Topiramate Plasma Research Articles

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.

Bioanalytical LC‐MS/MS method validation for plasma determination of topiramate in healthy Indian volunteers

A LC-MS/MS method for plasma topiramate analysis is delineated involving least number of healthy volunteers. Topiramate and amlodipine internal standard (IS) were extracted by simple centrifuge-coupled solid-phase extraction and reverse-phase chromatographic separation was performed on an Ascentis C(18) column. Turbo-spray negative-ion mode multiple-reaction monitoring was selected for mass pair detection at m/z 338.3 --> 78.0 and m/z 407.3 --> 295.5 for analyte and IS respectively. The method showed a dynamic linearity range from 10.4 to 2045.0 ng/mL, lower limit of quantitation achieved at 10.4 ng/mL and finally a mass spectrometric total run time of within 2.5 min for human sample analysis. Bioequivalence was assessed successfully using this fully validated method on 16 fasted Indian male subjects with 25 mg topiramate tablet administration. An appropriate study design describes plasma samples collection up to 216 h post dose in two periods, separated by a 28 day washout period. The challenge of half-life matching for test and reference drug was achieved with 73.43 +/- 9.68 and 73.06 +/- 14.03 h, respectively, and intra-subject coefficient of variation achieved within 11% for AUCs and C(max) evaluated by non-compartmental pharmacokinetic analysis. The results of LCMS topiramate complete method validation supported by pharmacokinetic study have not been published before, and are presented and discussed for the first time in this article.

Serum concentration/dose ratio of topiramate during pregnancy

To study the impact of pregnancy on the serum concentration/dose ratio (C/D-ratio) of topiramate (TPM). Twelve women with epilepsy using TPM during pregnancy, and 15 pregnancies were studied. The main target variable was the C/D-ratio at baseline and during pregnancy. Additional variables were changes in TPM dose, concomitant use of other antiepileptic drugs, seizure frequency, and pregnancy outcome. Clinical and pharmacological data were obtained from the women's medical records. The average C/D-ratios in the second and third trimester were 30% (p = 0.002, n = 11) and 34% (p = 0.001, n = 8) lower than the baseline values, respectively. The interindividual variability was pronounced. Increased seizure frequency was common in pregnant women using TPM, but a correlation to the decline in TPM C/D-ratio could not be established from our data. Dose-corrected serum concentrations of TPM appear to decline gradually throughout pregnancy. The underlying mechanisms are not known. Increased glomerular filtration may play a major role. During pregnancy, therapeutic drug monitoring of TPM may be useful.

Temozolomide treatment does not affect topiramate and oxcarbazepine plasma concentrations in chronically treated patients with brain tumor-related epilepsy

Medical management of brain tumor-related epilepsy is complicated by interactions between antiepileptic and chemotherapeutic drugs. We studied the effect of temozolomide therapy on the disposition of the new antiepileptic drugs topiramate (TPM) or oxcarbazepine (OXC). Fifteen patients chronically treated with TPM or OXC in monotherapy starting a chemotherapeutic treatment with temozolomide were enrolled in the study, of which ten were available for the final analyses. Blood samples were collected before temozolomide treatment (T(0)), at its end (T(7)) and after further 1-3 weeks (T(14)-T(28)). For each patient, more than one treatment cycle was studied. Topiramate and OXC mono-10-hydroxy derivative (MHD) plasma concentrations were determined by hplc coupled with ion spray mass spectrometer (TPM) or ultraviolet (MHD) detection. Mean TPM concentrations were 5.4 +/- 2.4 microg/ml at T(0) vs. 5.5 +/- 2.4 microg/ml at T(7) (n = 14), and 5.4 +/- 2.4 microg/ml at T(0) vs. 5.6 +/- 2.8 microg/ml at T(14)-T(28) (n = 14). Mean MHD concentrations were 16.4 +/- 7.6 microg at T(0) vs. 18.5 +/- 9.0 microg/ml at T(7) (n = 5), and 16.8 +/- 7.0 microg/ml at T(0) vs. 18.0 +/- 8.7 microg/ml at T(14)-T(28) (n = 8) (all comparisons not statistically significant; Student's t-test for paired samples). Temozolomide treatment did not affect TPM plasma concentrations in chronically treated patients. Data for MHD in OXC-treated patients were similar, but, due to the small sample size, results should be interpreted cautiously.These findings confirm that TPM (and possibly OXC) are a reasonable choice of antiepileptic drug in patients with brain tumor-related epilepsy.

Topiramate monotherapy in the treatment of newly or recently diagnosed epilepsy

Background: The efficacy of topiramate (TPM) as an adjunctive treatment for epilepsy has been established in placebo-controlled clinical trials. Clinical trials of antiepileptic monotherapy usually evaluate low and high doses of study drug or compare study drug with another active agent. Objective: This article reviews available evidence for the use of TPM as monotherapy in patients with newly or recently diagnosed epilepsy. Methods: A search of MEDLINE, EMBASE, BIOSIS, SCISEARCH, and the Cochrane Database of Systematic Reviews (all years) for reports of controlled trials of TPM monotherapy in patients with recently diagnosed (within the previous 3 years) epilepsy was conducted in January 2008 using the terms topiramate, epilepsy, newly diagnosed, recently diagnosed, and monotherapy. Identified trials were included in the review if they were published in peer-reviewed journals and enrolled ≥20 patients. Results: Three randomized, double-blind, controlled trials met the criteria for inclusion in the review. In a comparison of TPM 50 and 500 mg/d, the higher dose was associated with significantly greater freedom from seizures at 6 months compared with the lower dose (54% vs 39%, respectively; P = 0.02). The time to first seizure was significantly associated with mean plasma TPM concentrations ( P = 0.015). In a comparison of TPM 50 and 400 mg/d, the time to first seizure was significantly longer with the higher dose compared with the lower dose ( P<0.001, Kaplan-Meier analysis), and the probability of 12-month seizure freedom was significantly higher (76% vs 59%, respectively; P = 0.001). Again, the time to first seizure was significantly associated with mean plasma TPM concentrations ( P = 0.029). In a comparative study of TPM 100 and 200 mg/d, carbamazepine 600 mg/d, and valproate 1250 mg/d, there was no significant difference in rates of 6-month seizure freedom with TPM 100 and 200 mg/d (49% and 44%, respectively), carbamazepine (44%), and valproate (44%). Adverse events in the 3 studies were similar between TPM dose groups, although the incidence generally increased with increasing doses, occurred early in treatment, and decreased with prolonged therapy. In a pooled analysis of the 3 trials, the most commonly occurring adverse events during dose titration were paresthesia (25%), fatigue (16%), dizziness (13%), somnolence (13%), and nausea (10%); the most frequent adverse events during maintenance therapy were headache (20%), decreased appetite (11%), and weight loss (11%). Conclusion: In the 3 studies reviewed, TPM monotherapy was effective and generally well tolerated in patients with newly diagnosed epilepsy.

Determination of plasma topiramate concentration using LC‐MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteers

A rapid, simple and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS/MS) for topiramate analysis in human plasma has been applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a simple liquid extraction of topiramate and prednisone (internal standard) with acetonitrile and separation by HPLC equipped with a Capcell Pak C18 column using acetonitrile-0.1% triethylamine (80:20, v/v) as a mobile phase. Detection was carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(-) and selectivity was achieved by MS/MS analysis, m/z 338.0 --> 77.5 and m/z 357.1 --> 327.2 for topiramate and prednisone, respectively. The method had a total run time of 2.5 min and showed good linearity over a working range of 20-5000 ng/mL in human plasma with a lower limit of quantification of 20 ng/mL. No metabolic compounds were found to interfere with the analysis. The inter-day and intra-day accuracy were in the ranges of 99.24-116.63 and 93.45-108.68%, respectively, and inter-day and intra-day precisions were below 6.24 and 5.25%, respectively. This method was successfully applied for pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 96 h after an oral administration of 100 mg of topiramate in 24 healthy Korean volunteers.

Topiramate and cortical excitability in humans: a study with repetitive transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) delivered at 5 Hz frequency and suprathreshold intensity progressively increases the size of muscle evoked potentials (MEPs) and the duration of the cortical silent period (CSP) in normal subjects. The aim of this study was to evaluate the effects of topiramate (TPM) at different doses on cortical excitability variables tested with rTMS. We tested the facilitation of the MEP size and CSP duration evoked by focal rTMS in eight patients before and after treatment with TPM at different doses for chronic neuropathic pain. In each patient, rTMS (5 Hz frequency-120% resting motor threshold) was applied at baseline and during the TPM induction phase (drug intake schedule: week I 25 mg/day, week II 50 mg/day, week III 75 mg/day, week IV 100 mg/day) and total TPM plasma concentrations were measured. The effects on the MEP size of 5 Hz-rTMS delivered over repeated sessions were tested in eight control subjects. TPM had no effect on the resting motor threshold. Antiepileptic treatment at increasing doses abolished the normal rTMS-induced MEP facilitation. ANOVA showed that this was a dose-related effect. Accordingly, in patients receiving TPM at higher doses (75 and 100 mg) rTMS failed to elicit the MEP facilitation. TPM left the progressive lengthening of the CSP during the rTMS train unchanged. In control subjects, rTMS applied over repeated sessions elicited a constant increase in MEP size. Our results suggest that TPM modulates the excitatory intracortical interneurons probably by altering rTMS-induced synaptic potentiation. These drug-induced effects are related to TPM doses and plasma concentrations. In conclusion, rTMS may be useful for quantifying the effectiveness of antiepileptic drugs and for assessing individual responses to different drugs but acting through similar mechanisms, thus combining functional neurophysiological information and laboratory data.

Topiramate for Co-Occurring Bipolar Disorder and Disruptive Behavior Disorders

Back to table of contents Previous article Next article Letters to the EditorFull AccessTopiramate for Co-Occurring Bipolar Disorder and Disruptive Behavior DisordersDREW H. BARZMAN M.D.MELISSA P. DELBELLO M.D.,DREW H. BARZMAN M.D.Search for more papers by this authorMELISSA P. DELBELLO M.D.Search for more papers by this author,Published Online:1 Aug 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Although studies have suggested that topiramate is helpful in the treatment of bipolar disorder, no study, to our knowledge, has examined its usefulness in treating co-occurring bipolar disorder and disruptive behavior disorders in children and adolescents (1) . The literature on co-occurring bipolar disorder and disruptive behavior disorders is rather limited. In our case study presented here, we defined response with an endpoint Clinical Global Impression (CGI) improvement rating of 1 (“very much improved”) or 2 (“much improved”) for both mania and overall illness (including bipolar disorder and disruptive behavior disorders). Six (67%) out of nine of our hospitalized patients (ages 10 to 14) with bipolar disorder and disruptive behavior disorders responded to adjunctive topiramate with good tolerability. The mean dose was 78 mg/day (range=50–150 mg/day).“Miss A” was a 14-year-old African American girl with conduct disorder, bipolar disorder, and reactive attachment disorder. She had no history of substance abuse. She was arrested for domestic violence and had a history of lying, running away, felony assault, stealing, carrying firearms, truancy, destroying property, and arson. Approximately 2 months prior to being detained in juvenile detention, the patient had discontinued her medications, which included haloperidol, aripiprazole, quetiapine, and glucophage because of weight gain. She subsequently lost approximately 40 pounds. While in juvenile detention, the patient continued to display prominent disruptive behaviors of arguing, physical fighting, destroying property, deceitfulness, oppositionality, and defiance. Besides mood lability, distractibility, and acts of self-harm, there was no evidence of depression or mania. The patient refused mood stabilizers and atypical antipsychotics because of the possibility of weight gain.Doses of topiramate started at 25 mg once in the morning for 5 days and then increased to 25 mg twice daily. After 15 days taking 50 mg/day, the patient’s dose of topiramate was increased to 25 mg in the morning and 50 mg at bedtime. For the next 7 days, she was administered a dose of 75 mg/day and had no behavioral outbursts. She became more cooperative with staff and did not require restraints. The staff noted a significant improvement in her disruptive behaviors as well.Although her mania was much improved, she continued to display some emotional lability and distractibility. Therefore, her disruptive behavior symptoms improved independently and more significantly than her mood-related symptoms. She had CGI improvement ratings of 2 for mania and 1 for overall illness. Despite her reports of poor concentration and transient hyperactivity, there was no evidence for these or other side effects, such as weight gain or difficulties with verbal communication.As illustrated, topiramate monotherapy may be effective in treating disruptive behavior disorders, independent from its therapeutic effect for mania that is possibly related to its efficacy in decreasing impulsivity in binge eating disorder, borderline personality disorder, and pathological gambling disorder in adults. Because of a favorable side effect profile, including possible weight loss, medication compliance may be less of a problem. Further randomized controlled studies of adjunctive and monotherapy topiramate treatment are needed. Future studies should assess aggression as an outcome measure with the Overt Aggression Scale.Cincinnati, OhioReference1. Barzman DH, DelBello MP, Kowatch RA, Warner J, Rofey D, Stanford K, Rappaport K, Daniels JP, Strakowski SM: Adjunctive topiramate in hospitalized pediatric patients with bipolar disorders. J Child Adolesc Psychopharmacol 2005; 15:931–937Google Scholar FiguresReferencesCited byDetailsCited ByTopiramate augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study8 July 2010 | Journal of Psychopharmacology, Vol. 25, No. 5Determination of plasma topiramate concentration using LC-MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteersBiomedical Chromatography, Vol. 22, No. 8Medical Management of Pediatric Mood DisordersPediatric Annals, Vol. 36, No. 9Pharmacotherapy for Child and Adolescent Mood DisordersPsychiatric Annals, Vol. 37, No. 7Effects of TopiramateSTEFAN P. KRUSZEWSKIM.D.,STEVEN G. KLOTZM.D.,1 March 2007 | American Journal of Psychiatry, Vol. 164, No. 3Drs. Barzman and DelBello ReplyDREW H. BARZMAN, M.D.MELISSA P. DelBelloM.D., M.S.,1 March 2007 | American Journal of Psychiatry, Vol. 164, No. 3Current awareness: Pharmacoepidemiology and drug safety1 January 2007 | Pharmacoepidemiology and Drug Safety, Vol. 16, No. 2 Volume 163Issue 8 August, 2006Pages 1451-1452THE AMERICAN JOURNAL OF PSYCHIATRY August 2006 Volume 163 Number 8 Metrics PDF download History Published online 1 August 2006 Published in print 1 August 2006

Topiramate for Co-Occurring Bipolar Disorder and Disruptive Behavior Disorders

Back to table of contents Previous article Next article Letters to the EditorFull AccessTopiramate for Co-Occurring Bipolar Disorder and Disruptive Behavior DisordersDREW H. BARZMAN M.D.MELISSA P. DELBELLO M.D.,DREW H. BARZMAN M.D.Search for more papers by this authorMELISSA P. DELBELLO M.D.Search for more papers by this author,Published Online:1 Aug 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Although studies have suggested that topiramate is helpful in the treatment of bipolar disorder, no study, to our knowledge, has examined its usefulness in treating co-occurring bipolar disorder and disruptive behavior disorders in children and adolescents (1) . The literature on co-occurring bipolar disorder and disruptive behavior disorders is rather limited. In our case study presented here, we defined response with an endpoint Clinical Global Impression (CGI) improvement rating of 1 (“very much improved”) or 2 (“much improved”) for both mania and overall illness (including bipolar disorder and disruptive behavior disorders). Six (67%) out of nine of our hospitalized patients (ages 10 to 14) with bipolar disorder and disruptive behavior disorders responded to adjunctive topiramate with good tolerability. The mean dose was 78 mg/day (range=50–150 mg/day).“Miss A” was a 14-year-old African American girl with conduct disorder, bipolar disorder, and reactive attachment disorder. She had no history of substance abuse. She was arrested for domestic violence and had a history of lying, running away, felony assault, stealing, carrying firearms, truancy, destroying property, and arson. Approximately 2 months prior to being detained in juvenile detention, the patient had discontinued her medications, which included haloperidol, aripiprazole, quetiapine, and glucophage because of weight gain. She subsequently lost approximately 40 pounds. While in juvenile detention, the patient continued to display prominent disruptive behaviors of arguing, physical fighting, destroying property, deceitfulness, oppositionality, and defiance. Besides mood lability, distractibility, and acts of self-harm, there was no evidence of depression or mania. The patient refused mood stabilizers and atypical antipsychotics because of the possibility of weight gain.Doses of topiramate started at 25 mg once in the morning for 5 days and then increased to 25 mg twice daily. After 15 days taking 50 mg/day, the patient’s dose of topiramate was increased to 25 mg in the morning and 50 mg at bedtime. For the next 7 days, she was administered a dose of 75 mg/day and had no behavioral outbursts. She became more cooperative with staff and did not require restraints. The staff noted a significant improvement in her disruptive behaviors as well.Although her mania was much improved, she continued to display some emotional lability and distractibility. Therefore, her disruptive behavior symptoms improved independently and more significantly than her mood-related symptoms. She had CGI improvement ratings of 2 for mania and 1 for overall illness. Despite her reports of poor concentration and transient hyperactivity, there was no evidence for these or other side effects, such as weight gain or difficulties with verbal communication.As illustrated, topiramate monotherapy may be effective in treating disruptive behavior disorders, independent from its therapeutic effect for mania that is possibly related to its efficacy in decreasing impulsivity in binge eating disorder, borderline personality disorder, and pathological gambling disorder in adults. Because of a favorable side effect profile, including possible weight loss, medication compliance may be less of a problem. Further randomized controlled studies of adjunctive and monotherapy topiramate treatment are needed. Future studies should assess aggression as an outcome measure with the Overt Aggression Scale.Cincinnati, OhioReference1. Barzman DH, DelBello MP, Kowatch RA, Warner J, Rofey D, Stanford K, Rappaport K, Daniels JP, Strakowski SM: Adjunctive topiramate in hospitalized pediatric patients with bipolar disorders. J Child Adolesc Psychopharmacol 2005; 15:931–937Google Scholar FiguresReferencesCited byDetailsCited byTopiramate augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study8 July 2010 | Journal of Psychopharmacology, Vol. 25, No. 5Determination of plasma topiramate concentration using LC-MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteersBiomedical Chromatography, Vol. 22, No. 8Medical Management of Pediatric Mood DisordersPediatric Annals, Vol. 36, No. 9Pharmacotherapy for Child and Adolescent Mood DisordersPsychiatric Annals, Vol. 37, No. 7Effects of TopiramateSTEFAN P. KRUSZEWSKIM.D.,STEVEN G. KLOTZM.D.,1 March 2007 | American Journal of Psychiatry, Vol. 164, No. 3Drs. Barzman and DelBello ReplyDREW H. BARZMAN, M.D.MELISSA P. DelBelloM.D., M.S.,1 March 2007 | American Journal of Psychiatry, Vol. 164, No. 3Current awareness: Pharmacoepidemiology and drug safety1 January 2007 | Pharmacoepidemiology and Drug Safety, Vol. 16, No. 2 Volume 163Issue 8 August, 2006Pages 1451-1452THE AMERICAN JOURNAL OF PSYCHIATRY August 2006 Volume 163 Number 8 Metrics PDF download History Published online 1 August 2006 Published in print 1 August 2006

Topiramate Pharmacokinetics in Children with Epilepsy Aged from 6 Months to 4 Years

To study the pharmacokinetics of topiramate (TPM) at steady state in children younger than 4 years comedicated with other antiepileptic drugs (AEDs). Twenty-two children aged 6 months to 4 years with pharmacoresistant partial or generalized epilepsy were enrolled in an open-label prospective study. Children were assigned to different groups according to comedication with enzyme-inducing AEDs (n = 8), valproic acid (VPA) (n = 6), or other AEDs not known to affect drug metabolism (neutral AEDs, n = 7). One child was receiving treatment with both enzyme-inducing AEDs and VPA. After dose titration, blood samples were collected at steady state just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning dose of TPM. Pharmacokinetic parameters were determined by a noncompartmental method. TPM apparent oral clearance (CL/F) was significantly higher in children taking enzyme-inducing AEDs (85.4 +/- 34.0 ml/h/kg) than in those receiving VPA (49.6 +/- 13.6 ml/h/kg) or neutral AEDs (46.5 +/- 12.8 ml/h/kg). Conversely, dose-normalized areas under the plasma TPM concentration curves (0-12 h) were significantly lower in enzyme-induced patients than in patients receiving VPA or other AEDs. Compared with children not receiving enzyme inducers, children younger than 4 years who receive concomitant enzyme-inducing AEDs need higher doses (milligrams per kilogram) to achieve comparable plasma TPM concentrations.

Age and antiepileptic drugs influence topiramate plasma levels in children

The influence of age and comedication on the dose-to-level ratio of topiramate was examined in 91 children with epilepsy treated with topiramate. The topiramate dosing and plasma concentrations, as well as those of their concomitant antiepileptic drugs were examined retrospectively. The dose-to-level ratio was used as a measure of clearance and was calculated as the weight-normalized topiramate dose (mg/kg/day) divided by the steady-state trough plasma drug level in the child. The children were classified in age groups and treatment groups; topiramate was administered with an enzyme inducer (n = 32), with a nonenzyme inducer (n = 49), or as monotherapy (n = 10). The topiramate clearance in children aged 0-8 years compared with those aged 9-17 years was more than twofold higher if treated with an enzyme-inducing antiepileptic drug and 1.5-fold higher if treated with a nonenzyme inducer. Children receiving enzyme inducers had a more than twofold higher clearance compared with those who did not. Within all age groups, significant differences in topiramate clearance were observed between those receiving enzyme inducers and those receiving nonenzyme inducers or monotherapy. Thus younger age and concomitant enzyme inducers, both acting independently, significantly increased the clearance of topiramate in children. This effect has to be considered to optimize treatment in the individual patient.

The plasma pharmacokinetics and cerebral spinal fluid penetration of intravenous topiramate in newborn pigs.

Pre-clinical studies suggest that the anticonvulsant topiramate confers neurologic protection against ischemia. An intravenous formulation of topiramate has been developed for administration during conditions such as hypoxia-ischemia when enteral absorption may be unpredictable. The plasma pharmacokinetics, cerebrospinal fluid (CSF) penetration and pharmacodynamics of intravenous topiramate were studied in an established piglet model of hypoxia-ischemia. The plasma pharmacokinetics of topiramate were studied in a group of chronically instrumented conscious piglets (n = 8), and in a group of piglets following an episode of hypoxia-ischemia (n = 8). These groups were divided into equal dose cohorts in which two doses of intravenously administered topiramate, 5 and 40 mg/kg, were studied. The animals' heart rate, arterial pressure and EEG were monitored. Plasma for topiramate concentration was sampled for up to 26 h. A single CSF topiramate concentration was determined 1 h following drug administration. Topiramate was quantified using a specific LC/MS assay. The animals tolerated intravenous topiramate well, with no significant changes in physiologic and neurologic parameters. Plasma topiramate concentrations following an intravenous dose were best described by a bi-exponential equation, with a mean clearance of 39+/-18 ml/h/kg, and a terminal half-life of 14.3 (range 7.5-48.1) h. A dose of 5 mg/kg was sufficient to maintain plasma drug concentrations greater than 10 micro M for 24 h. CSF topiramate concentration at 1 h was 12+/-1 micro M and 109+/-26 micro M at the 5 and 40 mg/kg doses, respectively. Topiramate administered intravenously was well tolerated. Slow clearance of the drug allowed for maintenance of potential neuroprotective concentrations following a single dose of drug for 24 h. High drug penetration into the CSF is an ideal pharmacologic characteristic of any potential neuroprotective agent. The pharmacokinetic profile of intravenously administered topiramate, including its penetration into the CSF, appears to achieve this goal.

Plasma topiramate concentrations influenced by dosage

Plasma topiramate concentrations influenced by dosage

Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response.

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59, P < 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73, P < 0.0001). In particular, CL/F values in children aged less than 10 years (112 +/- 82 mL/kg/h, mean +/- SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 +/- 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 +/- 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 +/- 2.2 micrograms/mL, n = 30) and those having no clinical improvement (5.2 +/- 2.2 micrograms/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.

Topiramate Therapeutic Monitoring in Patients With Epilepsy: Effect of Concomitant Antiepileptic Drugs

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.

A study of topiramate pharmacokinetics and tolerability in children with epilepsy

The pharmacokinetic and safety profile of topiramate as adjunctive therapy was assessed in pediatric patients with epilepsy in an open-label, 4-week, single-center study. Six children from each of the following age groups were enrolled: 4-7 years, 8-11 years, and 12-17 years. Patients received topiramate 1 mg/kg/day for 1 week, with subsequent progressive weekly increases in dosage to 3, 6, and then 9 mg/kg/day or 800 mg/day, whichever was less. Topiramate oral plasma clearance (CL/F) was independent of dose, and steady-state plasma concentrations increased in proportion to dose. Weight-normalized topiramate CL/F was higher ( P = 0.003) in pediatric patients receiving enzyme-inducing concomitant antiepileptic drugs (AEDs) (mean = 70.1 mL/minute/70 kg) than in those not receiving enzyme-inducing AEDs (mean = 33.1 mL/minute/kg). Topiramate CL/F in children was approximately 50% greater than that observed in adults regardless of the type of concomitant AED therapy. Thus steady-state plasma topiramate concentrations for the same mg/kg dose will be approximately 33% lower in pediatric patients than in adult patients. The most frequently reported treatment-emergent adverse events considered related to topiramate therapy included anorexia, fatigue, and nervousness, and no patient discontinued therapy. This study indicates that, in children 4-17 years of age, topiramate has linear pharmacokinetics, 50% higher clearance than in adults, and is generally well tolerated.

Topiramate: a new antiepileptic drug.

To review proposed mechanisms of action, clinical pharmacology, efficacy, safety, and tolerability of the antiepileptic drug (AED) topiramate. All available data from the clinical development program--published and unpublished data (provided by investigators or the RW Johnson Pharmaceutical Research Institute)--were analyzed, with emphasis on the results of double-blind, placebo-controlled trials. Data from open-label studies provided information about long-term efficacy and tolerability. Topiramate is highly effective in the control of previously therapy-resistant partial seizures, with or without secondary generalization. In the refractory adult patient population enrolled in controlled clinical trials, seizures were reduced by 50% or more in 27-47% of patients compared with 0-18% in placebo-treated patients and by 75% or more in 9-36% of the patients compared with 0-9% of those receiving placebo. The most common adverse effects involve the central nervous system and are mild to moderate in nature. Adverse effects include somnolence, fatigue, psychomotor slowing, and concentration problems. The currently recommended dosing is lower and titration slower than schedules used in the clinical trials; this may improve the tolerability of topiramate. Topiramate has few interactions with currently available AEDs, but phenytoin concentrations increased in some patients. Topiramate can be used initially as adjunctive therapy. Plasma topiramate concentrations are reduced substantially when used with enzyme-inducing AEDs. Open-label data and a single double-blind trial suggest that topiramate monotherapy may be effective. Open-label data also indicate that topiramate may be effective in generalized seizures of nonfocal origin, including those associated with Lennox-Gastaut syndrome. The robust clinical effects of topiramate expand the therapeutic options for patients with epilepsy. Controlled clinical trials are needed to verify initial observations that topiramate may be effective against a broad spectrum of seizure types and to directly compare efficacy and tolerability with other new and standard AEDs.

Topiramate

Clinical evidence is emerging that topiramate (TPM) may be effective in pediatric epilepsies. Topiramate pharmacokinetics appear to be linear in children when administered in dosages up to 9 mg/kg/d. Mean oral clearance is 44% to 54% higher in children when compared with historical data from adults; steady-state plasma TPM concentrations for the same mg/kg dose are expected to be 33% lower in children. While double-blind, placebo-controlled trials of adjunctive TPM therapy in Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures, and refractory partial-onset seizures in children are ongoing, preliminary results of pilot studies and the open-label extension phases of these double-blind studies suggest TPM may be effective as adjunctive therapy in a broad range of seizure disorders. In the open-label extension phase of a double-blind trial, the proportion of patients with Lennox-Gastaut syndrome experiencing 50% or greater reduction in seizures was 47%. Likewise, seizures were reduced 50% or more with TPM adjunctive therapy in 64% of children with partial-onset seizures and in 67% of patients with primary generalized tonic-clonic seizures treated with open-label during the extension phase of two separate double-blind studies. Preliminary experience suggests that TPM monotherapy can be successfully substituted for another antiepileptic drug in some children. The results of the well-controlled trials are needed to confirm these preliminary observations of TPM effectiveness in pediatric epilepsies.

Drug interaction profile of topiramate.

In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cytochrome P450 isoforms show an effect of TPM only on the CYP2Cmeph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.

Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages

We conducted a randomized double-blind comparison of three doses of the novel antiepileptic drug (AED) topiramate (200, 400, and 600 mg/day) and placebo as adjunctive therapy in patients with refractory partial onset epilepsy receiving one or two other AEDs at therapeutic concentrations. A total of 181 patients completed the 12-week baseline phase and were randomized to double-blind therapy. Median percent reductions from baseline in average monthly seizure rate, the principal efficacy evaluation, were 13% for placebo, 30% for topiramate 200 mg/day, 48% for topiramate 400 mg/day, and 45% for topiramate 600 mg/day. For the seizure rate comparison of active drug to placebo p values were: topiramate 200 mg/day, p = 0.051; topiramate 400 mg/day, p = 0.007; topiramate 600 mg/day, p < 0.001. Percent responders ( > or = 50% reduction in seizure rates) were 18% for placebo, 27% for topiramate 200 mg/day, 47% for topiramate 400 mg/day (p = 0.013), and 46% for topiramate 600 mg/day (p = 0.027). A significant (p = 0.003) reduction in secondarily generalized seizures compared with placebo treatment was also documented with topiramate. Topiramate plasma concentrations were closely related to dosage, and there were no significant interactions between topiramate and other AEDs. The minimal effective dose of topiramate in this study population was approximately 200 mg/day. Mild or moderate CNS symptoms were the primary treatment-emergent adverse events, but treatment-limiting adverse events occurred in only 9% of patients given topiramate compared with 7% given placebo. Results of this initial well-controlled study in patients indicate that topiramate is a very promising new AED.