 10mg/kg/day i.p.), and levetiracetam (LEV, 50mg/kg/day i.p.) on brain development. Prenatal exposure to LTG induced hippocampal and cortical malformations in a dose-dependent manner, at maternal plasma concentrations within the clinically occurring range. These abnormalities were not observed after exposure to PB, TP and LEV. These observations raise concerns about potential clinical correlates and call for detailed comparative investigations on the consequences of AED use during pregnancy.