Severity of Topiramate-Related Working Memory Impairment Is Modulated by Plasma Concentration and Working Memory Capacity.

Drug side effects that impair cognition can lead to diminished quality of life and discontinuation of therapy. Topiramate is an antiepileptic drug that elicits cognitive deficits more frequently than other antiepileptic drugs, impairing multiple cognitive domains including language, attention, and memory. Although up to 40% of individuals taking topiramate may experience cognitive deficits, we are currently unable to predict which individuals will be most severely affected before administration. The objective of this study was to show the contributions of plasma concentration and working memory capacity in determining the severity of an individual's topiramate-related cognitive impairment. Subjects were enrolled in a double-blind, placebo-controlled crossover study during which they received a single dose of either 100, 150, or 200 mg topiramate. Working memory function was assessed using a modified Sternberg working memory task with 3 memory loads administered 4 hours after dosing. After adjustment for differences in working memory capacity, each 1 µg/mL of topiramate plasma concentration was associated with a 3.6% decrease in accuracy for all memory loads. Placebo effects occurred as a function of working memory capacity, with individuals with high working memory capacity experiencing less severe placebo-related impairment compared with those with low working memory capacity. Our results demonstrate that severity of topiramate-related cognitive deficits occurs as a function of both drug exposure and baseline cognitive function. By identifying patient- and exposure-related characteristics that modulate the severity of cognitive side effects, topiramate dosing strategies may be individually tailored in the future to prevent unwanted cognitive impairment.

An alternating polarity switching assay for quantification of oxycodone and topiramate: An application of LC-MS/MS method in support to PK/PD study in rodents.

In mass spectrometry, compounds that have different ionization properties experience challenges in simultaneous analysis. In the present paper, the authors proposed a polarity switching (+ve and -ve) LC-MS/MS method to analyze oxycodone and topiramate in a single run. The developed method was validated in the range of 5-1000 ng/mL for oxycodone and 20-5000 ng/mL for topiramate as per the US FDA guidelines. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode to analyze oxycodone and topiramate simultaneously using oxycodone-d6 and topiramate-d12 as internal standards, respectively. Sample preparation was performed in 96-well protein precipitation plates using acetonitrile. Processed samples were analyzed using a C18 column with a gradient mobile phase composed of 10 mm ammonium formate with 0.1% formic acid and acetonitrile. The method was validated for selectivity, specificity, linearity, precision and accuracy, dilution integrity and stability. After validation, this method was successfully applied to quantify oxycodone and topiramate in plasma of concomitantly treated Sprague Dawley (SD) rats.

Topiramate Blood Levels During Polytherapy for Epilepsy in Children.

BACKGROUND: The therapeutic range of topiramate (TPM) blood level is not set because the efficacy and safety are not considered to be related to the level. However, the therapeutic target without side effects is necessary, so the optimal range of TPM blood level was analyzed in this study. STUDY QUESTION: This study was conducted to evaluate the efficacy of TPM over 2 years and the utility of measuring blood levels of TPM during the follow-up of epileptic patients. STUDY DESIGN: Thirty patients (18 males, 12 females; age range, 6 months-15 years) were treated with TPM for epilepsy. The initial dosage of TPM was 1-3 mg·kg·d. If the effect proved insufficient after 2 weeks, the dosage was increased to 4-9 mg·kg·d. MEASURES AND OUTCOMES: Blood levels of TPM were measured by liquid chromatography-tandem mass spectrometry at 1, 6, 12, and 24 months after levels reached steady state. The efficacy of TPM was evaluated by the reduction in epileptic seizure rate (RR) at the time of blood sampling. Statistical analysis was performed using the Mann-Whitney U test. RESULTS: A positive correlation was seen between blood levels and maintenance dosages, but no correlation was observed between blood levels and RR. Any significant difference was not identified in TPM levels between the effective group (RR ≥50%) and the ineffective group (RR <50%; P = 0.159). In the subgroup of patients who did not use valproic acid, a significant difference in TPM levels was apparent between the effective and ineffective groups (P = 0.029). The optimal range of TPM was advocated 3.5-5.0 µg/mL. The optimal range was set, so that ranges did not overlap between the effective and ineffective groups. No patients experienced any side effects. CONCLUSIONS: Measuring blood levels of TPM based on the classification of concomitant drugs and adjusting the dosage to reach the optimal range were recommended.

Microseizures Induced by Topiramate.

A 22-year-old Japanese male with trisomy 21 was diagnosed with West syndrome at 4 months old. After the suppression of epileptic spasms using adrenocorticotropic hormone therapy, he had complex partial seizures and bilateral frontal epileptic discharges on EEG. Although the introduction of topiramate (TPM) decreased the seizures during wakefulness, frequent episodes of brief eye-opening appeared during sleep while the patient was taking TPM (400 mg/day). EEG showed fast activity at the times of eye-opening. The episodes of eye-opening during sleep and the fast activities disappeared upon TPM discontinuation. This is the first report of TPM-induced microseizures similar to benzodiazepine-induced microseizures.

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 30 µg/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.

Drug-resistant epilepsy and topiramate: Plasma concentration and frequency of epileptic seizures.

Topiramate (TPM) is a second-generation antiepileptic drug (AED), acting on drug-resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (Cp ), and frequency of epileptic seizures. A cross-sectional analytical study was developed with patients aged 18-60 years, for diagnosis of drug-resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty-seven patients were included, 83.8% of the patients presented Cp below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 µg/mL in TPMCp , while the use of inducers predicted a reduction of 2.97 µg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 µg/mL in TPMCp decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with Cp below the therapeutic range, the mean number of seizures per month was greater than those with Cp within the therapeutic range. The prescribed dose and the use of AED inducers influence Cp of TPM, likewise the low Cp of first-line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures.