Plasma Topiramate Concentrations Research Articles

Pharmacokinetics and bioequivalence evaluation of two oral formulations of topiramate tablets in healthy Chinese male volunteers under fasting and fed conditions.

Topiramate is an antiepileptic drug (AED) that is effective in treating various types of epilepsy. This study evaluated the bioequivalence and safety of two topiramate tablets in healthy Chinese subjects under fasting and fed conditions. We designed an open-label, randomized, single-dose, two-period, crossover trial protocol. Two independent trials were conducted, each including 26 volunteers. In the fed trial, subjects were randomly assigned to two groups (1:1 ratio) to receive either 100mg of test formulation or reference formulation of topiramate. After a 21-day washout period, crossover administration was implemented. The fasting trial design was similar to that of the fed trial. Plasma concentrations of topiramate were determined using a validated method (high-performance liquid chromatography-tandem mass spectrometry, HPLC-MS/MS). Pharmacokinetic (PK) parameters such as maximum plasma drug concentration (Cmax), time to reach maximum concentration (Tmax), and the area under the plasma concentration-time curve from time 0 to 72h (AUC0-72) were calculated using a non-compartment model to evaluate the bioequivalence of two formulations. The safety of volunteers was monitored during the entire study. In the fasting trial, 90% confidence intervals (CIs) of geometric mean ratios (GMRs) of the test to reference formulations were 101.26-112.94% for Cmax and 98.50-102.69% for AUC0-72, all within the recognized bioequivalence range of 80.00-125.00%. In the fed trial, 90% CIs of GMRs of the test to reference formulations were 92.08-101.54% for Cmax and 95.81-99.79% for AUC0-72, both were within the bioequivalence range of 80.00-125.00%. Research findings indicated that the two topiramate formulations were bioequivalent and had a favorable safety profile.

Physiologically based pharmacokinetic modeling and simulation of topiramate in populations with renal and hepatic impairment and considerations for drug-drug interactions.

Topiramate (TPM) is a broad-spectrum antiepileptic drug (AED) commonly prescribed for approved and off-label uses. Routine monitoring is suggested for clinical usage of TPM in special population due to its broad side effect profile. Therefore, it is crucial to further explore its pharmacokinetic characteristics. Physio-chemical properties of TPM were initially determined from online database and further optimized while establishing the PBPK model for healthy adults using the PK-Sim software. The model was then extrapolated to patients with renal impairment and patients who were hepatically impaired. A drug-drug interaction (DDI) model was also built to simulate plasma TPM concentrations while concomitantly used with carbamazepine (CBZ). The goodness-of-fit method and average fold error (AFE) method were used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. Almost all of the predicted concentration fell within twofold error range of corresponding observed concentrations. The AFE ratio of predicted to observed values of Cmax and AUC0-inf was all within 0.5 and 2. It is recommended that the doses be reduced to 70%, 50%, and 40% of the healthy adult dose for the chronic kidney disease (CKD) stage 3, stage 4, and stage 5 patients, respectively, and reduced to ~70%, and 35% for the Child-Pugh-B, and Child-Pugh C scored patient with hepatic impairment, respectively. If TPM is co-administered with CBZ, increasing TPM doses to 150%-175% of the monotherapy dose is recommended according to model simulation.

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.

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.

Brain’s compensatory response to drug-induced cognitive impairment

ABSTRACTIntroduction: Topiramate (TPM), a frequently prescribed antiseizure medication, can cause severe cognitive side-effects. Though these side-effects have been studied behaviorally, the underlying neural mechanisms are unknown. In a double-blind, randomized, placebo-controlled, crossover study of TPM’s impact on cognition, nine healthy volunteers completed three study sessions: a no-drug baseline session and two sessions during which they received either TPM or placebo. Electroencephalogram was recorded during each session while subjects performed a working-memory task with three memory-loads.Results: Comparing TPM with baseline we found the following results. (a) TPM administration led to declines in behavioral performance. (b) Fronto-central event-related potentials (ERP) elicited by probe stimuli, representing the primary task network activity, showed strong memory-load modulations at baseline, but the magnitude of these load-dependent modulations was significantly reduced during TPM session, suggesting drug-induced impairments of the primary task network. (c) ERP responses over bilateral fronto-temporal electrodes, which were not load sensitive at baseline, showed significant memory-load modulations after TPM administration, suggesting the drug-related recruitment of additional neural resources. (d) At fronto-central scalp sites, there was significant increase in response amplitude for low memory-load during TPM session compared to baseline, and the amplitude increase was dependent on TPM plasma concentration, suggesting that the primary task network became less efficient under TPM impact. (e) At bilateral fronto-temporal electrodes, there were no ERP differences when comparing low memory-load trials, but TPM administration led to an increase in ERP responses to high load, the magnitude of which was positively correlated with task performance, suggesting that the recruited neural resources were beneficial for task performance. Placebo–TPM comparison yielded similar effects albeit with generally reduced significance and effect sizes.Conclusion: Our findings support the hypothesis that TPM impairs the primary task network by reducing its efficiency, which triggers compensatory recruitment of additional resources to maintain task performance.

