Topiramate Concentrations Research Articles

Caffeine Decreases Topiramate Levels in Zebrafish Larvae in a Pentylenetetrazol-Induced Seizure Model.

Epilepsy ranks as the second-most prevalent neurological disease, and is characterized by seizures resulting in neurobiological and behavioral impairment. Naturally occurring in coffee beans or tea leaves, the alkaloid caffeine (CAF) is the most prevalent global stimulant. Caffeine has been observed to influence epileptic seizures and the efficacy of antiepileptic medications, with a notable impact on topiramate (TPM). This study aimed to explore the influence of CAF on TPM's anticonvulsant effects in zebrafish larvae within a PTZ-induced seizure model, concurrently determining TPM concentrations through a sophisticated analytical approach based on ultrahigh-performance liquid chromatography and subsequent mass spectrometric detection. Zebrafish larvae four days post-fertilization were incubated for 18 h with varying doses of TPM or combinations of CAF + TPM, and locomotor activity was then assessed. Seizures were induced by introducing a PTZ solution to achieve a final concentration of 20 mM. Utilizing liquid chromatography-mass spectrometry (LC-MS/MS), TPM levels in the larvae were quantified. CAF co-administration (especially in higher doses) with TPM caused a decrease in the average locomotor activity in the larvae compared to TPM alone. Moreover, CAF decreased TPM levels in the larvae at all investigated doses. In conclusion, these findings offer a novel perspective on the interplay between CAF and TPM, shedding light on previously unexplored facets. The potential impact of CAF consumption in assisting with epileptic seizure control, unless proven otherwise, suggests a noteworthy consideration for future research and clinical practices.

UGT1A polymorphism rs4148324 associated with topiramate plasma concentration to dose ratio in children with epilepsy.

The objective of this study is to evaluate the association between genetic polymorphisms and the concentration to dose ratio of topiramate in children with epilepsy. A cohort of 163 pediatric patients with epilepsy receiving topiramate therapy were enrolled. The ultra-performance liquid chromatography-tandem mass spectrometry method was employed to measure the trough plasma concentration of topiramate at steady-state. These concentrations were normalized by dividing them by the ratio of total daily dose to body weight, yielding the concentration to dose ratio (CDR) of topiramate. MassArray system identified 30 single nucleotide polymorphisms associated with the pharmacokinetics and pharmacodynamics of topiramate. The CDR values were logarithmic transformed (lnCDR) for normal distribution. The association between the identified genetic polymorphisms and lnCDR was assessed using the PLINK software, employing linear regression analysis with adjustments by epilepsy types, estimated glomerular filtration rate, alanine aminotransferase, valproic acid, phenobarbital, and oxcarbazepine. Variant rs4148324 (UGT1A1/3/4/5/6/7/8/9/10, BETA=0.182, P = 0.010) was significantly associated with lnCDR of topiramate. Patients carrying the G allele exhibited higher normalized topiramate plasma concentrations. No other significant associations were found. In pediatric patients receiving topiramate therapy, rs4148324 was associated with normalized topiramate plasma concentration. Further studies are warranted to validate and confirm the findings.

Population pharmacokinetics of topiramate in Chinese children with epilepsy.

Topiramate, a broad-spectrum antiepileptic drug, exhibits substantial inter-individual variability in both its pharmacokinetics and therapeutic response. The aim of this study was to investigate the influence of patient characteristics and genetic variants on topiramate clearance using population pharmacokinetic (PPK) models in a cohort of Chinese pediatric patients with epilepsy. The PPK model was constructed using a nonlinear mixed-effects modeling approach, utilizing a dataset comprising 236 plasma concentrations of topiramate obtained from 181 pediatric patients with epilepsy. A one-compartment model combined with a proportional residual model was employed to characterize the pharmacokinetics of topiramate. Covariate analysis was performed using forward addition and backward elimination to assess the influence of covariates on the model parameters. The model was thoroughly evaluated through goodness-of-fit analysis, bootstrap, visual predictive checks, and normalized prediction distribution errors. Monte Carlo simulations were utilized to devise topiramate dosing strategies. In the final PPK models of topiramate, body weight, co-administration with oxcarbazepine, and a combined genotype of GKIR1-UGT (GRIK1 rs2832407, UGT2B7 rs7439366, and UGT1A1 rs4148324) were identified as significant covariates affecting the clearance (CL). The clearance was estimated using the formulas CL (L/h) = 0.44 × (BW⁄11.7)0.82 × eOXC for the model without genetic variants and CL (L/h) = 0.49 × (BW⁄11.7)0.81 × eOXC × eGRIK1-UGT for the model incorporating genetic variants. The volume of distribution (Vd) was estimated using the formulas Vd (L) = 6.6 × (BW⁄11.7). The precision of all estimated parameters was acceptable. Furthermore, the model demonstrated good predictability, exhibiting stability and effectiveness in describing the pharmacokinetics of topiramate. The clearance of topiramate in pediatric patients with epilepsy may be subject to the influence of factors such as body weight, co-administration with oxcarbazepine, and genetic polymorphism. In this study, PPK models were developed to better understand and account for these factors, thereby improving the precision and individualization of topiramate therapy in children with epilepsy.

Decreased serum concentrations of antiseizure medications in children with drug resistant epilepsy following treatment with ketogenic diet.

To examine the potential influence of a ketogenic diet on serum concentrations of antiseizure medications (ASMs) in children with drug resistant epilepsy. We investigated the serum concentrations of ASMs in 25 children with drug resistant epilepsy, 2-13 years of age, treated with a classical ketogenic diet for 12 weeks. The patients were recruited from the National Centre for Epilepsy from August 15th, 2017, to January 24th, 2022. Changes in ASM serum concentrations were analyzed using a mixed effect model analysis. Significance level was set at P < 0.05 for all comparisons. The participants used 12 different ASMs during the study. The mean number of ASMs was 2.4 (±SD 0.7). None of the participants changed the type or dose of the ASMs during the intervention period. The serum concentrations of clobazam (n = 9, P = 0.002), desmethylclobazam (n = 9, P = 0.010), and lamotrigine (n = 6, P = 0.016) decreased significantly during the dietary treatment. The analytes with the largest reduction in serum concentration after 12 weeks of dietary treatment were clobazam (mean change -38%) and desmethylclobazam (mean change -37%). We found no significant change in the serum concentrations of levetiracetam, topiramate, and valproic acid. We identified a significant decrease in the serum concentrations of clobazam, desmethylclobazam, and lamotrigine following a 12-week ketogenic diet intervention in children with drug resistant epilepsy. An unintended decrease in the serum concentrations of ASMs may render the patient prone to seizures. Measurements of ASM serum concentrations might be useful in patients on a ketogenic diet, especially in patients with lack of efficacy of the dietary treatment.

Utility of a fluorescent probing strategy for designing a distinctive chemically mutagenized reaction for the determination of an antiepileptic agent; topiramate

In many experimental applications, fluorescent probes (fluorophores or just fluors) have replaced more traditional methods because of their adaptability, sensitivity, and quantifiability. The target analyte molecule (Topiramate) does not include any fluorogenic or chromophoric groups; hence it has no fluorescence in its native state or light absorptive power when exposed to ultraviolet light, thus; it is impossible to analyze it directly and must be undergone chemical mutagenicity in its molecular structure. This phenomenon can be achieved through fluorescent probing or labeling with tagging reagent. Consequently, the current analytical methodology depends on the fluorescence probe development via the ninhydrin reagent's utility to birth a condensed fluorescent derivative that can be tracked fluorimetrically. The final product was monitored at λem 482 nm after excitation at λex 381 nm. Under appropriate conditions, topiramate's primary amine group can condense with ninhydrin (β-diketone) and phenylacetaldehyde in a buffered solution. A new, green, feasible, and selective fluorometric strategy for topiramate assay has been presented in this work. The method offers linearity at a topiramate concentration range of 0.5 – 8 μg mL−1. The method's quantum yield was rated, and the validation parameters were examined following the International Council for Harmonisation (ICH) rules. Finally, the proposed probe was efficiently employed in the topiramate testing in the batched powder and available dosage form with high accuracy, and there was no significant effect with the existence of excipients. The findings indicate an impressive alignment with the reference documented method, showing no major variations in precision and accuracy.

