Postmortem biochemical investigation results in situations of fatal mechanical compression of the neck region.

Biochemical investigations performed in cases of mechanical asphyxia have provided diverging information over time. The purpose of the study presented herein was threefold: to investigate the postmortem stability of a series of molecules (thyroglobulin, iodothyronines, calcitonin, and parathyroid hormone) in blood after death, to determine the same molecules in a series of cases of suicidal hangings for which antemortem serum samples were available, and to measure the same molecules in postmortem serum obtained from different sampling sites thereby evaluating the distribution of these molecules in the specific samples. Preliminary results indicated postmortem stability of thyroglobulin, calcitonin, and parathyroid hormone levels, decreasing total and free T4 levels, and increasing total and free T3 concentrations. Our findings also showed that antemortem mechanical force applied to the neck region (hanging cases) may be accompanied by increased thyroglobulin in peripheral (femoral) blood, though a certain number of cases with nonincreased thyroglobulin levels may be observed. Lastly, our results revealed that hanging, manual, and ligature strangulation cases may be accompanied by increased thyroglobulin, total T3, and free T3 values in postmortem serum specimens obtained from blood sampled at different sampling sites, even in the absence of microscopically identified thyroid gland tissue damage. Such increases are more constant and important in arterial and venous blood samples obtained from sampling sites located in close vicinity of the thyroid gland.

Copeptin in acute coronary syndromes and heart failure management: State of the art and future directions.

Over the past two decades, the use of multiple biomarkers has changed cardiovascular disease management. Recently, several trials have assessed the diagnostic and prognostic performances of copeptin, especially in patients with heart failure or acute coronary syndromes. Primary results are interesting, with copeptin looking promising for: the management of patients who present at emergency departments early after chest pain onset and the risk stratification of patients with heart failure. The purpose of this article is to review the data on the place of copeptin in the management of patients with chest pain or heart failure.

Single-centred experience with levosimendan in paediatric decompensated dilated cardiomyopathy.

BACKGROUND: Children with dilated cardiomyopathy in advanced heart failure may spend a long time awaiting heart transplantation. Consequently, mechanical circulatory support is sometimes required as a bridge to transplantation. Levosimendan, a positive inotropic agent, has been reported to be safe and efficient for the treatment of paediatric heart failure. AIMS: To report our experience with levosimendan in children with decompensated dilated cardiomyopathy. METHODS: Paediatric patients with dilated cardiomyopathy on the transplant waiting list and with criteria for mechanical support were included in this single-centred retrospective study. Each patient received at least one 24-hour infusion of levosimendan before mechanical circulatory support was considered. Biological and echocardiographic data were analysed. RESULTS: Six patients were included over a 24-month period. The median age was 25.5months (7.7-34.2months); 82 infusions were performed. Median B-type natriuretic peptide concentration decreased significantly between days 0 and 2 (2443ng/L [1458-3819ng/L] vs 1358ng/L [1025-2534ng/L]; P=0.003). While only a trend was noted in left ventricular ejection fraction improvement (P=0.054 by Simpson's method and P=0.068 by the Teicholz method), the subaortic velocity time integral rose significantly between days 0 and 8 (12.8cm/s [10-14.5cm/s] vs 15.3cm/s [14.3-16.9cm/s]; P=0.041). CONCLUSIONS: Levosimendan seems to improve haemodynamics in children with decompensated dilated cardiomyopathy; repeated infusions may delay the need for mechanical circulatory support while awaiting heart transplantation. This therapeutic agent should be systematically considered in this setting, in addition to conventional inotropic drugs.

Simultaneous analysis of 22 antiepileptic drugs in postmortem blood, serum and plasma using LC-MS-MS with a focus on their role in forensic cases.