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 18-60years, 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 1.0mg/kg/d promoted an increase of 0.68μg/mL in TPMCp , while the use of inducers predicted a reduction of 2.97μg/mL (P<.001). Multiple Poisson regression predicts that an increase of 1.0μg/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.

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.

Influence of caffeine on the protective activity of gabapentin and topiramate in a mouse model of generalized tonic-clonic seizures.

Caffeine may interact with classical antiepileptic drugs (AEDs), reducing their anticonvulsant effects in basic seizure models. The aim of the present study was to ascertain whether intraperitoneal caffeine (acute or chronic for 15 days) could attenuate the anticonvulsant effect of some newer AEDs: gabapentin (GBP) and topiramate (TPM) against electroconvulsions in mice. Maximal electroshock (MES)-induced mouse seizure model was used for the estimation of the anticonvulsant activity of TPM whilst the protective activity of GBP was evaluated in the threshold test for maximal (tonic) convulsions. Adverse effects were evaluated by measurement of long-term memory (the step-through passive avoidance task) and motor coordination (chimney test). Plasma AED concentrations were also measured to determinate any pharmacokinetic contribution to the observed effects. Caffeine (both acute and chronic at 23.1 and 46.2mg/kg) significantly reduced the protective effects of TPM against MES. As regards GBP, caffeine (acutely at 46.2mg/kg and chronically at 23.1 or 46.2mg/kg) significantly diminished the GBP-induced increases in the electroconvulsive threshold. In addition, caffeine did not affect the free plasma concentrations of TPM or GBP. Acute and chronic caffeine (23.1 and 46.2mg/kg) enhanced the impairment of motor coordination in mice pretreated with GBP whilst an opposite effect was observed in TPM injected mice and pretreated with chronic caffeine at 46.2mg/kg. The results indicate that newer AEDs, GBP or TPM behave in the exactly same way as classical antiepileptics in mice challenged with caffeine. This hazardous effect of caffeine is not subject to tolerance.

Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens

Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009–2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch. Our results should be confirmed by large, prospective, blinded, randomized controlled studies in people with epilepsy.

Pharmacokinetic-Pharmacodynamic Modeling of Intravenous and Oral Topiramate and Its Effect on the Symbol-Digit Modalities Test in Adult Healthy Volunteers.

A sequential pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol-Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19-55 years of age), using both oral and a novel stable-labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration-SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings.

Simple and sensitive high performance liquid chromatography method with fluorescence detection for therapeutic drug monitoring of topiramate

A simple, sensitive, accurate, precise and inexpensive HPLC method with fluorescence detection, suitable for routine therapeutic drug monitoring (TDM) of an antiepileptic drug topiramate, was developed and validated. The determination of plasma topiramate concentration was carried out after precolumn derivatization, using 4-chloro-7-nitrobenzofurazan as a fluorescent labeling agent and bendroflumethiazide as an internal standard. The standard calibration curve was linear over the concentration range of 0.01-24 μg/mL (r² > 0.9998). The intra- and inter-day accuracies expressed as bias were from 1.4 to 9.9% and from 1.9 to 10.2%, respectively. The intra- and inter-day precisions were below 7.9% and 2.7%, respectively. The validated method was applied for the measurement of plasma topiramate concentrations in patients with epilepsy. The reported method is appropriate for TDM of topiramate as well as for pharmacokinetic and bioequivalence studies.

Pharmacokinetic-pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers.

The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM). Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions. Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ~100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l(-1) increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions. This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.

