Population pharmacokinetics of intravenous valproic acid in Korean patients

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.     

Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children

Objective: To establish a regression equation to properly estimate the unbound serum concentration of valproic acid (VPA) from its total serum concentration; the relationship between total and unbound serum VPA concentrations was retrospectively characterized. Methods: Data were obtained from the clinical examination records that were routinely archived during therapeutic drug monitoring. The screening encompassed 342 records of 108 paediatric patients whose total and unbound VPA concentrations had been determined. The relationship between total and unbound VPA concentrations was characterized according to the Langmuir equation by taking account of inter‐individual variability with the nonmem program. Results: The total VPA concentration (C_t) in the screened patients ranged from 5·5 to 179·8 μg/mL, and the unbound VPA concentration (C_f) increased in a non‐linear manner as the total VPA concentration increased. Taking account of the effects of antiepileptics concurrently administered, the VPA dissociation constant (K_d) and maximum binding site concentration (B_m) were 7·8 ± 0·7 and 130 ± 4·5 μg/mL respectively, for the regression equation, C_t = C_f + B_m·C_f/(K_d + C_f). An alteration in the unbound concentration was seen in patients who were treated with the combination of VPA and ethosuximide and in those who received two additional antiepileptics. Conclusions: A regression equation for estimation of the unbound VPA concentration, based on total VPA concentration collected during routine therapeutic drug monitoring was established. Use of two additional antiepileptics and ethosuximide treatment was considered as potential factors affecting unbound VPA concentration.     

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients

Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam-valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0.3-32.6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144.0 TBW-0.172 1.14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17.2 TBW-0.264 DOSE0.159 0.821CZP 0.896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17.9% decrease in valproic acid clearance.     

Reversible parkinsonism and cognitive decline due to a possible interaction of valproic acid and quetiapine

What is known and Objective: Combination therapy with valproic acid plus quetiapine is recommended as one of the first‐line approaches to treatment of manic or mixed episodes in patients with bipolar disorder. Case summary: A 66‐year‐old patient with this psychiatric disease developed parkinsonism and cognitive decline during concomitant treatment with both drugs. The rapid onset of symptoms soon after use of the combination suggested an interaction/using the Karch‐Lasagna criteria, the interaction was judged to be definite. What is new and Conclusion: Their evidence on a pharmacokinetic drug interaction between the two drugs is conflicting but possible underlying mechanisms proposed include CYP3A4 inhibition. As concomitant use of valproate and quetiapine is now quite frequent in bipolar disorder, this potential interaction should be closely monitored, especially in the elderly.     

Lack of pharmacokinetic interaction between valproic acid and a traditional Chinese medicine, Paeoniae Radix, in healthy volunteers

BACKGROUND AND OBJECTIVE: In addition to the standard antiepileptic drugs, traditional Chinese medicines (TCMs) are used for the treatment of epilepsy in oriental countries. The interactions between antiepileptic drugs and TCMs represent a potential problem in clinical application. Because valproic acid (VPA), one of the most widely prescribed antiepileptic drugs, may be administered concomitantly with Paeoniae Radix (PR), one of the famous TCMs, in some epileptic patients, the present study was conducted to evaluate the influences of PR on the pharmacokinetics of VPA. METHOD: The pharmacokinetics of VPA were investigated in a randomized, open-label, two-way crossover study. Six healthy volunteers received the following treatments in a crossover design: (i) 1.2 g extract powder of Paeoniae Radix once daily for 7 days and one 200 mg VPA gastro-resistant tablet on day 7 and (ii) one 200 mg VPA gastro-resistant tablet alone on day 7. Serial plasma samples were obtained on day 7. Total and free (unbound) VPA plasma concentrations were determined by fluorescence polarization immunoassay (FPIA). Safety measures included laboratory tests (haematology, serum chemistry and urinalysis) and adverse event monitoring. Statistical comparisons of pharmacokinetic parameters were performed with the Student paired t-test. RESULTS: Overall clinical safety was satisfactory. The mean maximum plasma concentration of VPA was attained at within 6 h after oral administration of VPA alone and 3-4 h after oral administration of VPA in combination with PR. The plasma level of VPA declined with a half-life of 11.71 and 11.91 h, respectively. No statistically significant difference was obtained in any of the pharmacokinetic parameters (Tmax, Cmax, AUC, t1/2, MRT, CL/F and Vd/F) of VPA between the two treatments. Also, there was no significant difference in the protein binding rates of VPA. CONCLUSION: PR did not significantly affect the absorption, distribution, metabolism and elimination of VPA in healthy volunteers.     

LC-MS/MS法测定人血浆中丙戊酸的浓度

目的建立快速、灵敏的液相色谱-串联质谱(LC-MS/MS)法测定人血浆中丙戊酸的浓度。方法采用乙腈沉淀蛋白法处理人血浆样本,选用Shimpack VP-ODS色谱柱(150mm×2.0mm I.D,5μm),以甲醇:5mmol/L乙酸铵(55∶45,v/v)为流动相,流速为0.4mL/min,采用API3200型三重四极杆串联质谱仪的多重反应监测(MRM)扫描方式进行监测,电喷雾离子化源,负离子方式,选择监测离子反应分别为m/z 142.9→m/z 142.9(丙戊酸)和m/z 179.0→m/z 179.0(1-庚烷磺酸)。结果丙戊酸和内标1-庚烷磺酸的保留时间分别为3.03、2.38min;血浆中丙戊酸的线性范围为0.800~80.0μg/mL(r0.99),定量下限为0.800μg/mL;批内、批间精密度(RSD)均小于15%;准确度(RE)均在±15%的范围以内;平均提取回收率为(84.1±2.4)%;平均基质效应因子为(104.3±2.0)%。稳定性试验中,在各种贮存条件下的血浆中,丙戊酸均较稳定。结论该方法适用于人血浆中丙戊酸浓度的测定及丙戊酸半钠缓释片的人体药代动力学研究。     

Adjunctive topiramate enhances the risk of hypothermia associated with valproic acid therapy

Background: Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate‐associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia. Objective: We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia. Methods: This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration’s Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs. Results: We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3½– 82 years). Body temperatures ranged from 29·5 °C (moderate hypothermia) to 35 °C (mild hypothermia) with a median of 34 °C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hyopthermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5·845 for phenobarbital to 2·956 for gabapentin. Hypothermia was reported 4·7 times more frequently when topiramate was used than was statistically expected. Conclusion: We have found hypothermia, defined as an unintentional drop in body core temperature to <35 °C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4·72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO₃^? and increase blood ammonia levels.     

Poor applicability of estimation method for adults to calculate unbound serum concentrations of valproic acid in epileptic neonates and infants

Objective:  To characterize the relationship between total and unbound concentrations of valproic acid (VPA) in epileptic neonates and infants, the clinical examination records of those patients archived via therapeutic drug monitoring (TDM) activities were retrospectively analyzed.
Methods:  The screening encompassed 249 records of 114 epileptic patients aged 0–19 years old, who were treated with VPA monotherapy and whose total and unbound VPA concentrations were determined. These data were divided into groups according to the patients' age. In each group, the relationship between total and unbound VPA concentrations was compared to a reference profile, and the deviation from the reference was evaluated. The reference profile was calculated using the Langmuir equation, in which two parameters Kd and Bm were set to 7·8 and 130 μg/mL, respectively, according to our previous findings.
Results:  The relationship between total and unbound VPA concentrations of patients of 0 years old considerably deviated from the reference, and their unbound VPA concentrations were generally higher compared to the corresponding reference values. It is suggested that the large deviation is related to the fact that the serum albumin concentrations of patients younger than 1 year old tend to be lower than those of patients in other age groups.
Conclusion:  Since the relationship between the VPA concentrations of epileptic neonates and infants is noticeably different from the reference, the unbound serum VPA concentrations of these patients are not adequately estimated using the same method as that for grown-ups. The unbound VPA concentrations of neonates and infants should be explicitly determined via TDM activities.     

Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole

What is known and Objective: The antipsychotic, aripiprazole, plus lithium or valproate demonstrates rapid and significant improvement in manic symptoms that is sustained over the long term. A previous report showed that therapeutic doses of either lithium or valproate had no clinically significant effects on the pharmacokinetics of aripiprazole. We aimed to determine the effects of co‐administration of aripiprazole on the steady‐state pharmacokinetics of lithium or valproate in healthy subjects. Materials and Methods: Two similarly designed, open‐label, single‐sequence studies were conducted. Healthy subjects received daily oral doses of either lithium (450 mg every 12 h) or valproate (500 mg every 12 h) on Days 1–7. Following Day 7 was a 2‐day washout period, and on Day 10, subjects began receiving oral doses of aripiprazole (10 mg once daily) for 2 days. Aripiprazole was then titrated from 10 to 20 mg once daily to establish tolerance of aripiprazole. On Day 14, the dose was escalated and subjects received aripiprazole 30 mg once daily for 13 days. Beginning on Day 20, subjects received lithium (450 mg every 12 h) or valproate (500 mg every 12 h) concomitantly with aripiprazole 30 mg once daily through Day 26. Serial blood samples for serum lithium or valproate concentration determination were collected for up to 12 h post‐lithium or valproate administration on Days 7 and 26. Results: The lithium study enrolled 32 healthy subjects (72% completed the study), and the valproate study enrolled 48 healthy subjects (58% completed the study). In both studies, the 90% confidence intervals for the ratios of population geometric means, with and without aripiprazole, were contained within 80% and 125% for both the C_max and AUC_τ, respectively. Furthermore, the addition of aripiprazole did not change the median T_max of lithium or valproate (4 h). Thus, the addition of aripiprazole did not affect the steady‐state pharmacokinetics of lithium or valproate. The majority of subjects (76·9% for aripiprazole plus lithium and 68·4% for aripiprazole plus valproate) reported adverse events, but this adverse event profile is consistent with what has been observed in other studies. What is new and Conclusion: The addition of aripiprazole to either lithium or valproate had no clinically meaningful effects on the pharmacokinetics of either drug. In addition, co‐administration of aripiprazole with lithium or valproate demonstrated no unexpected safety signals in healthy subjects.     

Adverse drug reactions induced by valproic acid

Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity.     

Life Threatening Intoxication with Sodium Valproate

Two female epileptics, 19 and 27 years old, were admitted after ingestion of an overdose of sodium valproate. The patients were comatose for 6 and 7 days and required mechanical ventilation for 7 and 10 days. Both patients were in deep coma for several days after serum concentrations had dropped into the therapeutic range. Serum concentrations of sodium valproate were 3348 μmol/L (482?mg/mL) in one patient and more than 10,000 μmol/L (1440?mg/mL) in the other. Drug elimination followed first order kinetics, and the plasma half-lives of sodium valproate were 19 and 20 hours, respectively. Their anemia, leucopenia and thrombocytopenia required transfusion. Liver enzymes were only moderately elevated, but one of the patients developed acute pancreatitis. There were no apparent sequelae two weeks after discharge from the hospital.