Potential for confusion among topiramate oral solution concentrations and errors related to nonspecific PRN frequencies

Potential for confusion among topiramate oral solution concentrations and errors related to nonspecific PRN frequencies

Topiramate inhibits the proliferation of bladder cancer cells via PI3K/AKTR signaling pathway

Purpose: To explore new treatment options for bladder cancer (BC) based on topiramate (TPM).Methods: The MTT assay and flow cytometry were used to determine the effect of topiramate on partial growth-related malignant phenotype of BC cells. Expression levels of apoptosis-related biomarkers and signaling pathway-related factors were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. In vivo experiments were conducted to investigate the role of TPM on tumor growth in mice with bladder cancer.Results: The MTT results showed that topiramate blocked the growth of BC cells (p &lt; 0.05). Growth inhibition was positively correlated with TPM concentration. Flow cytometry results revealed that bladder cancer cell apoptosis rose with increase in TPM concentration, while the mRNAs of apoptosisassociated factors Bcl-2 and Mcl-1 were down-regulated in a concentration-based manner by TPM (p &lt; 0.05). Western blot assay indicated that Bax and Caspase-3 proteins were up-regulated, and the higher the concentration of TPM, the more significant the protein expression levels (p &lt; 0.05).Conclusion: Topiramate (TPM) slows down the rate of growth of BC cells and accelerates their rate of apoptosis through the regulation of P13K/AKT/mTOR signaling pathway. Thus, the compound has potentials for development as an anti-bladder cancer agent.

Effects of Lamotrigine and Topiramate on Glial Properties in an Astrocyte-Microglia Co-Culture Model of Inflammation.

BackgroundAstrocytes and microglia are involved in the pathophysiology of epilepsy and bipolar disorder with a link to inflammation. We aimed to investigate the effects of the antiepileptic and mood-stabilizing drugs lamotrigine (LTG) and topiramate (TPM) on glial viability, microglial activation, cytokine release, and expression of gap-junctional protein connexin 43 (Cx43) in different set-ups of an in vitro astrocyte-microglia co-culture model of inflammation.MethodsPrimary rat co-cultures of astrocytes containing 5% (M5, representing “physiological” conditions) or 30% (M30, representing “pathological, inflammatory” conditions) of microglia were treated with different concentrations of LTG and TPM for 24 hours. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to measure the glial cell viability. The microglial activation state was analyzed by immunocytochemistry. The pro-inflammatory tumor necrosis factor-α (TNF-α) and anti-inflammatory transforming growth factor-ß1 (TGF-ß1) cytokine levels were measured by enzyme-linked immunosorbent assay. The astroglial Cx43 expression was quantified by western blot.ResultsA significant reduction of the glial cell viability after incubation with LTG or TPM was observed in a concentration-dependent manner under all conditions. LTG caused no significant alterations of the microglial phenotypes. Under pathological conditions, TPM led to a significant concentration-dependent reduction of microglial activation. This correlated with increased astroglial Cx43 expression. TNF-α levels were not affected by LTG and TPM. Treatment with higher concentrations of LTG, but not with TPM, led to a significant increase in TGF-ß1 levels in M5 and M30 co-cultures.ConclusionsDespite the possible glial toxicity of LTG and TPM, both drugs reduced inflammatory activity, suggesting potential positive effects on the neuroinflammatory components of the pathogenesis of epilepsy and bipolar disorder.

Monitoring topiramate concentrations at delivery and during lactation

ObjectiveTo determine transplacental passage of topiramate and its transport to colostrum, mature maternal milk and breastfed infants, we examined data from 27 women treated with topiramate from 2004 to 2020. MethodsIn this cohort study, maternal serum, umbilical cord serum, milk and infant serum levels were measured by gas chromatography in the delivery subgroup, the colostrum subgroup (3–4 days postpartum) and the mature milk subgroup (7–30 days postpartum). Paired umbilical cord serum, maternal serum, breastfed infant serum, and milk levels were used to assess the ratios of umbilical cord/maternal serum, milk/maternal serum and infant/maternal serum levels. ResultsTopiramate levels varied from 1.0 to 7.1 mg/L in maternal serum and from 0.8 to 6.2 mg/L in umbilical cord serum, and the mean umbilical cord/maternal serum ratio was 0.93 ± 0.11. At 3–4 days after delivery, topiramate concentrations were 1.4–8.4 mg/L in maternal serum, 1.5–8.6 mg/L in milk and 0.3–4.4 mg/L in infant serum. The mean milk/maternal serum ratio was 0.99 ± 0.45, and the mean infant/maternal serum ratio was 0.25 ± 0.15. At 7–30 days after delivery, maternal serum levels varied from 1.9 to 9.7 mg/L, milk levels ranged from 2.3 to 10.6 mg/L and infant serum levels ranged from 0.3 to 6.5 mg/L. The mean milk/maternal serum ratio was 1.07 ± 0.31, and the mean infant/maternal serum ratio was 0.51 ± 0.27. ConclusionsWe extended information about free transplacental passage of topiramate and its extensive transport to maternal milk with lower serum concentrations in breastfed infants in the largest group of patients ever reported to our knowledge. Data availability statementAuthors declare that take full responsibility for the data, the analyses and interpretation, and the conduct of the research; that they have full access to all of the data; and that they have the right to publish all data. Authors were not participations in industry-sponsored research and corporate activities for evaluation of a manuscript.

Effects of topiramate on adipocyte differentiation and gene expression of certain carbonic anhydrase isoenzymes

Abstract Background Topiramate, an antiepileptic drug, besides its known effects in neurons, is a carbonic anhydrase inhibitor and causes weight loss in treated subjects, but, the mechanisms of weight loss effect have not been yet identified.. Objective In this study, effects of topiramate on 3T3-L1 adipocyte differentiation and expressions of carbonic anhydrase I, II, III, VA, VB were investigated to determine possible roles of carbonic anhydrase isoenzymes and adipocytes in weight loss effect of topiramate. Material and methods Adipocyte differentiation was detected by Oil Red O staining. Carbonic anhydrase I, II, III, VA, VB expressions were determined by Real-Time PCR method. Results It was found that topiramate induced adipogenesis at all concentrations (p &lt; 0.0001). CA expressions increased significantly with adipogenesis (p = 0.0001). Topiramate stimulated adipogenesis in 3T3-L1 cells and reduced CA II, VA and VB and, an increased CA III expression was observed at low concentrations. CA II, VA and, VB expressions were found increased and CA III expression decreased at high topiramate concentrations. Conclusion It was concluded that changes in CA III expression were consistent with its reduction in obesity, alterations of CA II, VA and VB expressions could be attributed to compensation mechanism of cells.

Pharmacokinetic interaction of brivaracetam on other antiepileptic drugs in adults with focal seizures: Pooled analysis of data from randomized clinical trials