The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system

Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin-sensitizing effect of topiramate both in vivo and in vitro. Male C57Bl/6J mice were fed a run-in high-fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high-fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the CNS were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of ATP-sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed in vivo and in cultured muscle cells. In hyperinsulinaemic-euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (∼4 μg·mL(-1) ) improved insulin sensitivity (glucose infusion rate + 58%). Using 2-deoxy-D-[(3) H]glucose, we established that topiramate improved the insulin-mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin-sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither in vivo nor in cultured muscle cells. In conclusion, topiramate stimulates insulin-mediated glucose uptake in vivo through the CNS. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the CNS.

Plasma topiramate concentrations resulting from doses associated with neuroprotection against white matter injury and stroke in two strains of rat pups

Cerebral white matter (WM) injury and stroke are common neuropathological injuries in newborns with congenital heart defects (CHDs) requiring surgery. Previous investigations in Long Evans rat pups subjected to hypoxia-ischemia found that intraperitoneal (i.p.) topiramate (TPM) at 30 mg/kg, but not 50 mg/kg, conferred neuroprotection. In Sprague-Dawley pups, a dose of 30 mg/kg protected against stroke. Concentrations associated with neuroprotective doses were not measured. The aims of this investigation were to determine concentrations associated with neuroprotective doses and to investigate the pharmacokinetics (PK) of i.p. TPM. Concentration-time data following administration of 30 and 50 mg/kg doses were analyzed using nonlinear mixed-effect modeling. Mean predicted steady-state maximum and average concentrations following 30 mg/kg TPM were 31.3 and 16.8 μg/ml in Long Evans and 39.9 and 24.4 μg/ml in Sprague-Dawley pups. Mean predicted steady-state maximum and average concentrations following 50 mg/kg TPM were 52.1 and 28.1 μg/ml in Long Evans and 66.5 and 40.6 μg/ml in Sprague-Dawley pups. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.0470 ml/min and 22.2 ml, respectively, for Long Evans and 0.0325 ml/min and 19.7 ml, respectively, for Sprague-Dawley pups. TPM concentrations associated with neuroprotective doses were determined. Body size and strain were significant covariates on CL/F and V/F. Results provide targets for future neuroprotection studies.

The effect of topiramate plasma concentration on linguistic behavior, verbal recall and working memory

This is the first study of the effect of topiramate on linguistic behavior and verbal recall using a computational linguistics system for automated language and speech analysis to detect and quantify drug-induced changes in speech recorded during discourse‐level tasks. Healthy volunteers were administered a single, 100‐mg oral dose of topiramate in two double-blind, randomized, placebo-controlled, crossover studies. Subjects' topiramate plasma levels ranged from 0.23 to 2.81μg/mL. We found a significant association between topiramate levels and impairment on measures of verbal fluency elicited during a picture description task, correct number of words recalled on a paragraph recall test, and reaction time recorded during a working memory task. Using the tools of clinical pharmacology and computational linguistics, we elucidated the relationship between the determinants of a drug's disposition as reflected in plasma concentrations and their impact on cognitive functioning as reflected in spoken language discourse.

Extended-Release Topiramate (USL255) Exhibits Linear Dose-Proportional Pharmacokinetic Characteristics (P06.128)

Objective: Evaluate dose proportionality, linearity, and tolerability of USL255 at 25, 50, 100, 200, and 400 mg. Background Upsher-Smith Laboratories, Inc. has developed USL255, a novel, once-daily, extended-release topiramate (TPM) formulation. USL255 provides equivalent TPM exposure as compared with immediate-release TPM (TMP-IR) administered twice-daily, yet exhibits an improved pharmacokinetic (PK) profile (eg, lower C max , higher C min , decreased fluctuation index [FI]). Design/Methods: This Phase I, single-dose, open-label, 5-way crossover study evaluated the PK profile of USL255 in healthy subjects. Dose proportionality was determined using a power model approach, where PK parameters were considered proportional if the confidence interval (CI) for the ratios of dose-normalized geometric mean values (R dnm ) or geometric least-squares means (GLSM) were completely contained between 0.8 – 1.25. Linearity was assessed by modeling, and deviation from linearity was tested using the type I F test (α=.05). Tolerability was evaluated through adverse event (AE) monitoring, vital sign measurements, and clinical laboratory evaluations. Results: Total TPM exposure for USL255 was dose proportional and linear from 25 mg – 400 mg. Maximum TPM plasma concentration neared dose-proportionality for the 100 mg – 400 mg doses (R dnm 90%;CI, 1.10 – 1.27). Subsequent analyses compared the dose-normalized C max values of USL255 400 mg to 200 mg, and 200 mg to 100 mg; 90% CIs for these analyses were completely contained between 0.80 – 1.25, indicating that C max changed proportionally with dose. All USL255 doses were well tolerated, and the percentage of subjects who experienced a treatment-emergent AE generally increased with ascending doses. Conclusions: Single-dose USL255 TPM exposure was dose proportional and linear from 25 mg to 400 mg, and C max appeared dose proportional over the higher doses (100 mg – 400 mg), suggesting that USL255 may provide a once-daily alternative to TPM-IR with flexible dosing (25 mg – 400 mg), predictable plasma concentrations, and a favorable tolerability profile. Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Halvorsen has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.Dr. Halvorsen holds stock and/or stock options in Medtronic, Stryker, Elan, Teva, Gilead, and Pfizer. Dr. Lambrecht has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.Dr. Lambrecht holds stock and/or stock options in Medtronic, Inc. Dr. Todd has received personal compensation for activities with Upsher-Smith Laboratories, Inc., as an employee. Dr. Todd holds stock and/or stock options in Pfizer Inc.

