Pharmacokinetics Of Lamotrigine Research Articles

Algorithm for lamotrigine dose adjustment before, during, and after pregnancy

Treatment with lamotrigine (LTG) during pregnancy is associated with a pronounced risk of seizure deterioration, because pregnancy accelerates LTG elimination. The extent to which pregnancy affects LTG pharmacokinetics is unpredictable and varies considerably among patients. We propose an algorithm for systematic LTG plasma concentration monitoring and dose adjustment to guide the clinician between the risk of seizure deterioration and LTG toxicity by maintaining a stable LTG concentration, using the optimal prepregnancy target concentration as a reference. The reference LTG plasma concentration (RC) should be determined before pregnancy or as early in pregnancy as possible. After conception, plasma concentration of LTG should be measured every 4 weeks throughout pregnancy. When the LTG plasma concentration falls below the RC, the dose of LTG should be increased by 20-25%. Post-partum, the plasma concentration of LTG should be measured within the first or second week, and if the LTG plasma concentration is higher than the RC, the LTG dose should be reduced by 20-25% and the procedure repeated until RC is re-established. Seizure deterioration during pregnancy may be prevented or reduced by closely and systematically following our proposed algorithm.

Are lamotrigine kinetics altered in menopause? Observations from a drug monitoring database

To assess possible alterations in the pharmacokinetics of lamotrigine (LTG) in menopause, we reviewed the database of the drug monitoring service at the Karolinska University Hospital. Dose/plasma concentration (D/C) ratios of LTG in different age groups of women under treatment with LTG were compared with ratios for men. For further comparison, D/C ratios were calculated for men and women treated with carbamazepine (CBZ). D/C ratios were available for 752 men and 1115 women on LTG, and for 3464 men and 3088 women on CBZ. The D/C ratios of CBZ were very similar among men and women in all age groups under study. In contrast, LTG D/C ratios seemed to decline in women 51–55 years of age, and were in this age group significantly lower among women than among men ( P < 0.05). Our data suggest that there may be a transient decline in clearance of LTG in conjunction with presumed menopause.

Population pharmacokinetics of lamotrigine in patients with epilepsy

The purpose of this study was to derive a population pharmacokinetics (PPK) model of lamotrigine clearance as well as to identify and describe factors that influence it in Serbian patients with epilepsy. A total of 40 steady-state serum concentrations from 38 adult and pediatric patients with epilepsy, collected during routine therapeutic drug monitoring, were used for the analysis. To determine the influence of different covariates on the estimate of lamotrigine clearance we built a non-linear mixed-effects one-compartment model with the first order elimination and without absorption. Typical mean value of lamotrigine clearance, estimated by the base model (without covariates), in our population was 1.15 l h-1. The final model showed that lamotrigine clearance increased with total body weight, daily dose and concomitant administration of carbamazepine, and decreased with concomitant administration of valproate. The magnitude of carbamazepine and valproate effect was +1.13 l h-1 and -1 l h-1, respectively. The final model was validated in a group of 15 epileptic patients, showing good predictive performance. The derived model describes well lamotrigine clearance in terms of characteristics of Serbian patients, offering basis for rational individualization of lamotrigine dosing regimens.

Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period

To prospectively analyse the pharmacokinetics of lamotrigine (LTG) during pregnancy and lactation in a consecutive series of epileptic pregnant women. Nine women on LTG-monotherapy were studied during pregnancy, delivery and lactation, until a mean of 3 weeks postpartum. Maternal blood samples were available from all trimesters as well as umbilical cord blood samples of the newborn 24 and/or 48 h postpartum. In 4 cases we additionally determined the LTG-concentration in breast milk. The median LTG-clearance was elevated by 197% during the first trimester, 236% and 248% during the second and third trimester respectively. A maximum of 264% was reached at delivery. An average LTG-dose increase by 250% had to be undertaken in order to obtain therapeutic serum levels. In puerperium LTG-clearance decreased again to reach the initial concentrations approximately at the third week postpartum. The median LTG-concentration ratio of the umbilical cord blood to maternal serum was 1.01 (range: 0.56-1.42), while the median LTG-concentration ratio of breast milk to maternal serum was 0.59 (range: 0.35-0.86). Our study confirms the therapeutic relevant changes of LTG-clearance during pregnancy and lactation in women on LTG-monotherapy. Since LTG crosses the placenta, a close monitoring of both mother and newborn is indispensable.