In recent years, there has been a growth in reports of antiepileptic drugs (AEDs) being misused on their own or in combination with other drugs of abuse in a variety of toxicological case types such as drug abuse, suicide, overdose and drug facilitated crime. To our knowledge, there are no simultaneous quantification methods for the analysis of the most commonly encountered AEDs in postmortem whole blood and clinical plasma/serum samples at the same time. A simple, accurate and cost-effective liquid chromatography-tandem mass spectrometric (LC-MS-MS) method has been developed and validated for the simultaneous quantification of carbamazepine (CBZ) and its metabolite CBZ-10,11-epoxide, eslicarbazepine acetate, oxcarbazepine and S-licarbazepine as a metabolite, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, phenobarbital, phenytoin and its metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin, retigabine (ezogabine) and its metabolite N-acetyl retigabine, rufinamide, stiripentol, topiramate, tiagabine, valproic acid, vigabatrin and zonisamide in postmortem whole blood, serum and plasma which would be suitable for routine forensic toxicological analysis and therapeutic drug monitoring. All AEDs were detected and quantified within 17 min without endogenous interferences. The correlation coefficient (R(2)) was >0.995 for all AEDs with accuracy ranging from 90 to 113% and precision <13% for all analytes. The recovery ranged from 70 to 98%. No carryover was observed in a blank control injected after the highest standard and the matrix effect was acceptable and ranged from 90 to 120%. The method has been successfully verified using authentic case samples that had previously been quantified using different methods.

Analyte and internal standard cross signal contributions and their impact on quantitation in LC-MS based bioanalysis.

Cross signal contributions between an analyte and its internal standard (IS) are very common due to impurities in reference standards and/or isotopic interferences. Despite the general awareness of this issue, how exactly they affect quantitation in LC-MS based bioanalysis has not been systematically evaluated. In this research, such evaluations were performed first by simulations and then by experiments using a typical bioanalytical method for tiagabine over the concentration range of 1-1000 ng/mL in human EDTA K(3) plasma. The results demonstrate that when an analyte contributes to IS signal, linearity and accuracy can be affected with low IS concentration. Thus, minimum IS concentrations have been obtained for different combinations of concentration range, percentage of cross contribution, and weighting factor. Moreover, while impurity in analyte reference standard is a factor in cross signal contribution, significant systematic errors could exist in the results of unknown samples even though the results of calibration standards and quality controls are acceptable. How these systematic errors would affect stability evaluation, method transfer, and cross validation has also been discussed and measures to reduce their impact are proposed. On the other hand, the signal contribution from an IS to the analyte causes shifting of a calibration curve, i.e. increase of intercept, and theoretically, the accuracy is not affected. The simulation results are well supported by experimental results. For example, good inter-run (between-run) accuracy (bias: -2.70 to 5.35%) and precision (CV: 2.07-10.50%) were obtained when runs were extracted with an IS solution containing 1-fold of the lower limit of quantitation.

Increase in tiagabine serum concentration with coadministration of gemfibrozil.

OBJECTIVE: To report a case of possible acute tiagabine toxicity secondary to administration of gemfibrozil. CASE SUMMARY: A 39-year-old male was taking tiagabine 16 mg orally 3 times per day and carbamazepine 500 mg orally twice per day for complex partial seizures secondary to mesial temporal sclerosis. He was found to have type IV hypertriglyceridemia and was prescribed gemfibrozil. Because he reported severe confusion and altered consciousness shortly after a single 600-mg dose of gemfibrozil, he was admitted for controlled challenge with that drug. A single 300-mg dose of gemfibrozil resulted in lightheadedness and led to a 59% and 75% increase in total tiagabine serum concentrations at 2 and 5 hours, respectively, without significant change in baseline carbamazepine concentrations. DISCUSSION: This is the first report of an interaction between the widely used antihyperlipidemic drug gemfibrozil and tiagabine. Since tiagabine, which was originally developed as an antiepileptic medication, is now being used widely for a variety of other indications such as anxiety and depression, there is an increased risk for clinically significant interactions with gemfibrozil. CONCLUSIONS: Increased total and unbound tiagabine concentrations following a single 300-mg dose of gemfibrozil and reproduction of clinical symptoms with gemfibrozil rechallenge suggests the toxicity our patient experienced was due to a pharmacokinetic drug interaction. Use of the Horn Drug Interaction Probability Scale showed a probable interaction between gemfibrozil and tiagabine.

Seizures in a pediatric patient with a tiagabine overdose.

INTRODUCTION: Tiagabine (TGB) is a novel antiepileptic that decreases GABA uptake. The literature contains one report of an adult with epilepsy who ingested up to 1 gram of TGB and developed status epilepticus. We reported on a pediatric patient who ingested significantly less TGB but still developed tonic-clonic seizures. CASE REPORT: A previously healthy, 13 kg, two-year-old girl developed generalized tonic-clonic seizure activity at home approximately 1 hour after ingesting 90 mg of her grandmother's TGB (forty five 2 mg tablets). At the hospital she had two 5 minute seizures at 1.5 and 3.5 hours post ingestion. Her serum TGB levels were 530 and 130 ng/ml approximately 5 and 11 hours post-ingestion (5-70 ng/ml trough levels with most probable range for seizure control). She was discharged 27 hours post ingestion, and she was in good condition. CONCLUSION: An overdose of TGB, a novel anti-epileptic, can cause convulsive seizures.

Saccadic eye velocity after selective GABAergic treatment with tiagabine in healthy volunteers.

BACKGROUND: Saccadic eye velocity (SEV) has been shown to be a reliable neurophysiological tool for the assessment of gamma-aminobutyric acid GABA(A) receptor sensitivity. Administration of benzodiazepines targeting the GABA(A) receptor decreases SEV in healthy volunteers. Tiagabine is a new antiepileptic drug which acts via selective blockade of GABA reuptake. Therefore, we examined the effects of tiagabine on saccade parameters. METHODS: SEV was analyzed in 8 healthy volunteers before and after 7 days of tiagabine treatment. Subjects received tiagabine in a daily dose of 15 mg. Saccades were measured using a noninvasive infrared oculographic device. Amplitude, latency, and SEV were analyzed as a function of treatment and target eccentricity. RESULTS: SEV and saccade latency increased with target amplitude. Treatment with tiagabine had no significant effect on SEV and saccade amplitude. A trend was found for increased latencies after tiagabine. CONCLUSION: In contrast to findings with benzodiazepines, tiagabine treatment had no impact on SEV in healthy volunteers. The subchronic tolerance effects or the different site of action on the GABA(A)/BZD receptor complex may account for this deviating profile.

Nipecotic acid: systemic availability and brain delivery after nasal administration of nipecotic acid and n-butyl nipecotate to rats.

PURPOSE: The purpose of this research was to characterize nipecotic acid pharmacokinetics in blood and brain after intravenous (i.v.) and nasal administration of nipecotic acid and its n-butyl ester. METHODS: Nipecotic acid and its n-butyl ester were administered to rats i.v. and intranasally (n = 5 rats/drug per route), and nipecotic acid pharmacokinetics in blood were characterized. Nipecotic acid concentration-time profiles were determined in blood by noncompartmental and compartmental methods. Nipecotic acid was also dosed i.v. and its n-butyl ester was dosed by nasal and i.v. routes, and brain levels of nipecotic acid over the subsequent 4 h (n = 5 rats/time point per route) were assessed. RESULTS: The absolute systemic availability of nipecotic acid after nasal dosing was 14%. After i.v. and nasal dosing of the n-butyl ester, nipecotic acid systemic availability was 97% and 92%, respectively. Both i.v. and nasal administration of the n-butyl ester resulted in a significantly longer terminal half-life and larger mean resident time and volume of distribution for nipecotic acid than was observed after an i.v. nipecotic acid dose. Total brain exposure to nipecotic acid was not significantly different after nasal and i.v. dosing of the n-butyl ester. However, the brain/blood nipecotic acid ratio declined significantly with time after i.v. and nasal dosing of the ester prodrug. Nipecotic acid was not detectable in brain after i.v. dosing of nipecotic acid. CONCLUSIONS: The use of an ester formulation was crucial to delivering nipecotic acid to the brain. Preliminary evidence strongly suggests ester hydrolysis is rate limiting to nipecotic acid brain delivery. Once nipeoctic acid was formed, it displayed tissue trapping in brain. Parenteral dosing of nipecotic acid esters is unnecessary for systemic or brain delivery of nipecotic acid and possibly other CNS active zwitterion esters.

The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus).

PURPOSE: Tiagabine is a unique antiepileptic drug with a novel mechanism of action. Whilst some limited data are available as to the peripheral blood pharmacokinetics of tiagabine, data regarding the kinetics of tiagabine in the central brain compartment are very limited. We therefore sought to investigate serum, cerebrospinal fluid (CSF) and frontal cortex and hippocampal extracellular fluid (ECF) kinetic inter-relationship of tiagabine in a freely moving rat model. METHODS: Adult male rats were implanted with either a jugular vein catheter and a cisterna magna catheter for blood and CSF sampling, respectively, or a blood catheter and a microdialysis probe in the hippocampus and frontal cortex (for ECF sampling). Tiagabine was administered intraperitoneal (i.p.) at 20 or 40 mg/kg and blood, CSF and ECF were collected at timed intervals for the measurement of tiagabine concentrations by high performance liquid chromatography. RESULTS: Tiagabine concentrations in blood and CSF rose linearly and dose-dependently and time to maximum concentration (Tmax) was 15 and 29 min, respectively. Mean CSF/serum tiagabine concentration ratios (range, 0.008-0.01) were much smaller than the mean free/total tiagabine concentration ratios in serum (0.045 +/- 0.003). Entry of tiagabine into brain ECF (frontal cortex and hippocampus) was rapid with Tmax values of 31-46 min. Distribution of tiagabine in brain was not brain region specific with values in the frontal cortex and hippocampus being indistinguishable. Whilst elimination from CSF was comparable to that of serum, half-life (t(1/2)) values in ECF were three times longer. CONCLUSIONS: Tiagabine is associated with linear kinetic characteristics and with rapid brain penetration. However, CSF concentrations are not reflective of free non-protein-bound concentrations in serum. The observation that tiagabine elimination from the brain is threefold slower than that seen in blood, may explain as to the relatively long duration of action of tiagabine.

Pharmacodynamic analysis of the anticonvulsant effects of tiagabine and lamotrigine in combination in the rat.

PURPOSE: The pharmacodynamic interaction between the antiepileptic drugs (AEDs) tiagabine (TGB) and lamotrigine (LTG) was characterized on basis of the anticonvulsant effect in the cortical stimulation model in the rat. METHODS: The study was conducted according to a partial crossover design, in which both drugs were infused intravenously to achieve linear increases in the plasma concentration in the absence and presence of a steady-state concentration of the second drug. The anticonvulsant effect was quantified by counts of four specific ictal signs (eye closure, forelimb clonus, forelimb extension, and head jerk). A potential pharmacokinetic interaction was accounted for by determination of total plasma concentrations of both drugs. RESULTS: When given separately, both TGB and LTG suppressed all ictal signs in a concentration-dependent manner, with the exception of eye closure, which was not suppressed by LTG. The interaction between both drugs was estimated by response surface analysis by using the difference between the observed effect and the additive effect to identify synergistic drug concentrations. This analysis showed that the pharmacodynamic interaction between TGB and LTG is synergistic for the ictal signs of eye closure and head jerk. In contrast, the interaction was additive for the ictal signs of forelimb clonus and forelimb tonus. CONCLUSIONS: This study demonstrates the usefulness of ictal-component analysis for studying the pharmacodynamic interaction between AEDs. Quantification of both the nature and the magnitude of the interaction between TGB and LTG led to the identification of two ictal signs that were synergistically suppressed. This approach offers a theoretical basis to identify and optimize drug combinations that are useful to treat refractory epilepsy.

Assay for nipecotic acid in small blood samples by gas chromatography-mass spectroscopy.

An analytical method for nipecotic acid quantification in rat blood was developed utilizing a stable isotope internal standard and capillary gas chromatography-mass spectroscopy. The method involves a solid phase extraction step followed by a two-step derivatization. The analytes are separated by capillary gas chromatography and detected by selected ion monitoring of their base peaks at 180 and 185 m/z, respectively. The assay has a limit of detection (LOD) of 10 ng/ml and a limit of quantification of 26 ng/ml in 200 microl of rat whole blood. The linear range of the assay covers from 26 to 6500 ng/ml (r2=0.9996, n=9). The coefficient of variation was less than 10% at concentrations of 50, 1000 and 5000 ng/ml. The assay was used to characterize the pharmacokinetics of R-(-)-nipecotic acid in a rat. R-(-)-nipecotic acid clearance was 4.2 ml/min, its half-life was 1.5h and its volume of distribution at steady state was 325 ml.

Interactions of tiagabine with some antiepileptics in the maximal electroshock in mice.

Tiagabine (TGB), a new potent gamma-aminobutyric acid (GABA) uptake inhibitor, is widely applied in adjunctive treatment of partial seizures in humans. Although, polytherapy is not an initial method of epilepsy treatment, clinicians often combine TGB with other antiepileptics as add-on therapy for assuring the anticonvulsant protection in patients with refractory seizures. To evaluate the character of pharmacological interactions between TGB and some antiepileptics, the isobolographic analysis was used as a suitable method for determining the exact types of interactions. Determination of an influence of TGB on the protective effects of diphenylhydantoin (DPH), carbamazepine (CBZ), valproate (VPA), phenobarbital (PB), lamotrigine (LTG), topiramate (TPM), and felbamate (FBM) in maximal electroshock-induced seizures was essential for this study. To exclude or confirm a pharmacokinetic character of observed interactions, the free plasma and brain concentrations of antiepileptic drugs (AEDs) studied were evaluated by using the immunofluorescence or high-pressure liquid chromatography (HPLC).TGB (up to 2.5 mg/kg) remained ineffective upon the electroconvulsive threshold, whilst the drug in doses of 5 and 10 mg/kg significantly raised the electroconvulsive threshold in mice. According to the isobolography, TGB appears to act synergistically with VPA. The remaining combinations tested exerted additive interactions. A pharmacokinetic character of interaction between TGB and VPA was evidently corroborated either in plasma or brains. Moreover, TGB significantly reduced the plasma and brain concentrations of DPH; however, pharmacokinetic events were not accompanied by any changes in anticonvulsant activity of the latter. Finally, the isobolographic analysis revealed that combinations of TGB with VPA exerted synergistic (supra-additive) interaction resulting from a pharmacokinetic interaction.

Tiagabine adjunctive therapy in children with refractory epilepsy: a single-blind dose escalating study.

Tiagabine, a specific gamma-aminobutyric acid-uptake inhibitor, has been shown to be reasonably well tolerated and efficacious as adjunctive treatment for partial seizures in adults and is now being investigated in children. This 4-month, single-blind study evaluated the tolerability, safety and preliminary efficacy of ascending doses (0.25-1.5 mg/kg/day) of tiagabine add-on therapy in 52 children over the age of 2 years with different syndromes of refractory epilepsy. Adverse events, mostly mild to moderate, were reported by 39% of children during the single-blind placebo period and by 83% of children during tiagabine treatment. The events predominantly affected the nervous system with asthenia (19%), nervousness (19%), dizziness (17%) and somnolence (17%) being the most common. Only three children (6%) withdrew because of adverse events. Tiagabine appeared to reduce seizures more in localisation-related epilepsy syndromes than in generalised epilepsy syndromes. Twenty-three patients with localisation-related epilepsy syndromes were included and 17 of these patients entered the fourth dosing period. The 17 patients had a median reduction of seizure rate in the fourth month of treatment of 33% compared with baseline. In comparison, 13 of 22 children with seven different generalised epilepsy syndromes entered the fourth dosing period with a median change of seizure rate of 0%. Two patients experienced single episodes of status epilepticus during treatment; both cases resolved. Tiagabine showed efficacy mainly in localisation-related syndromes and was well tolerated by most children in a group of very refractory patients and warrants further study in children with epilepsy.

Population pharmacokinetics of tiagabine in epileptic patients on monotherapy.

A retrospective study of the population pharmacokinetics of tiagabine was performed from sparse data collected in a multicentre clinical trial in patients with newly diagnosed partial seizures. The purpose was to estimate the inter patient variability and to study the influence of various demographic, environmental and pathophysiological parameters on the pharmacokinetics of tiagabine in patients on monotherapy. A total of 593 plasma concentrations from 130 patients dosed with 2.5, 5, 7.5 or 10 mg tiagabine twice daily were used for modelling. A one-compartment open model with first-order absorption and elimination was fitted to the concentration-time data using the NONMEM program. Selection of covariates was initially performed using stepwise linear regression analyses. The selected covariates were incorporated in the population model and the importance of each covariate was investigated by means of backwards elimination. A one-compartment model with first-order absorption and elimination adequately described the tiagabine concentration-time profile. The apparent clearance as well as the apparent volume of distribution were both significantly correlated to body height in a nonlinear relationship. No other demographic, environmental or clinical chemical parameters were identified as covariates although only a few pathological values of the latter were present in the data. The mean values of CL/f was 6.10 l/h, of V/f was 62.0 l and of k(a) was 1.25 h(-1) for a subject of 170-cm height. The population half-life was 5.72 h. The apparent clearance and volume of distribution of tiagabine in epilepsy patients on monotherapy were both dependent on body height. Prospective studies are required in order to reveal if dose adjustments based on body height will result in improved therapeutic outcome.