A sensitive capillary GC‐MS method for analysis of topiramate from plasma obtained from single‐dose studies

Topiramate (Topamax®) is an antiepileptic medication used as adjunctive and monotherapy in patients with epilepsy and for migraine prophylaxis. A GC-MS assay was developed that was capable of detecting topiramate plasma concentrations following a single rectal or oral dose administration. Topiramate plasma samples were prepared by solid-phase extraction and were quantified by GC-MS analysis. The topiramate standard curves were split from 0.1 to 4 µg/mL and from 4 to 40 µg/mL in order to give a more accurate determination of the topiramate concentration. The accuracy of the standards ranged from 94.6 to 107.3% and the precision (%CV) ranged from 1.0 to 5.3% for both curves at all concentrations. The %CV for quality controls was <7.6%. The assay is both accurate and precise and will be used to complete future pharmacokinetic studies.

Effect of pregnancy on topiramate pharmacokinetics in rabbits

Pregnancy is associated with various physiological changes that may lead to significant alterations in the pharmacokinetic profiles of many drugs. The present study was designed to investigate the potential effects of pregnancy on the pharmacokinetics of topiramate (TPM) in the rabbit model.Nineteen female New Zealand white rabbits (nine pregnant and 10 non-pregnant) were used in this study. Blood samples were collected from the animals just before receiving TPM orally at a dose of 20 mg/kg and then serially for up to 24 h. TPM plasma samples were analysed using a validated tandem mass spectrometric (LC-MS/MS) method.The mean values of TPM pharmacokinetic parameters (t1/2, Tmax, AUC0–∞, and CL/F) were significantly modified in pregnant rabbits as compared with non-pregnant group. Pregnancy significantly (P < 0.05) increased TPM half-life (t1/2), time to attain the maximum plasma concentration (Tmax), and the area under TPM plasma concentration–time curve (AUC0-∞) and decreased the drug’s oral clearance (CL/F) compared with non-pregnancy state in rabbits.The present study demonstrates that pregnancy alters the pharmacokinetics of TPM in rabbits in late gestational period and considerable inter-animal variability was observed. The findings of the present study indicate that TPM CL/F is decreased during late pregnancy in the rabbit model.

A Nonlinear Mixed Effects Modelling Analysis of Topiramate Pharmacokinetics in Patients with Epilepsy

Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment with carbamazepine, valproic acid, benzodiazepines, and risperidone on topiramate pharmacokinetics was evaluated. Additionally, the relationship between topiramate plasma concentration and clinical response was investigated. Volume of distribution of topiramate was 0.518 l/kg. For a typical patient oral clearance was estimated at 1.47 l/h, with interindividual variability of 39.2%. Clearance was 70% higher in patients co-treated with carbamazepine and was found to increase with patient age. Somnolence was the most frequently observed adverse event. Incidence of headache was associated with topiramate plasma concentration. Somnolence, ataxia, tremor, speech disorders and fatigue were associated with adjunctive therapy with carbamazepine, valproic acid, benzodiazepines, risperidone, and clozapine. No association of topiramate plasma concentration with frequency of seizures or patient quality of life was observed. The developed model can be used for Bayesian estimation of pharmacokinetic parameters based on sparse plasma samples and for selection of optimum dosing in routine patient care.