A non‐randomized study to investigate the effects of the atypical antipsychotic aripiprazole on the steady‐state pharmacokinetics of lamotrigine in patients with bipolar I disorder

To determine the effect of aripiprazole on steady-state pharmacokinetics of lamotrigine in patients with bipolar I disorder who were clinically stable on lamotrigine (100-400 mg/day) for >or=4 weeks. In this open-label study, aripiprazole was administered at 10 mg/day for 3 days, 20 mg/day for 3 days, then 30 mg/day for 8 days. Blood samples were collected on Days -1 and 14 for determination of lamotrigine steady-state pharmacokinetic parameters. Safety and tolerability were assessed. Eighteen patients were administered aripiprazole in combination with lamotrigine. Geometric mean (GM) values for lamotrigine maximum plasma concentration were similar for lamotrigine alone (26 ng/mL) and with co-administered aripiprazole (23 ng/mL). GM values for plasma lamotrigine area under the concentration-time curve (AUCtau) were comparable for lamotrigine alone (434 ng/h/mL) and with co-administered aripiprazole (394 ng/h/mL). Median T(max) of lamotrigine alone and combined with aripiprazole was 1.98 and 0.77 h, respectively. No changes to lamotrigine dose-normalized plasma trough concentrations were observed with co-administered aripiprazole. Sixteen patients (88.9%) experienced >or=1 adverse event (AE), the most common of which was insomnia (n = 6). Aripiprazole had no meaningful effect on lamotrigine steady-state pharmacokinetics in patients with bipolar I disorder. No dosage adjustment of lamotrigine is required and the combination was generally safe and well tolerated.

Seradyn Quantitative Microsphere System Lamotrigine Immunoassay on a Hitachi 911 Analyzer Compared With HPLC-UV

Lamotrigine (LTG) is used currently as monotherapy or, more frequently, as add-on therapy with other antiepileptic drugs. It demonstrates efficacy against partial seizures, primary and secondary tonic clonic seizures, absence seizures, and drop attacks. LTG pharmacokinetics is complicated by coadministration with other antiepileptic drugs such as valproic acid, phenytoin, or carbamazepine. The wide interpatient variability in LTG dosage required to attain therapeutic plasma LTG concentrations for seizure control suggests that LTG is a good candidate for therapeutic drug monitoring (TDM). In this study, we compared the quantitative microsphere system (QMS) LTG immunoassay with the LTG high-performance liquid chromatography-ultra violet (HPLC-UV) assay routinely employed for TDM in our laboratory. Samples tested by these methods were patient samples presented for TDM and from a quality assurance program. Quality control material demonstrated within- and between-run (n = 6) coefficient of variation and biases of less than 10%. Patient samples demonstrated a Deming regression of QMS = 1.09 HPLC-UV - 0.17 and quality assurance program samples had a Deming regression of QMS = 1.03 HPLC-UV - 0.11. Patient samples demonstrated a mean bias of 6.1% and quality assurance program samples had a mean bias of 0.2%. The QMS LTG assay had a clinically small but significant overestimation of plasma LTG concentrations. It may be useful as a convenient alternative method that would provide TDM guidance if a chromatographic assay was not available.

Changes in Lamotrigine Pharmacokinetics during Pregnancy and the Puerperium

To assess changes in the pharmacokinetics of the anti-epileptic drug lamotrigine (LTG) during pregnancy, plasma LTG concentrations at steady-state were determined at different intervals during 11 pregnancies in 10 women with epilepsy stabilized on long-term LTG therapy. In the five pregnancies that could be assessed both during gestation and after delivery, plasma LTG concentrations increased on average by 164% (range +75 to +351%) between the last observation during pregnancy and the puerperium (P < 0.05). When all pregnancies monitored during pregnancy were considered, plasma LTG concentrations declined by an average of 20% (range -64% to +13%) between the first and the last assessment before delivery. These findings confirm that plasma LTG concentrations decrease markedly during pregnancy and that, at least in some cases, this effect occurs as early as the first trimester. Because there is a large interindividual variability in the magnitude and time course of the pregnancy-associated pharmacokinetic changes, it is desirable to establish baseline plasma LTG concentrations in all women of childbearing potential and to monitor LTG levels at frequent intervals during pregnancy and the puerperium.

Population Pharmacokinetics of Lamotrigine with Data from Therapeutic Drug Monitoring in German and Spanish Patients with Epilepsy

This study develops a population pharmacokinetic model for lamotrigine (LTG) in Spanish and German patients diagnosed with epilepsy. LTG steady-state plasma concentration data from therapeutic drug monitoring were collected retrospectively from 600 patients, with a total of 1699 plasma drug concentrations. The data were analyzed according to a one-compartment model using the nonlinear mixed effect modelling program. The influences of origin (Germany or Spain), sex, age, total body weight, and comedication with valproic acid (VPA), levetiracetam, and enzyme-inducing antiepileptic drugs (phenobarbital [PB], phenytoin [PHT], primidone [PRM], and carbamazepine [CBZ]) were investigated using step-wise generalized additive modelling. The final regression model for LTG clearance (CL) was as follows: CL(L/h) = 0.028*total body weight*e(-0.713*VPA)*e0.663*PHT*e0.588*(PB or PRM)*e0.467*CBZ*e0.864*IND, where IND refers to two or more inducers added to LTG treatment; this factor as well as VPA, PHT, PB, PRM, and CBZ take a value of zero or one according to their absence or presence, respectively. The administration of inducers led to a significant increase in mean LTG CL (values of 0.045-0.070 L/h/kg vs. 0.028 L/h/kg being reached in monotherapy), whereas VPA led to a significant decrease in CL (0.014 L/h/kg). Thus, comedication with these analyzed drugs can partly explain the interindividual variability in population LTG CL, which decreased from the basic model by more than 40%. The proposed model may be very useful for clinicians in establishing initial LTG dosage guidelines. However, the interindividual variability remaining in the final model (clearance coefficient of variation close to 30%) make these a priori dosage predictions imprecise and justifies the need for LTG plasma level monitoring to optimize dosage regimens. Thus, this final model allows easy implementation in clinical pharmacokinetic software and its application in dosage individualization using the Bayesian approach.

Population Pharmacokinetics of Lamotrigine in Elderly Patients

Lamotrigine is being used more frequently in elderly patients. Dosing of lamotrigine in elderly patients is based largely on studies from younger adults and not evidence-based data from elderly patients. The goal of this study is to determine the pharmacokinetic parameters, such as clearance, and the factors that have a significant effect on these parameters to provide evidence-based information that can be used to dose elderly patients taking lamotrigine. Lamotrigine plasma concentrations from 148 elderly patients (aged 59-92 years) were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check. The results showed that the blood urea nitrogen/serum creatinine ratio, weight, and phenytoin use significantly affect apparent clearance of lamotrigine. These results show that clinicians may need to take into account these covariates when dosing lamotrigine in this population.

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

To further characterize pregnancy-induced alterations in the pharmacokinetics of lamotrigine (LTG). 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. 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. 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.

Steady‐state Pharmacokinetics of Lamotrigine when Converting from a Twice‐daily Immediate‐release to a Once‐daily Extended‐release Formulation in Subjects with Epilepsy (The COMPASS Study)

To compare the pharmacokinetics (PK) of lamotrigine (LTG) when converting from twice-daily immediate-release (LTG-IR) to once-daily extended-release (LTG-XR) in subjects with epilepsy. An open-label, conversion study was conducted, consisting of a 2-week LTG-IR Baseline Phase, followed by a 2-week LTG-XR Treatment Phase and a 1-week LTG-IR Phase. Forty-four subjects (> or =13 years of age) were enrolled and grouped as metabolically neutral (15), induced (15), or inhibited (14) based on the effects of the concomitant antiepileptic drugs (AEDs) on the clearance of LTG. The primary outcome was LTG PK parameters upon conversion. Secondary outcomes included seizure frequency, adverse events, and subject's preference. LTG-XR and LTG-IR regimens were similar with respect to area under curve from 0 to 24 h (AUC (0-24)), apart from the induced group, where the AUC (0-24) of LTG-XR was on average 21% lower than for LTG-IR. A reduction in the LTG Cmax was observed for LTG-XR compared to LTG-IR resulting in a decrease in the peak-to-trough fluctuation in serum LTG concentrations. The steady-state, dose-normalized, trough concentrations for LTG-XR were similar to those of LTG-IR. The median time to peak concentration (Tmax) following administration of LTG-XR ranged from 4 to 6 h, 6 to 10 h, and 9 to 11 h in the induced, neutral, and inhibited groups, respectively. In comparison, the median Tmax following administration of LTG-IR was between 1 and 1.5 h. Trough concentrations of LTG can be maintained on conversion from twice-daily LTG-IR to once-daily LTG-XR at the same total daily dose.

Pharmacokinetics and Drug Interactions with Zonisamide

Polypharmacy is a widely employed treatment strategy in epilepsy, particularly for individuals with poorly controlled seizures. Drug combinations should be carefully considered to minimize the potential for unfavorable interactions. Older-generation antiepileptic drugs (AEDs) are well known for their pharmacokinetic interaction potential, which generally results from alterations in the metabolism of concomitant drugs due to effects on the cytochrome P450 (CYP) and uridine glucuronyl transferase enzyme systems. Newer agents, such as zonisamide, are less likely to cause adverse drug interactions. A series of interaction studies has revealed zonisamide to be without effect on the steady-state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine. However, zonisamide is principally inactivate by CY3A4-dependent reduction. Consequently, carbamazepine, phenytoin, and phenobarbital all increase its clearance, an interaction that may necessitate a dosage increase, but which will also permit more rapid attainment of steady-state zonisamide concentrations. Otherwise, zonisamide is essentially devoid of clinically significant interactions with other AEDs, oral contraceptives and, indeed, all other classes of therapeutic agents investigated to date. As a result, it is reasonable to conclude that zonisamide has a favorable pharmacokinetic profile and that it may be a useful and uncomplicated agent when employed as adjunctive therapy in refractory epilepsy.

Monitoring salivary lamotrigine concentrations

Lamotrigine concentrations were measured simultaneously (as far as was feasible) in stimulated and unstimulated saliva samples, and in plasma, from seven adult volunteers over a 32 h period following a single 50 mg dose of the drug, and in 20 children and adolescents during the course of routine antiepileptic therapy. In individuals there was a close correlation between the measurements at least 2 h after ingestion of the drug. Concentrations in stimulated and unstimulated saliva were similar; the stimulation produced little change in the saliva secretion rate. The saliva-to-plasma concentration ratio increased linearly by 0.78% for each 1 mg/L plasma lamotrigine concentration, with a mean value of 48.8% at a plasma lamotrigine concentration of 10 mg/L. With appropriate precautions as to the timing of saliva collections, and a single plasma lamotrigine concentration measurement to calibrate the salivary values in the individual, salivary lamotrigine concentration measurement appears to be a practicable approach to therapeutic drug monitoring. This has significant implications for the elucidation of the pharmacokinetics of lamotrigine in the paediatric population.

Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects

Limited data are available about the effect of lopinavir and low-dose ritonavir on glucuronidation. Lamotrigine undergoes glucuronidation. We studied the effect of lopinavir/ritonavir on the pharmacokinetics of lamotrigine and vice versa. Twenty-four healthy subjects received 50 mg lamotrigine once daily on days 1 and 2 and 100 mg twice daily on day 3 through day 23. Lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) was added on day 11. Depending on the decrease in lamotrigine trough level between days 10 and 20, either the study was stopped (<20% decrease) or a dose increase was applied from day 23 to day 31, as follows: increase to 150 mg lamotrigine twice daily if there was a 20% to 33% decrease, increase to 200 mg twice daily if there was a 34% to 66% decrease, and increase to 300 mg twice daily if there was a greater than 66% decrease. On days 10, 20, and 31, 12-hour pharmacokinetic curves were drawn. The mean decrease in lamotrigine trough level between days 10 and 20 was 55.4% (n = 18). A dose increment to 200 mg lamotrigine twice daily was used in all subjects. The area under the plasma concentration-time curve (AUC) values of lamotrigine on day 20 (with lopinavir/ritonavir) and day 10 (without lopinavir/ritonavir) were bioinequivalent, with a point estimate of 0.50 (90% confidence interval, 0.47-0.54). After dose adjustment of lamotrigine to 200 mg twice daily, the AUC on day 31 (n = 15) was bioequivalent to that on day 10, with a point estimate of 0.91 (90% confidence interval, 0.82-1.02). The median AUC ratios of lamotrigine 2N-glucuronide to lamotrigine on day 10 and day 20 were 0.57 (interquartile range, 0.39-0.75) and 1.12 (interquartile range, 0.87-1.31). Pharmacokinetic parameters for lopinavir/ritonavir were similar to historical controls. Lopinavir/ritonavir decreases the AUC of lamotrigine, probably by induction of glucuronidation. A dose increment to 200% of the initial lamotrigine dose is needed to achieve concentrations similar to those with lamotrigine alone. Lamotrigine does not appear to affect the pharmacokinetics of lopinavir/ritonavir.

Lamotrigine Pharmacokinetics During Anticonception and Pregnancy

Lamotrigine (LTG) is a modern, effective and well-tolerated antiepileptic drug (AED) with an expected low teratogenic potential and therefore regarded as a relative safe drug for women of reproductive age. Recent studies, however, have demonstrated that co-administration of LTG and combined oral contraceptives (OCs) and pregnancy interfere with the metabolism of LTG with the risk of therapeutic failure. It is therefore recommended that plasma level of LTG should be closely monitored before and after introduction or discontinuation of OCs and monthly during pregnancy. Keywords: Lamotrigine, pharmacokinetics, anticonception, pregnancy, interaction

Lamotrigine pharmacokinetic/pharmacodynamic modelling in rats

The aim of this study was to perform a pharmacokinetic/pharmacodynamic (PK/PD) modelling of lamotrigine following its acute administration to rats. Adult male Wistar rats were given 10 mg/kg of lamotrigine intraperitoneally. Plasma and brain samples were obtained at predetermined times over 120 h post-dose and analysed by liquid chromatography. The anticonvulsant profile against maximal electroshock seizure stimulation was determined over 48 h after dosing. As a linear relationship between lamotrigine plasma and brain profiles was observed, only the plasma data set was used to establish the PK/PD relationship. To fit the effect-time course of lamotrigine, the PK/PD simultaneous fitting link model was used: the pharmacokinetic parameters and dosing information were used in the one-compartment first-order model to predict concentrations, which were then used to model the pharmacodynamic data with the sigmoid Emax model, in order to estimate all the parameters simultaneously. The following parameters were obtained: Vd = 2.00 L/kg, k(abs) = 8.50 h(-1), k(el) = 0.025 h(-1), k(e0) = 3.75 h(-1), Emax = 100.0% (fixed), EC50 = 3.44 mg/L and gamma = 8.64. From these results, it can be stated that lamotrigine is extensively distributed through the body, its plasma elimination half-life is around 28 h and a lamotrigine plasma concentration of 3.44 mg/L is enough to protect 50% of the animals. When compared with humans, the plasma concentrations achieved with this dose were within the therapeutic concentration range that had been proposed for epileptic patients. With the present PK/PD modelling it was possible to fit simultaneously the time-courses of the plasma levels and the anticonvulsant effect of lamotrigine, providing information not only about the pharmacokinetics of lamotrigine in the rat but also about its anticonvulsant response over time. As this approach can be easily applied to other drugs, it becomes a useful tool for an explanatory comparison between lamotrigine and other antiepileptic drugs.

Pregabalin Drug Interaction Studies: Lack of Effect on the Pharmacokinetics of Carbamazepine, Phenytoin, Lamotrigine, and Valproate in Patients with Partial Epilepsy

Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.

Clinical Science

Abstract Pregabalin Drug Interaction Studies: Lack of Effect on the Pharmacokinetics of Carbamazepine, Phenytoin, Lamotrigine, and Valproate in Patients with Partial Epilepsy Martin J. Brodie, Elaine A. Wilson, David L. Wesche, Christine W. Alvey, Edward J. Randinitis, Edward L. Posvar, Neil J. Hounslow, Nicola J. Bron, G.L. Gibson, and Howard N. Bockbrader Pregabalin (Lyrica) is a new drug that has been approved in the EU as add-on treatment for partial seizures, and as treatment of peripheral neuropathic pain, in adults. Because many patients with partial seizures require more than one antiepileptic drug (AED) to achieve the best seizure control they can, it is important to determine whether new drugs for treating partial seizures may interact with commonly used AEDs. This paper reports the results of several drug–drug interaction studies of pregabalin and commonly used AEDs. In these studies, pregabalin was given to patients who were each taking one AED, either valproate, phenytoin, lamotrigine, or carbamazepine, to treat their epilepsy. Adding pregabalin to monotherapy with valproate, phenytoin, lamotrigine, or carbamazepine had no effect on the concentrations in the blood of any of these four drugs. Likewise, when concentrations of pregabalin in the blood were measured in these same patients, the concentrations were similar to those seen in the blood of subjects from earlier studies who had received pregabalin by itself. These findings indicate that pregabalin does not interact with any of these four common AEDs. The combinations of pregabalin with either valproate, phenytoin, lamotrigine, or carbamazepine were generally well tolerated by the patients in these studies, and when side effects did occur, they were typically mild to moderate and resolved quickly. Together, these studies demonstrate that pregabalin may be safely added to therapy with valproate, lamotrigine, phenytoin, or carbamazepine without concern for drug–drug interactions.

Lack of Clinically Significant Pharmacokinetic Interactions Between Zonisamide and Lamotrigine at Steady State in Patients With Epilepsy

The present study was designed to assess the effect of the addition of zonisamide (ZNS) on lamotrigine (LTG) disposition and the safety of the combination under steady-state conditions in patients with epilepsy. A secondary objective was to characterize ZNS pharmacokinetics (PK) in the presence of LTG. Twenty subjects (male and female 18 to 55 years old) stabilized on LTG monotherapy (150-500 mg/d) took part in a 2-center, open-label, 1-way drug interaction study. ZNS was gradually increased to 200 mg twice daily over a 3-week period, and 3 PK profiles were performed: on days -7 and -1 to assess the PK of oral LTG administered alone and on day 35, after 14 days of ZNS at the maximal tolerated dose, to evaluate the effect of ZNS on LTG PK and to characterize ZNS PK in the presence of LTG. Eighteen subjects completed the study. Steady-state dosing of ZNS did not significantly affect the mean Cmin (mean +/- SD: 2.8 +/- 1.4 vs 3.5 +/- 2.4 microg/mL), Cmax (5.1 +/- 3.0 vs 5.1 +/- 3.0 microg/mL), AUC0-12 (45.5 +/- 22.6 vs 50.3 +/- 32.1 microg.h/mL), and CL/F (2778.5 +/- 1368.5 vs 3052.1 +/- 2744.9 mL/h) of LTG measured before (day -1) and after (day 35) ZNS administration, respectively. Further, 90% confidence intervals for the geometric mean ratios (day 35/day -1) fell within the no-effect range of 0.80-1.25. The fraction of dose of total and unconjugated LTG excreted in urine was not significantly different between baseline and ZNS treatment, but the renal clearance of LTG decreased significantly with ZNS dosing (P = 0.01). On the other hand, the PK parameters measured for ZNS in the presence of LTG were consistent with an absence of LTG effect on ZNS PK. The coadministration of ZNS and LTG was generally well tolerated. Steady-state safety and PK of LTG and ZNS are not affected significantly when these two drugs are coadministered at clinically relevant doses, indicating that no dosage adjustment of either drug should be required when they are used in combination.

A bi-directional pharmacokinetic interaction study of lamotrigine and the Combined Oral Contraceptive (COC) pill in healthy subjects

This study was designed to investigate the effects of Microgynon 30 (COC, 30mcg ethinylestradiol + 150mcg levonorgestrel) on the pharmacokinetics (PK) of lamotrigine (LTG) and the effects of lamotrigine on the PK of the COC. This was an open-label study of 22 healthy young females. Subjects took COC for 21 days, followed by a 7 day pill-free interval, according to standard prescribing instructions. On Day 29, subjects restarted COC and began LTG (starting dose 25mg/day, titrated to a maximum of 300mg/day, according to standard prescribing instructions).