ObjectiveTo assess the effect of brivaracetam (BRV) on steady-state plasma concentrations of commonly prescribed antiepileptic drugs (AEDs). MethodsData were pooled from five randomized, double-blind, placebo-controlled efficacy studies (NCT00175929, NCT00175825, NCT00490035, NCT00464269, and NCT01261325) in which adults with refractory epilepsy, and receiving stable doses of 1–2 AEDs, initiated adjunctive treatment with BRV (or placebo) for up to 12 weeks, following a 4–8 week baseline period. Concentrations of carbamazepine, carbamazepine epoxide, clobazam, clonazepam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine (MHD), phenobarbital, phenytoin, pregabalin, topiramate, valproic acid and zonisamide, were measured during baseline and during BRV or placebo evaluation periods. Log-transformed data for patients receiving BRV dosages of 50–200 mg/day (or placebo) were evaluated using repeated measures analysis of covariance. Geometric least-squares means ratios of respective AED concentrations (treatment vs baseline) and their 90% confidence intervals (CIs) were calculated. Relevant interaction of BRV on the respective AED was inferred if CIs were entirely outside of 0.80–1.25 limits. ResultsWithin the population for analysis (n = 1402), relevant interaction was observed for carbamazepine epoxide alone which increased up to 2-fold from baseline due to inhibition of epoxide hydrolase by BRV, and the effect size was not influenced by concomitant valproic acid. Relevant interaction was not observed for other AEDs. ConclusionIn adults with focal seizures, adjunctive BRV treatment does not affect plasma concentrations of the evaluated AEDs but increases carbamazepine epoxide metabolite. Carbamazepine dose reduction should be considered if tolerability issues arise.

Topiramate pharmacokinetics in neonates undergoing therapeutic hypothermia and proposal of an optimised dosing schedule.

The adequate dosing of topiramate in neonates undergoing therapeutic hypothermia has not been established. The aim of this study was to design a dosing schedule capable of providing topiramate serum concentrations within the accepted therapeutic range. Neonates (n=52) with hypoxic ischaemic encephalopathy and subjected to therapeutic hypothermia were dosed with topiramate, 5mg/kg on day one and 3mg/kg on days two to five, to decrease seizure events. A total of 451 topiramate serum concentrations obtained in the patients were used to develop a population pharmacokinetic model using a non-linear mixed-effects modelling approach. A one-compartment model with first-order absorption and two different clearance terms, one for the cooling period and another for the post-warming period, were used to describe the concentration-time topiramate data. The probability of no-seizure events could not be related to topiramate concentrations, which was attributed to excessively low topiramate concentrations. A modified dosage schedule was designed with the aim of obtaining more than 90% of patients with topiramate concentrations within the therapeutic range after the first dose. The dosage schedule of topiramate in these patients should be modified with the aim of decreasing the frequency of seizure events.

Individual Differences in Working Memory Capacity Predict Topiramate-Related Cognitive Deficits.

Topiramate (TPM) and lorazepam (LZP) are two examples of frequently prescribed medications that are associated with a high incidence of cognitive impairment; however, the factors that underlie interindividual differences in side effect profiles have not been fully characterized. Our objective was to determine whether working memory capacity (WMC), the amount of information that can be stored and manipulated in memory over short time intervals, is one such factor. Twenty-nine healthy volunteers completed a double-blind, randomized, placebo-controlled crossover study during which they received placebo (PBO), TPM, and LZP in random order. Four hours after drug administration, a blood draw was taken to establish drug concentrations, and subjects performed a verbal working memory task while the accuracy and reaction time of their responses were recorded. Working memory capacity was calculated based on accuracy rates during the PBO session, and the role of WMC in moderating the severity of drug-related cognitive impairment was assessed by examining drug-related performance changes from PBO as a function of WMC. Both TPM and LZP had a negative impact on task performance, although only TPM-related deficits were modulated by WMC; high WMC was associated with more severe impairments and heightened sensitivity to increasing TPM concentrations. We have identified a potential clinical risk factor, high WMC, which is associated with drug-related adverse cognitive events. These data provide objective evidence in support of clinical observations that high-functioning patients are more likely to experience severe cognitive impairments.

Determination of topiramate by capillary electrophoresis with capacitively-coupled contactless conductivity detection: A powerful tool for therapeutic monitoring in epileptic patients.

Topiramate (TPM) is the main antiepileptic drug used for the control of partial and generalized seizures in both adults and children. In association with clinical observations, the analysis of plasmatic concentration of TPM is of utmost importance for the individual adjustment of the administered dose to the patient. In the present work, a bioanalytical method was developed and validated for TPM analysis in plasma samples by capillary electrophoresis with capacitively-coupled contactless conductivity detection (CE-C4 D). A simple background electrolyte composed of 15 mmol/L triethylamine, hydrodynamic injections (0.8 psi for 5 s) and a moderate separation voltage (20 kV) were used, rendering relatively short analysis times (<3 min). The sample pre-treatment was carried out by liquid-liquid extraction using methyl terc-butyl ether as solvent and 200 μL of plasma. The method was validated according to the official guidelines from the European Medicine Agency and showed linearity in plasmatic concentration range from 1 to 30μg/mL, which covers the clinically-relevant interval. The lower limit of quantification of 1 μg/mL obtained also allows following patients with low dosage of the drug. The method was successfully applied to analysis of plasma samples and allowed the identification of 80% under-medicated patients in the analyzed patient pool.

Influence of propafenone on the anticonvulsant activity of various novel antiepileptic drugs in the mouse maximal electroshock model.

The main mechanism of action of propafenone (antiarrhythmic drug) involves the inhibition of the fast inward sodium current during phase 0 of the action potential. Sodium channel-blocking activity is also characteristic for some antiepileptic drugs. Therefore, it could be assumed that propafenone may also affect seizures. In the present study, we evaluated the effect of propafenone on the protective effect of oxcarbazepine, lamotrigine, topiramate and pregabalin against the maximal electroshock-induced seizures in mice. Anticonvulsant activity of propafenone was assessed with the maximal electroshock seizure threshold (MEST) test. Influence of propafenone on the anticonvulsant activity of antiepileptic drugs was estimated in the mouse maximal electroshock model (MES). Drug-related adverse effects were determined in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Brain concentrations of antiepileptics were assessed by fluorescence polarization immunoassay. Propafenone at doses 60-90mg/kg significantly increased the threshold of seizures, in turn at doses 5-50mg/kg did not affect this parameter. Administration of propafenone at the subthreshold dose of 50mg/kg increased antielectroshock activity of oxcarbazepine, topiramate and pregabalin, but not that of lamotrigine. As regards adverse effects, propafenone alone and in combination with antiepileptic drugs did not significantly impair motor coordination or long-term memory in mice. Propafenone (50mg/kg) significantly increased the brain level of pregabalin. Brain concentrations of topiramate and oxcarbazepine were not affected. Our findings show that propafenone has own anticonvulsant action and enhances efficacy of oxcarbazepine, topiramate and pregabalin, but not that of lamotrigine, at least in experimental condition.

Effect of ketogenic diet and other dietary therapies on anti-epileptic drug concentrations in patients with epilepsy.

The ketogenic diet (KD) is an effective high-fat, adequate-protein, low-carbohydrate diet for patients with refractory epilepsy. The aim of this study was to investigate the potential effects of the KD and other dietary therapies on the concentrations of anticonvulsants in patients with epilepsy. Patients with epilepsy who were treated with the KD and other dietary therapies for more than 30days with at least one measurement performed both before and during the diet were evaluated. The mean serum concentrations and the mean serum concentrations per weight per daily dose per bioavailability (F) of anti-epileptic drugs (AEDs) before and during the treatment were assessed. We also compared the rates of events out of reference ranges of the AEDs between before and during the KD and other dietary therapies. We compared the serum albumin, alanine transaminase and aspartate transaminase data of patients with valproic acid before and during the KD. One-hundred thirty-nine patients including 81 male patients were enrolled. The median age of the patients was 2.91 (0.15-15.46) years. The median duration of the dietary therapies was 153 (35-2307) days. After the dietary therapies, the serum concentrations of carbamazepine, lamotrigine, levetiracetam, topiramate and valproic acid decreased, whereas that of phenobarbital slightly increased. However, statistical significance was found only with valproic acid (67.07±25.89μg/mL vs 51.00±20.19μg/mL, P<.05). The serum concentrations per weight per daily dose per drug F significantly decreased for valproic acid (1.38±1.39×10-2 vs 0.82±0.82×10-2 μgdmL-1 F-1 ) and phenobarbital (6.66±7.20×10-2 vs 4.75±4.07×10-2 μgdmL-1 F-1 , P<.05). The rate of occurrence of events out of reference ranges significantly increased with valproic acid (36.08% vs 57.23%, P<.05). Most anti-epileptic drug serum concentrations remained stable during the KD and other related dietary therapies except those of valproic acid. Therefore, serum concentrations of valproic acid should be monitored when the KD and other dietary therapies are concomitantly administered.

BENEFIT OF TOPIRAMATE IN THE TREATMENT OF SYMPTOMS OF BORDERLINE PERSONALITY DISORDER: A TYPICAL REVIEW

Topiramate is a new antiepileptic drug (AED) that has been approved worldwide (in more than 80 countries) for the treatment of various kinds of epilepsy. It is currently being evaluated for its effect in various neurological and psychiatric disorders. Topiramate is used alone or with other medications to prevent and control seizures (epilepsy). This medication is also used to prevent migraine headaches and decrease how often you get them. The present review includes all available information like pharmacokinetics, pharmacological action and side effects. Moreover sometimes it is necessary to monitor the therapeutic concentration of Topiramate. The pharmacokinetics of topiramate are characterised by linear pharmacokinetics over the dose range 100-800 mg, low oral clearance (22-36 mL/min), which, in immunotherapy, is predominantly through renal excretion (renal clearance 10-20 mL/min), and a long half-life (19-25 hours), which is reduced when co administered with inducing AEDs such as phenytoin, phenobarbital and carbamazepine. This paper provides a critical review of the pharmacokinetic interactions of topiramate with old and new AEDs, an oral contraceptive, and the CNS-active drugs lithium, haloperidol, amitriptyline, risperidone, sumatriptan, propranolol and dihydroergotamine. The results of many of these drug interaction studies with topiramate have not been published before, and are presented and discussed for the first time in this article. Keywords: Antiepileptic drug, bipolar disorder, epilepsy, migraine, obesity, seizures, substance abuse, topiramate, weight loss.

Clinical effects of the suicide attempt with topiramate

ObjectivesWe report the case of a 45-year-old male diagnosed with mixed personality disorder brought the hospital for strange behavior. He is being treated with fluoxetine, lorazepam and topiramate; and visited his psychiatrist 72 hours ago.ResultsHe has an adequate level of consciousness and describes retrograde amnesia of the last 72 hours. We found blocks of thought and abnormal behaviors such as dressing and undressing or sorting his belongings repetitively. Urine was only positive for benzodiazepines. In arterial blood gas analysis it performed highlights compensated metabolic acidosis. After ruling out neurological diseases and administrating fluids i.v. the symptoms remitted, persisting only the amnesia, establishing the diagnosis of suicide attempt with topiramate.ConclusionsThe use out-of-guidelines of topiramate in personality and eating disorders is an increasingly common habit in daily clinical practice, as well as suicide attempts with this drug. In therapeutic doses, over 40% of patients taking topiramate, have asymptomatic metabolic acidosis, which in stressful situations may have clinical relevance. In case of acute poisoning, metabolic acidosis is more frequent and severe, manifesting itself by hyperventilation, hypertension and varying degrees of impaired consciousness and cognitive functions. There is also a paradoxical increase in the frequency of seizures. Treatment is supportive and there is no antidote, being lethal cases exceptional. Gastric lavage and administration of activated charcoal have limited use. The determination of plasma concentrations of topiramate is not available for most centers and is not useful in acute poisoning.

Population Pharmacokinetics of Topiramate in Japanese Pediatric and Adult Patients With Epilepsy Using Routinely Monitored Data.

Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L·h·70 kg without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L·h·70 kg. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.

Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring.

This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy. A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan-Meier method. Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 μmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days; P = 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P = 0.002). Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful.