Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients

OBJECTIVE: This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients. METHODS: Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model. RESULTS: The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision. CONCLUSION: The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.     

Disposition of sodium valproate in epileptic patients.

1 Serum levels of valproic acid have been determined at fixed intervals after the administration of single oral and intravenous doses (800 mg) to six epileptic patients receiving chronic treatment with other antiepileptic drugs. 2 Serum levels declined monoexponentially shortly after the intravenous administration. Biological half-lives averaged 9.0 +/- 1.4 h (s.d.). Volumes of distribution were 0.175 +/- 0.025 l/kg. There was a statistically significant negative correlation between volumes of distribution and serum half-lives (P less than 0.005). 3 After oral doses serum levels rose rapidly to peak values within 0.5--2 h. Biological availability was 96 +/- 9%. 4 Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in the patients. Total serum clearance was 85% higher in the patients as compared to the healthy subjects (P less than 0.001). Possible explanations for these findings are discussed.     

丙戊酸钠在癫痫患者中的群体药动学

目的建立丙戊酸钠在癫痫患者治疗中的群体药动学模型,为临床个体化给药提供参考。方法收集我院门诊60名癫痫患者丙戊酸钠稳态血药浓度监测数据和相应的人口学数据,应用非线性混合效应模型(non linearm ixed-effectmodel,NONMEM)程序对收集的数据进行分析,建立群体药动学模型。结果建立了癫痫患者口服丙戊酸钠群体药代动力学模型:CL/F=0.959×1.04x,(x=0,1),V/F=1.35,ka=2.38 h-1,说明丙戊酸的清除率与患者性别相关,即男性患者的清除率大于女性。结论初步建立癫痫患者口服丙戊酸钠群体药动学模型,为丙戊酸钠个体化用药提供理论基础。     

癫（疒/间）患儿丙戊酸钠血药浓度监测

目的 :分析丙戊酸钠 (VPA)治疗儿童癫血药浓度与量 效关系。方法 :以荧光偏振免疫法 (FPIA)对 81例癫患儿进行VPA血药浓度监测。结果 :有效控制癫发作的浓度为 (6 0 7± 13 7) μg·mL-1,其中 5 0～ 10 0 μg·mL-1范围的占 73 7%。结论 :血药浓度对VPA治疗癫的个体化用药具有重要的临床意义     

Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients

Summary In four refractory epileptic patients, peak plasma levels of sodium valproate occurred within 1.5 to 3 h after a single oral dose of valproate and the decline in plasma levels followed a monoexponential course with a t_1/2 of 11.4 ± 0.1 h. The mean value for apparent volume of distribution was 0.176 ± 0.013 l/kg and for total plasma clearance 0.0106 ± 0.0009 l/h/kg. Steady state plasma levels were predicted using the method of superposition utilizing pharmacokinetic parameters determined following a single dose of valproate and were 78–123% of the predicted values for two patients receiving valproate alone, and 37–64% of the predicted values for the two patients receiving carbamazepine in addition to valproate. In a further group of 20 patients the mean daily doses of valproate for 8 patients receiving valproate alone (25.4 ± 4.9 mg/kg) was significantly less than those for the 12 patients receiving concomitant anticonvulsant therapy (41.6 ± 12.3 mg/kg) (p<0.005). In addition, the steady state predose plasma levels of valproate were significantly higher in the valproate alone patients (90.3 ± 8.7 µg/ml) compared to the patients receiving additional anticonvulsants (75.3 ± 13.8 µg/ml) (p<0.01). The higher dose requirements of valproate and lower predose and steady state plasma levels for those patients on multiple anticonvulsants indicate an interaction between valproate and other anticonvulsants.     

丙戊酸钠治疗癫痫的血药浓度监测

目的研究丙戊酸钠治疗癫痫的疗效与血药浓度的关系.方法以荧光偏振免疫法测定135例癫痫患者丙戊酸钠血药浓度.结果丙戊酸钠单一用药的总有效率为80.6%,血药浓度在40～100μg     

Altered pharmacokinetics and metabolism of valproate after replacement of conventional valproate with the slow-release formulation in epileptic patients

Altered metabolism of valproate has been suggested as the mechanism of teratogenicity and hepatotoxicity of valproate. This study aimed at examining whether pharmacokinetics of a slow-release formulation of valproate affects valproate metabolism. Thirty-one epileptic patients were treated with fixed-doses of conventional valproate for at least 2 months. Thereafter, the drug was replaced with the same doses of slow-release formulation of valproate for 2 months. Blood samplings for determination of valproate and its metabolites by gas chromatography-mass spectrometry were performed at three time-points (just before morning dose and at 1 and 5 hr after morning dose) during both treatment phases. There was a significant difference (P < 0.005) in the mean serum concentration (+/- S.D.) of valproate after 1 hr between conventional valproate (63.1 +/- 27.9 microg/ml) and slow-release formulation of valproate (45.7 +/- 19.5 microg/ml). Mean serum concentrations (+/- S.D.) of 4-en and hydroxy metabolites after 5 hr were significantly reduced after replacement with slow-release formulation of valproate (4-en: 29.5 +/- 14.0-->23.0 +/- 15.3 ng/ml, 3-OH: 488.5 +/- 234.0-->419.6 +/- 171.1 ng/ml, 4-OH: 404.3 +/- 124.7-->342.8 +/- 147.6 ng/ml, 5-OH: 102.8 +/- 54.4-->81.0 +/- 43.6 ng/ml). The present study suggests that smaller diurnal fluctuations in valproate concentrations during treatment with slow-release formulation of valproate result in decreased formations of minor metabolites including 4-en, the most toxic metabolite.     

Pharmacokinetic modeling of heparin and its clinical implications

Experimental work on heparin has indicated that its half-life increases with dose. Two models to describe heparin's pharmacokinetic behavior are proposed, and the parameters in the models are fitted to experimental data. Both models exhibit an apparent first-order decay with a "half-life" that increases with dose. It is shown that, even though both models exhibit a bolus half-life of from 1 to 2 hr, over 2 days can be required for true steady-state conditions to be achieved in these models when a constant intravenous infusion of drug is given. The clinical implications of these models are discussed. Suggestions are made for further research on heparin kinetics.     

Pharmacokinetic modeling of heparin and its clinical implications

Experimental work on heparin has indicated that its half-life increases with dose. Two models to describe heparin's pharmacokinetic behavior are proposed, and the parameters in the models are fitted to experimental data. Both models exhibit an apparent firstorder decay with a halflife that increases with dose. It is shown that, even though both models exhibit a bolus half-life of from 1 to 2 hr, over 2 days can be required for true steadystate conditions to be achieved in these models when a constant intravenous infusion of drug is given. The clinical implications of these models are discussed. Suggestions are made for further research on heparin kinetics.This work was supported in part by the National Institutes of Health under Grant RR 0704811. The work was also supported in part by U.S. Government Grants MB 00146 and GM 23826, which were made to the Laboratory of Applied Pharmacokinetics at the University of Southern California, School of Medicine.     

Intra-dose variation in plasma protein binding of sodium valproate in epileptic patients.

1 The fluctuations in protein binding of sodium valproate during one dosing interval were studied in five patients stabilized on valproate and taking concurrent anticonvulsant therapy. 2 The patients took their usual morning dose of valproate (400-800 mg) and serial blood samples were collected by venepuncture at 0, 1, 2, 3, 4, and 6 h post-dose. 3 Free valproate was separated from protein bound drug by plasma ultrafiltration and the ultrafiltrate and total plasma valproate concentrations were measured by a gas chromatographic method. 4 The maximum and minimum concentrations in the ultrafiltrates occurred at the same times as in the plasma. However, the percentage fluctuation was always greater in the ultrafiltrates (range 192-412%) compared with the plasma (range 153-374%) due to the concentration-dependent nature of valproate protein binding. 5 If free valproate levels are to be monitored, knowledge of sampling time and dosage history is important for interpretation of the results.     

EMIT法与HPLC法测定人血中丙戊酸浓度的比较

目的：比较酶倍增免疫分析法（EMIT）与高效液相色谱法（HPLC）测定人丙戊酸血药浓度的方法学相关性。方法：用统计学方法比较EMIT法和HPLC法测定丙戊酸血药浓度的方法学效能指标差异,同时采用双变量回归与相关分析对HPLC法和EMIT法测定的结果进行比较。结果：在1～150mg/L浓度范围内,两种方法的准确度差异无统计学意义（P〉0.1）,而HPLC法精密度显著高于EMIT法（P〈0.01）。52例样本HPLC法测定结果（X）与EMIT法测定结果（Y）作回归分析,方程为：Y=0.9665X＋1.0674,r=0.9947（n=52）;两种方法测定结果经配对t检验,差异无统计学意义（P〉0.1）。然而,血药浓度〈10mg/L的7例患者测定结果差异有统计学意义（P〈0.01）。结论：丙戊酸血药浓度在1～150mg/L浓度范围内时,两种方法测定结果存在高度相关性,但HPLC法的精密度优于EMIT法。当丙戊酸血药浓度偏低（〈10mg/L）时,宜用HPLC法测定。     

The effect of valproate on bone mineral density in adult epileptic patients.

The effect of long-term valproate (VPA) treatment on bone mineral density (BMD) in adult epileptic patients is not clearly known, although several studies have been done in children. In adult epileptic patients (n = 50; 24 men, 26 women) treated with VPA, the bone mineral density at lumbar level (L1-L4) and neck, trochanter, and intertrochanter regions of left femur was studied by dual energy X-ray absorptiometry (DXA) at the beginning of the study and after 6 months, with the specific aim to evaluate the effect of long-term valproate monoteraphy on bone mineral density. Routine biochemical parameters were also evaluated. Sixty healthy control subjects were evaluated. Control subjects were similar to patient group with respect to age, race (all White), geographic area, and socioeconomic status. Lumbar and femural BMD values were significantly lower in patient group than control group (0.814 +/- 0.157 g/cm(2) versus 0.894 +/- 0.102 g/cm(2), P = 0.003) and (0.824 +/- 0.144 g/cm(2) versus 0.906 +/- 0.104 g/cm(2), P = 0.001), respectively. Osteopenia were detected in 13 of 60 control subjects (22%) and the others had no osteoporosis. In epileptic group, osteoporosis and osteopenia were detected in 8 subjects (16%), and in 26 subjects (52%), respectively. In epileptic group 16 subjects were normal (32%) at the lumbar regions, and 7 had osteoporosis (14%), 28 had osteopenia (56%), and 15 were normal (30%) at the femoral region. In the second measurements of the patients on valproate treatment, after 6 months, all of the DXA BMD values had worsened compared with the first measurements ( P = 0.001 for lumbar BMD values and P = 0.004 for femural BMD values). In the patient group, a significant inverse correlation was observed between duration of valproate therapy and all DXA BMD values in the first and second measurements. Parathyroid hormone, alkaline phosphatase, and phosphor levels of patients were significantly higher than those of control group (52 +/- 11 pg/ml versus 46 +/- 13 pg/ml, P = 0.013), (113 +/- 32 U/l versus 95 +/- 36 U/l, P = 0.006), and (4.50 +/- 0.5 mg/dl versus 4.0 +/- 0.7 mg/dl, P = 0.0001), respectively. However, all of the parameters were within the normal reference ranges. It has been concluded that long-term (more than one year) valproate treatment induces a decrease in bone mineral density in epileptic adults. However, the multivariate analysis did show no association between BMD changes and parathyroid hormone, alkaline phosphatase or phosphorus levels.     

Pharmacokinetic estimations from microdialysis data

Summary Microdialysis has recently been adapted for sampling the extracellular fluid of various organs in order to measure drug concentrations, and the first clinical application has been published. My aim here is to provide simple rules about how to analyse pharmacokinetic data from such studies. The plotting of data on a time scale and the estimation of C (0) and slopes is not a trivial problem when multicompartmental models are assumed or sampling intervals are unequal. I have developed formulae and algorithms to solve the problem. A simple rule of thumb is given, suggesting when these formulae need to be applied. It is shown that the calculations of half-life and slopes is similar to standard methods for equal sample intervals and that calculation of AUC and clearance may be even more accurate for microdialysis data than for ordinary blood sampling, because of the time-integral character of the dialysis method. I have dealt with both zero-order and first-order kinetics.     