Stereoselective central nervous system effects of the R- and S-isomers of the GABA uptake blocker N-(4, 4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid in the rat.

1. The 'effect compartment' model was applied to characterize the pharmacodynamics of the R- and S-isomers of tiagabine in conscious rats in vivo using increase in the beta activity of the EEG as a pharmacodynamic endpoint. 2. No pharmacokinetic differences in plasma were observed between R- and S-tiagabine. The values for clearance and volume of distribution at steady-state were 103+/-10 versus 90+/-6 ml min(-1) kg(-1) and 1.8+/-0.2 versus 1.6+/-0.2 l kg(-1) for the R- and S-isomer, respectively. In contrast, plasma protein binding showed a statistically significant difference with values of the free fraction of 5.7+/-0.5 and 11.4+/-0.6%. In addition the rate constant for transport to the effect compartment was also different with values of 0.027 versus 0.067 min(-1). 3. For both isomers the relationship between concentration and EEG effect was non-linear and successfully characterized on basis of the Hill equation. A statistically significant difference in the value of EC(50) of 328+/-11 versus 604+/-18 ng ml(-1) was observed for R- and S-tiagabine respectively. The values of the other pharmacodynamic parameters were identical. 4. It is concluded that the differences in in vivo pharmacodynamics of R- and S-tiagabine can be explained by stereoselective differences in both the affinity to the GABA-uptake transporter and the degree of non-specific protein binding in plasma and at the effect site.

Gas chromatography-mass spectrometry assay method for the therapeutic drug monitoring of the antiepileptic drug tiagabine.

A gas chromatography-mass spectrometry assay method suitable for the therapeutic drug monitoring of the antiepileptic drug tiagabine is described. Tiagabine and its desmethylated analogue used as internal standard were first extracted from serum by liquid-liquid extraction using an ethyl ether-isobutanol 98:2 mixture. Tiagabine and the internal standard were then methylated in the organic phase in presence of methanol by means of a safe and stable diazomethane derivative. After evaporation, the reconstituted extracts were chromatographed on a crosslinked phenyl methyl siloxane capillary column and detected by mass fragmentometry at m/z = 156. No other antiepileptic drug possibly administrated in polytherapy and no metabolite were found to interfere in the assay. The limit of quantification was 5 ng/ml. The precision and the accuracy were found to be suitable for the therapeutic drug monitoring of tiagabine.

Does percent reduction in seizure frequency correlate with plasma concentration of anticonvulsant drugs? Experience with four anticonvulsant drugs.

OBJECTIVE: To investigate the relationship between the percentage reduction in seizure frequency in patients with epilepsy and plasma concentrations after oral administration of 4 anticonvulsant drugs. METHODS: Patients with a minimum of 25% reduction in their seizure frequency from their baseline value were declared responders. The percentage reduction in seizure frequency was plotted against plasma concentrations with use of pharmacodynamic models (linear, log-linear, Emax, and sigmoidal Emax models). In addition to pharmacodynamic models, a logistic regression model was also fitted to the concentration-response data, with a value of 1 for responders and 0 for nonresponders. RESULTS: The concentration-effect relationship could not be adequately described either by the pharmacodynamic models or by the logistic regression analysis. CONCLUSIONS: Based on the results obtained from both pharmacodynamic models and logistic regression analysis the percentage reduction in seizure frequency may not be a true surrogate marker for anticonvulsant drugs to establish a pharmacodynamic relationship with plasma concentrations.

Population analysis of the pharmacokinetics of tiagabine in patients with epilepsy.

PURPOSE: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy. METHODS: In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach. RESULTS: The patients' average (+/-SD) weight and age were 73.8+/-20.7 kg and 32.1+/-12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates. CONCLUSIONS: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables.