Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy.

We retrospectively collected plasma level assessments performed in 96 adult patients with epilepsy on stable monotherapy, including 9 patients on clobazam (CLB), 34 on carbamazepine (CBZ), 24 on phenobarbital (PB), 9 on phenytoin (PHT), and 20 on valproate (VPA); these results were compared to those obtained in 54 adult patients on stable bitherapy with the association of CLB with either CBZ (n = 17), PB (n = 17), PHT (n = 5), or VPA (n = 15). Our results show that CLB has no significant effect on the level to dose ratio (LDR) of CBZ, PB, PHT, or VPA. Conversely, CBZ, PB, and PHT significantly decrease the LDR of CLB. CBZ and PHT significantly increase the LDR of N-desmethylclobazam (NCLB), the major metabolite of CLB. A significant increase in the NCLB/CLB ratio was found in CBZ + CLB, PB + CLB, and PHT + CLB bitherapies. These findings are of clinical significance: clobazam is useful as adjunctive treatment in human epilepsy and is often chosen as the benzodiazepine adjunctive drug in chronic resistant epilepsy. Sedative side effects may occur, especially in patients treated by a CBZ + CLB or PHT + CLB bitherapy, and both CLB and NCLB plasma levels should be monitored in such patients.     

Evaluation of therapeutic drug monitoring of antiepileptic drugs

Results of the therapeutic drug monitoring (TDM) of the concentration of antiepileptic drugs (AEDs), performed at Aseer Central Hospital over a 1-year period were evaluated. Most of the requests were for phenytoin (PHT) determination followed by carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB). Serum concentrations of PB, CBZ, VPA and PHT within the presumed therapeutic range constituted 87%, 73%, 45% and 33%, respectively. Valproic acid exhibited age differences in the proportion of concentrations below the presumed therapeutic range, such that subtherapeutic concentrations increased while therapeutic concentrations decreased with age. When the requests were related to particular patients, 71% of patients were on monotherapy with PHT as the most commonly used single drug and PB the least. Patients using 2 AEDs were found to constitute 23.5% of all patients with "PHT + CBZ" and "CBZ + VPA" being the most commonly prescribed 2 drugs combination. The frequency of concentrations within the therapeutic ranges decreased when 1 or 2 more drugs were used with either PHT or VPA. In addition, combination with PHT was associated with a reduction in mean CBZ concentration, while combination with CBZ was associated with a reduction in mean VPA concentration.     

Chronic valproic acid and coantiepileptic drug therapy and incidence of increases in serum liver enzymes

Results are described on the association of increased serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) activities with valproic acid (VPA) and coantiepileptic drug therapy in a group (n = 126) of randomly selected chronically medicated out-patients. The highest incidence (SGOT, 28.3%; SGPT, 26.1%) of elevations occurred in patients comedicated with VPA-phenobarbital (PB)-phenytoin (PHT) combinations, followed by those in the VPA-PB group (SGOT, 19.5%; SGPT, 7.3%). No SGPT elevations were detected in any patients (n = 40) on chronic VPA monotherapy, while SGOT was marginally elevated in 20% of the cases. Considering the total sample (n = 126), SGOT activities were found to be linearly and directly correlated with VPA plasma concentration (n = 126, r = 0.228, p less than 0.01), PB concentration (n = 86, r = 0.352, p less than 0.01), PHT concentration (n = 45, r = 0.336, p less than 0.01), sum of VPA-PB concentrations (n = 86, r = 0.440, p less than 0.001), and sum of VPA-PB-PHT concentrations (n = 45, r = 0.481, p less than 0.001). The corresponding correlations for SGPT activities were similar, except that no correlation was observed in the case of VPA monotherapy. Student's t tests for equality of means showed that the subgroup with abnormal enzyme activities had a significantly higher mean plasma concentration for PB, PHT, sum of VPA-PB, and sum of VPA-PB-PHT when compared with normal enzyme subgroup patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carbamazepine metabolism in humans: effect of concurrent anticonvulsant therapy

Free and total carbamazepine (CBZ) and carbamazepine-epoxide (CBZ-EP) plasma levels were obtained on 113 patients with epilepsy (18-61 years old) controlled on either monotherapy or coadministration with either phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), or all three. A subset of patients were administered tetradeuterium labeled CBZ to evaluate the effects of autoinduction and coadministration of VPA on the kinetics of CBZ and its metabolite CBZ-EP. Polytherapy had variable effect on free and total CBZ plasma levels compared to monotherapy. Coadministered PHT (co-PHT), or all three anticonvulsants together (PHT, PB, and VPA: co-AEDs) decreased free and total CBZ plasma levels. No change was noted for coadministered VPA (co-VPA). Compared to monotherapy the free and total CBZ-EP levels increased with co-VPA, less with coadministered PB (co-PB), and no change with co-PHT or co-AEDs. Protein binding of CBZ and CBZ-EP was not affected by any antiepileptic drugs studied. The free and total CBZ-EP/CBZ ratio was tripled with co-VPA or co-AED's, and doubled with co-PHT or co-PB. Isotope labeling did not demonstrate any differences in half-life (t1/2), plasma clearance (Cl), or volume of distribution (Vd). Compared to naive controls, monotherapy and co-VPA decreased CBZ t1/2 by 50%, and more than doubled the CBZ Cl without a significant change in the Vd. Autoinduction is one explanation for these changes with chronic CBZ therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic valproic acid therapy and incidence of increases in venous plasma ammonia

Results are described on the association of elevated ammonia (NH3) with valproic acid (VPA) therapy in a large group (n = 157) of randomly selected, chronically medicated (greater than 2 years) outpatients. The highest incidence (45.5%) of elevations occurred in patients comedicated with VPA-phenobarbital (PB)-phenytoin (PHT) combinations, followed by VPA-PB (33.3%) and VPA-PHT (15.4%). No NH3 elevations were detected in all patients (n = 38) on chronic VPA monotherapy. Considering the total sample (n = 157), NH3 concentrations were found to be linearly and directly correlated with VPA plasma concentration (n = 125, r = 0.249, p less than 0.001), PB concentration (n = 86, r = 0.411, p less than 0.001), sum of VPA-PB concentration (n = 60, r = 0.721, p less than 0.001), and sum of VPA-PB-PHT concentration (n = 33, r = 0.802, p less than 0.001). When patients in the subgroups (n = 73) that included all the patients with elevated NH3 were separated into one group (n = 47) with normal NH3 (less than or equal to 0.70 micrograms/ml) and one group (n = 26) with elevated NH3 (greater than or equal to 0.71 micrograms/ml), Student's t tests for equality of means showed that the group with elevated NH3 had a significantly higher mean plasma concentration for VPA, PB, sum of VPA-PB, and sum of VPA-PB-PHT (all at p less than 0.001) when compared with the normal group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactions between zonisamide and conventional antiepileptic drugs in the mouse maximal electroshock test model.

Despite the major advances in antiepileptic drug (AED) therapeutics, about one third of patients with epilepsy still do not have adequate seizure control with currently available AEDs when prescribed as monotherapy. Typically, in this setting polytherapy with two or more AEDs is used. Zonisamide (ZNS) is a new AED effective in the treatment of refractory epilepsy and since it is only prescribed in polytherapy regimens, its interactions with other AEDs is of particular importance. The aim of this study was to isobolographically determine interactions between ZNS and four conventional AEDs: carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA), in the mouse maximal electroshock (MES)-induced seizure model. The total brain concentrations of conventional AEDs and ZNS were measured with immunofluorescence and high-pressure liquid chromatography (HPLC), respectively, in order to determine any pharmacokinetic contribution in any observed interactions. With isobolography, synergistic interactions were observed for the combination of ZNS plus VPA and ZNS plus PHT at the fixed-ratio of 1:1, while additivity was observed for their combinations at the remaining dose ratios of 1:3 and 3:1. In contrast, the interactions between ZNS and PB and between ZNS and CBZ, applied at the fixed-ratios of 1:3, 1:1 and 3:1 proved to be additive. None of these AED combinations were associated with motor and long-term memory impairment. Furthermore, whilst brain AED concentrations were unaffected by ZNS, PHT significantly increased and PB reduced brain ZNS concentrations. Thus, the resultant interactions between ZNS and PHT and between ZNZ and PB were consequent to both pharmacodynamic and pharmacokinetic components. Finally, one can conclude that because of the synergistic pharmacodynamic interaction between ZNS and VPA, this combination might be useful in clinical practice.     

Influence of coadministered antiepileptic drugs on serum antiepileptic drug concentrations in epileptic patients -quantitative analysis based on suitable transforming factor

We conducted a study to clarify the most suitable transforming factor related to the daily dose of antiepileptic drugs (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C(t) was revealed to be dependent on only one variable in terms of the transformed daily dose (D'). C(t) was proportional to the power function of D' for VPA and CBZ and was linearly proportional to D' for ZNS and PB. The L/D ratio is expressed as a linear function of C(t) for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C(t) of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C(t) to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C(t) to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0.80, respectively. VPA, CBZ, and PHT significantly increased (P<0.05) the L/D ratio of PB to 1.47, 1.18, and 1.19, respectively. The daily PHT dose was decreased to 0.89, 0.91, 0.90, and 0.84 the dose of PHT alone to maintain C(t) in the therapeutic range when VPA, CBZ, ZNS, and PB were coadministered, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated C(t) values were calculated using the value of each alteration ratio and compared with the measured ones. Each mean of prediction error was about 20%. Our results appear valid and these alteration ratios should be available for clinical use.     

Spotlight on the continual applicability of routine plasma monitoring antiepileptic drugs in the treatment of epilepsy.

The continual applicability of routine plasma measurement of antiepileptic drugs (AEDS) was assessed in 301 epileptic patients with mean age and body weight+/-SD of 30+/-10.6 years and 55+/-19 kg, respectively. The AEDS used included carbamazepine (CBZ), phenytoin (PHT) or valproic acid (VPA) which were given either alone (monotherapy) or in combination (polytherapy). The incidence of uncontrolled epilepsy was significantly higher (P<0.001) in polytherapy vs monotherapy of AEDS and when plasma levels of the drugs were in the subtherapeutic range (P<0.01 for PHT, and P<0.001 for CBZ). Subtherapeutic levels of CBZ were seen with fixed and reasonable doses of 600 mg of the drug given daily. Also, the concentration dose ratios of AEDS were significantly lower in polytherapy vs monotherapy. In conclusion, routine plasma monitoring of AEDS especially in uncontrolled cases of epilepsy could be considered as a fast tool for proper therapeutic approach and dose optimisation in these psychologically and socially devastating episodes.     

Influence of concomitant antiepileptic drugs on plasma lamotrigine concentration in adult Japanese epilepsy patients

Lamotrigine (LTG) is an antiepileptic drug (AED) that was approved in Japan in 2008. We evaluated the influence of AEDs that induce hepatic enzymes (including phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ)), valproic acid (VPA), and various combinations of these drugs, on plasma LTG concentration in adult Japanese epilepsy patients. A total of 621 patients (mean age 34.4±11.8 years) were evaluated retrospectively. We calculated the concentration to dose ratio (CD ratio) for LTG with different AED regimens, and employed multiple regression analysis to determine factors influencing the LTG concentration. There was a linear correlation between the dose and concentration of LTG in patients treated with LTG (group I), LTG+VPA (group II), LTG+inducers (group III), or LTG+VPA+inducers (group IV). The mean CD ratio of patients on LTG monotherapy was 1.43±0.4 (μg/mL)/(mg/kg). When LTG was combined with VPA, the CD ratio increased about 2.2-fold, but there was no significant correlation between the CD ratio and VPA concentration. The mean CD ratios calculated in patients receiving LTG+PHT, LTG+PB, and LTG+CBZ were 0.56, 0.84, and 0.91, respectively. Addition of PHT significantly reduced the CD ratio in a concentration-dependent manner, in comparison with PB and CBZ (p<0.005 and p<0.001, respectively). Stepwise multiple regression analysis showed that the coefficient of determination of groups I, II, III, and IV were 0.94, 0.94, 0.90, and 0.91, respectively. In the clinical setting, these findings can help to estimate LTG concentrations and predict the inducing or inhibiting effects of concomitant AEDs.     

Effect of the removal of individual antiepileptic drugs on antipyrine kinetics, in patients taking polytherapy.

1. Antipyrine (AP) clearance, half-life and volume of distribution were determined in 52 patients, taking one or more antiepileptic drug (AED), before and 4 weeks after the complete removal of phenytoin (PHT, n = 20), carbamazepine (CBZ, n = 15) and sodium valproate (VPA, n = 17). 2. PHT removal was associated with a mean 13% fall in AP clearance and a mean 16% increase in AP half-life, in patients who were also taking CBZ with or without barbiturates. There was no significant difference between patients who did, and did not, take barbiturates, in addition to CBZ. 3. CBZ removal was associated with a mean 45% fall in AP clearance and a mean 69% increase in AP half-life, if there was no inducing AED comedication, but had no effect on AP clearance and half-life if PHT and/or barbiturates were also being taken. 4. Removal of VPA had no effect on AP clearance or half-life. 5. The removal of PHT, CBZ and VPA had no significant effect on AP volume of distribution. 6. PHT appears to be a more powerful inducer of hepatic enzyme activity, as measured by the AP test, than is CBZ.     

Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data

The aim of the present study was to estimate valproic acid (VPA) clearance values for adult patients with epilepsy, using serum concentrations gathered during their routine clinical care. Retrospective steady state serum concentrations data (n=534) collected from 208 adult patients receiving VPA were studied. Data were analysed according to a one-compartment model using the NONMEM program. The influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) were investigated. The results of the population pharmacokinetics analysis were validated in a group of 30 epileptic patients. The final regression model for VPA clearance (Cl) was: $?rm Cl?left (?rm L/h ?right )=0?rm. 004?times TBW?times Dose ?0.304??rm ?times 1.363?,?rm CBZ?times 1. 541?,?rm PHT?times 1.397?,?rm PB.$ The inter-individual variability in VPA clearance, described by a proportional error model, had a variation coefficient (CV) of 23.4% and the residual variability, described using an additive model, was 11.4 mg/L. These results show that VPA clearance increased linearly with TBW, but increases nonlinearly with increasing VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a significant increase in VPA clearance. The model predictions in the validation group were found to have satisfactory precision and bias. In conclusion, inter-individual variability in VPA clearance can be partly explained by TBW, daily dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this variability to be reduced by 37.23% which may be very useful for clinicians when establishing the initial VPA dosage regimen. However, the magnitude of inter-individual plus residual variabilities, remaining in the final model, render these dosage predictions imprecise and justify the need for VPA serum level monitoring in order to individualize dosage regimens more accurately.     

The effects of phenytoin and carbamazepine on serum concentrations of mono-unsaturated metabolites of valproic acid.

Serum concentrations of valproic acid (VPA) and its mono-unsaturated metabolites, 2-propyl-2-pentenoic acid (2-en), 2-propyl-3-pentenoic acid (3-en) and 2-propyl-4-pentenoic acid (4-en), were measured in 36 epileptic patients. The subjects were divided into three subgroups, i.e., receiving VPA alone (n = 20: VPA group), VPA with phenytoin (n = 9: VPA + DPH group), and VPA with carbamazepine (n = 7: VPA + CBZ group). In the VPA group, the correlations between the serum concentration of VPA and those of the metabolites were significantly positive (r = 0.693, P less than 0.01 for 2-en; r = 0.584, P less than 0.01 for 3-en; and r = 0.868, P less than 0.001 for 4-en). The concentration/dose ratio of VPA was significantly lower, and the 4-en/VPA ratio was significantly higher in the VPA + CBZ group than in the VPA group (P less than 0.05). However, DPH had less effect on the concentration/dose ratio of VPA and the 4-en/VPA ratio than CBZ. This may be due partly to the relatively smaller therapeutic dose of DPH. These results suggest a correlation between the serum concentration of VPA and that of 4-en, and an increased metabolic conversion of VPA to 4-en by coadministration of CBZ. High serum concentrations of VPA and concomitant use of CBZ resulted in an elevation of the serum concentration of 4-en, which has been reported to be the most toxic metabolite of VPA.     

NONMEM法估算中国癫痫患者卡马西平的清除率

目的　考察中国癫痫患者卡马西平的群体药动学参数。方法　癫痫病例来自上海、北京两地 4所医院 ,采集服用卡马西平的 5 92例患者的稳态血药浓度 (n =70 3)。NONMEM程序估算分析时 ,采用一级吸收和消除的药动学模型并固定吸收速率、生物利用度和表观分布体积参数。结果　体重 (TBW )、剂量 (Dose)、合用丙戊酸钠 (VPA)且其日剂量大于 2 0mg·kg-1·d-1、苯妥英 (PHT)、苯巴比妥 (PB)和年龄大于 6 5岁的老年人 (ELDER)均为卡马西平清除率(CL)的影响因素。性别、合用氯硝西泮、妥吡酯不改变卡马西平的清除率。最终模型为 :CL(CL/F) (L/h) =1 32·Dose(g·kg-1·d-1) 0 42 1·TBW (kg) 0 .691·1 2 0 VPA·1 4 3PHT·1 14 PB·0 836 ELDER。讨论　根据中国癫痫患者的群体药动学模型 ,结合患者服用的剂量、体重和合并用药可估算其清除率 ,制定给药方案     

Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin - PHT, carbamazepine - CBZ, valproate - VPA and phenobarbital - PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.The results of this study were presented in part at the 8th Congress of the European Federation of Neurological Societies, held in Paris, France, on 4--7 September 2004 [Abstract available in Eur J Neurol 11(Suppl 2): 227, 2004].     

Population pharmacokinetics of lamotrigine with data from therapeutic drug monitoring in German and Spanish patients with epilepsy

This study develops a population pharmacokinetic model for lamotrigine (LTG) in Spanish and German patients diagnosed with epilepsy. LTG steady-state plasma concentration data from therapeutic drug monitoring were collected retrospectively from 600 patients, with a total of 1699 plasma drug concentrations. The data were analyzed according to a one-compartment model using the nonlinear mixed effect modelling program. The influences of origin (Germany or Spain), sex, age, total body weight, and comedication with valproic acid (VPA), levetiracetam, and enzyme-inducing antiepileptic drugs (phenobarbital [PB], phenytoin [PHT], primidone [PRM], and carbamazepine [CBZ]) were investigated using step-wise generalized additive modelling. The final regression model for LTG clearance (CL) was as follows: CL(L/h) = 0.028*total body weight*e(-0.713*VPA)*e0.663*PHT*e0.588*(PB or PRM)*e0.467*CBZ*e0.864*IND, where IND refers to two or more inducers added to LTG treatment; this factor as well as VPA, PHT, PB, PRM, and CBZ take a value of zero or one according to their absence or presence, respectively. The administration of inducers led to a significant increase in mean LTG CL (values of 0.045-0.070 L/h/kg vs. 0.028 L/h/kg being reached in monotherapy), whereas VPA led to a significant decrease in CL (0.014 L/h/kg). Thus, comedication with these analyzed drugs can partly explain the interindividual variability in population LTG CL, which decreased from the basic model by more than 40%. The proposed model may be very useful for clinicians in establishing initial LTG dosage guidelines. However, the interindividual variability remaining in the final model (clearance coefficient of variation close to 30%) make these a priori dosage predictions imprecise and justifies the need for LTG plasma level monitoring to optimize dosage regimens. Thus, this final model allows easy implementation in clinical pharmacokinetic software and its application in dosage individualization using the Bayesian approach.     

一线抗癫癎药物血药浓度监测结果分析

目的:对一线抗癫癎药物血药浓度监测结果进行回顾性分析,指导临床合理用药。方法:对801例服用一线抗癫癎药物病人的血药浓度进行分类汇总,并对结果进行统计学分析。结果:各药在有效血药浓度范围内的病例百分率差异显著(P<0.01),分别为丙戊酸钠(VPA)75.2%、苯巴比妥(PB)67.3%、卡马西平(CBZ)53.1%、苯妥英钠(PHT)20.8%。VPA使用率最高,为60.5%,其血药浓度存在性别差异(P<0.01)。CBZ血药浓度存在年龄差异(P<0.01)。多药联用血药浓度升高的病例增加(P<0.01),以PHT/CBZ方案最为突出。CBZ/VPA、PB/VPA方案在控制率、安全性方面比较好。结论:血药浓度监测对癫癎治疗具有极其重要的临床意义。     

Isobolographic analysis of interactions between losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model.

The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED(50add)) was 138 mg/kg, while the experimentally derived ED(50) for the mixture (ED(50mix)) was 85.2 mg/kg. The difference was significant at p<0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED(50add)=18.4 mg/kg versus ED(50mix)=26.7 mg/kg, p<0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED(50), however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED(50) values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the importance of measuring AED concentrations in studies designed to identify desirable AED combinations.     

PB:PRM ratio in patients with epilepsy treated with primidone

Phenobarbitone (PB) and primidone (PRM) plasma concentrations were measured in 88 patients of both sexes with different types of epilepsy and treated with PRM, alone or in association with carbamazepine (CBZ), phenytoin (PHT), ethosuximide (ESM) or valproic acid (VPA). A correlation was observed between the dose and the levels of both PRM and PB. Plasma PB:PRM ratio was high variable, especially interindividually. These changes seemed to be linked to age and particularly to pharmacological associations. In fact, PB:PRM ratio was increased with CBZ, ESM, VPA and PHT respectively. Moreover, a correlation was observed between the PB:PRM ratio and PHT plasma levels. The possibility of monitoring PB and PRM plasma levels during long-term treatment with PRM is discussed.     

Population pharmacokinetics of carbamazepine in Chinese epilepsy patients

AIM: To investigate the pharmacokinetic profile of carbamazepine (CBZ) in Chinese epilepsy patients. MATERIALS AND METHODS: Serum samples through concentrations at steady state (n = 687) were collected prospectively from 585 patients during routine clinical care. Data were analyzed by the non-linear mixed-effect modeling (NONMEM) technique with a one-compartment model of first-order absorption and elimination. RESULTS: The important determinants of clearance (CL) were total body weight (TBW); dose; patient age over 65 years (E); and comedication with phenytoin (PHT), phenobarbital (PB), or valproic acid (VPA) when VPA daily dose was greater than 18 mg/kg. The final pharmacokinetic model for relative CL and apparent distribution volume (V) were: Equation CONCLUSION: A population pharmacokinetic model was proposed to estimate the individual CL for Chinese patients receiving CBZ in terms of patient's dose, TBW, and comedications to establish a priori dosage regimens.     

Potential relationships between transaminase abnormality and valproic acid clearance or serum carnitine concentrations in Japanese epileptic patients

This study tested the hypothesis that the determinants of mild liver injury are prerequisites for more severe idiosyncratic hepatotoxicity. This study verified whether the possible risk factors for rare idiosyncratic valproic acid (VPA)-induced hepatotoxicity, VPA clearance and/or serum carnitine concentrations are common to those for a mild elevation in transaminases in VPA-treated patients. VPA clearance was calculated in 172 Japanese patients with epilepsy, using a non-linear mixed-effects regression program. Carnitine concentrations were determined in a subset of 60 patients. The relationships between VPA clearance, carnitine concentration and levels of transaminases and ammonia were evaluated by Pearson's correlation coefficients. The final model of VPA apparent clearance (CL/F) was as follows: CL/F (L h(-1) = 0.012 x (BW/40)(0.34) x dose(0.55) x 0.90(gender) x 1.32(PHT) x 1.11(CBZ) x 1.12(PB), where BW = total body weight (kg); gender = 1 if female, 0 if male; PHT/CBZ/PB = 1 if phenytoin, carbamazepine, or phenobarbital, respectively, is coadministrated, otherwise 0. Either a higher VPA clearance or acyl/free carnitine ratio and a lower total and/or free carnitine concentration, but not VPA concentration, were associated with the mild elevation in transaminases or ammonia. These results support the initial hypothesis, while also helping to clarify the mechanism of severe idiosyncratic hepatotoxicity with VPA.