Pharmacokinetics of sodium valproate in epileptic patients: Prediction of maintenance dosage by single-dose study

Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination ( phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.     

Pharmacokinetic analysis of the disposition of valproate in pregnant rats.

Kinetic analysis of valproate (VPA) disposition in pregnant rats was performed. A dose-dependent saturable plasma elimination was observed in both the control and pregnant rats. Saturation was more remarkable in the pregnant rats and this was assumed to be due to the decreased hepatic extraction by metabolism. Pharmacokinetic parameters were calculated using a two-compartment open model with a Michaelis-Menten-type elimination process from the central compartment. In the pregnant rats, the calculated values of Km and Vmax decreased significantly, by one-half of those of the control rats, whereas no significant difference was observed in distribution rate constants (k12, k21) and volumes of distribution (V1, Vdss) between two groups of rats. Furthermore, the hepatic extraction of VPA in the control and pregnant rats was investigated in order to explain nonlinear pharmacokinetics of VPA. The values of the hepatic extraction ratio in the control and pregnant rats were 39.9 and 22.4% at the steady state concentration of approximately 20 micrograms/ml, respectively. The extraction ratios in the pregnant rats were lower than those of the control rats. This fact may be one of the reasons why the elimination of VPA in the pregnant rats is more susceptible to saturation.     

癫痫患儿丙戊酸钠血药浓度的相关分析

目的 探讨癫痫患儿丙戊酸钠血药浓度与剂量等因素的相关性.方法 126例癫痫儿童按体重口服相应剂量(10-20mg·kg-1·d-1)德巴金糖浆,3-5天后采用高效液相法测定丙戊酸钠血药浓度并采用Pearson相关及偏相关分析结果.结果 Pearson相关分析发现体重与口服剂量,体重与年龄,年龄与剂量之间存在正相关相关系数分别为0.55、0.70、0.45(P<0.001).剂量与血药浓度之间也为正相关相关系数为0.33(P<0.01).偏相关分析发现剂量、体重与丙戊酸钠血药浓度的偏相关系数分别为0.55(P<0.001)、0.30(P<0.05).结论 样本研究发现2岁以下癫痫患儿丙戊酸钠血药浓度与剂量、体重存在一定相关关系,与年龄的相关性不显著.临床用药需考虑剂量、体重对血药浓度的影响.     

Pharmacokinetic interaction on valproic acid and recurrence of epileptic seizures during chemotherapy in an epileptic patient

AIMS: To report a pharmacokinetic interaction between valproic acid (VPA) and anticancer agents observed in an epileptic patient. METHODS: A 34-year old male epileptic patient receiving VPA underwent cisplatin-based chemotherapy for the treatment of a testicular tumour. The first chemotherapeutic cycle decreased the serum VPA concentration and caused severe generalized tonic-clonic seizures. Thus, thereafter, the serum VPA concentration was monitored along with the chemotherapy. RESULTS: In a patient receiving VPA daily, severe seizures were observed 7 weeks after the first chemotherapeutic cycle, at which the serum VPA concentration was found to be reduced by approximately 50% of the initial level (90-100 microg ml(-1)). The following cycles (six cycles over a 7-month period) also caused seizures in association with decreased serum VPA concentrations. In contrast, the serum concentration of phenytoin, which was given daily after the second chemotherapeutic cycle, remained at a therapeutic concentration (10-20 microg ml(-1)). After the completion of chemotherapy, the serum concentration of a tumour marker, hCGbeta, decreased to 1.2 ng ml(-1) from more than 120 ng ml(-1) prior to the chemotherapy in this patient. CONCLUSIONS: Careful monitoring of VPA concentrations are necessary during cisplatin-based chemotherapy because anticancer agents can reduce the serum concentration and antiepileptic activity of VPA.