Total Valproic Acid Levels Research Articles

Pharmacokinetic mechanisms underlying clinical cases of valproic acid autoinduction: A review

• Autoinduction is a frequent clinical phenomenon with antiepileptic drugs. • Clinical cases of valproic acid autoinduction may be underreported. • Multiple complex pharmacokinetic mechanisms underlie valproic acid autoinduction. • Free fraction levels are useful to diagnose and mange valproic acid autoinduction. Although enzyme induction by valproic acid (VPA) has been documented in several case reports, clinical reports of VPA autoinduction are rare. In contrast, other antiepileptic drugs (AED) and/or mood stabilizers, such as carbamazepine and phenytoin, are well-documented to increase other drugs' metabolism as well as their own. This review analyzes data from published case reports of VPA autoinduction to elucidate plausible mechanisms underlying VPA autoinduction to enhance clinicians' awareness of VPA autoinduction and its management. A literature search using the following search terms: (('valproic acid' OR 'valproate' OR 'VPA') AND ('autoinduction' OR 'auto-induction' OR 'induction' OR 'inducibility')) revealed 14 records. However, only three papers described clinical cases of VPA autoinduction, with one research paper investigating the role of β-oxidation in VPA autoinduction without a clinical case description. As shown in Table 1, VPA autoinduction in c ase 1 was primarily formulation-based, cases 2-4 were dose-related, and case 5 involved protein displacement reaction with co-prescribed ibuprofen. All reviewed cases were Caucasian males, with a mean age (SD) of 44.0±14.88, receiving a VPA formulation with different diagnoses, including bipolar disorder, schizophrenia, tuberous sclerosis, and traumatic brain injury. All VPA levels were trough levels obtained at the steady-state and analyzed by the same laboratories for each case. This review utilizes clinical data from a few published cases to present the complexities of pharmacokinetic mechanisms underlying VPA autoinduction. Nevertheless, clinicians should consider requesting free fraction along with the total VPA levels to diagnose and manage VPA autoinduction, particularly in clinically challenging patients.

The Effect of Sample Handling on Free Valproic Acid Levels

Valproic acid (VPA) is a broad-spectrum anticonvulsant drug. Under normal conditions, this drug is highly protein bound. However, in patients with hypoalbuminemia, the free fraction can increase substantially while the total VPA levels remain in therapeutic range. The neurologic activity and toxicity of the drug are directly related to free drug levels. Our in-house free VPA assay was validated using 20 patient samples obtained from a reference laboratory (RL1). It was further evaluated by parallel testing with RL1 using samples collected from our patients. Subsequently, sample handling effects were investigated by comparing free VPA levels measured in our laboratory to 3 selected RLs with different sample transportation conditions. No significant bias was observed between the in-house assay (y) and RL1 (x) assay in free VPA measurement (y = 1.12x + 0.072, r = 0.994). However, patient samples collected in our institution and sent to RL1 revealed significant negative bias (y = 0.776x - 3.861, r = 0.954). A large discrepancy in free VPA levels was further observed from identical aliquots of the same samples transported to 3 RLs in different conditions. Our study demonstrated that sample handling has significant impact on free VPA levels. The observed magnitude of variation exceeds a clinically acceptable limit and could alter clinical decisions.

Comparison of Serum Total Valproic Acid Levels and %CDT Values in Chronic Alcohol Addictive Patients in an Italian Clinic: A Retrospective Study.

BackgroundValproate is a broad-spectrum anticonvulsant that is effective in the treatment of tonic-clonic, myoclonic and absence seizures as well as in partial seizures as a second-line drug. It has been widely demonstrated in the literature that the effect of valproate on type-A γ-aminobutyric acid (GABA-A) receptors may reduce relapse to ethanol abuse. This retrospective study evaluated a 3-year period in which 42 patients from the Department of Alcoholism and Substance Abuse (DASA) were treated with valproate.ObjectivesWe compared different serum total valproic acid (VPA) concentrations, and the effectiveness of this drug in maintaining alcohol abstinence was evaluated by percentage of carbohydrate deficient transferrin (%CDT) values.MethodCDT is a biochemical marker used for identifying regular high alcohol consumption and monitoring abstinence in outpatients during treatment. Serum concentrations of valproate were divided into four groups: <10, 10–30, 31–50, and >50 µg/mL.ResultsThis study shows that a mean serum total VPA concentration >30 µg/mL is more effective in maintaining alcohol abstinence than a lower one (p < 0.05). In this study, mean serum total VPA concentrations between 31 and 50 µg/mL showed the same effectiveness as higher ones (>50 µg/mL); in fact, there was no significant difference in mean %CDT values between these two groups (p > 0.05). After at least 12 months’ treatment with valproate, mean platelet counts increased by 12 × 103/μL compared with baseline (254 ± 63 vs 242 × 103/μL, p > 0.05, respectively) in patients with mean serum total VPA levels <10 μg/mL; increased by 8 × 103/μL from baseline (253 ± 59 vs 245 × 103/μL, p > 0.05, respectively) in patients with levels between 10 and 30 μg/mL; decreased by 2 × 103/μL from baseline (265 ± 63 vs 267 × 103/μL, p > 0.05, respectively) in patients with levels between 31 and 50 μg/mL, and decreased by 48 × 103/μL from baseline (215 ± 56 vs 263 × 103/μL, p < 0.05, respectively) in patients with levels >50 μg/mL.ConclusionA mean serum total concentration lower than the currently accepted therapeutic level (50–100 µg/mL) may have the same effectiveness in maintaining alcohol abstinence with a lower risk of presenting side effects.

A Phase II Clinical Trial of Oral Valproic Acid in Patients with Castration-Resistant Prostate Cancers Using an Intensive Biomarker Sampling Strategy

Oral valproic acid (VPA), which is a histone deacetylase inhibitor, was used in a phase II trial to treat patients with castration-resistant prostate cancer (CRPC). Ten patients with CRPC were treated with oral VPA. Oral VPA was not well tolerated in this patient population at a dose targeted to a serum level less than 50 µg/L. The main toxicities were grades 1 and 2 neurologic events and grades 1 and 2 fatigue that caused interruption in the administration of oral VPA and dose delays. Two (20%) of 10 patients had prostate-specific antigen (PSA) responses, and one response was durable. Intensive biomarker collections (weekly) revealed that PSA levels were inversely correlated with total VPA levels. Histone acetylation could not be consistently observed in peripheral lymphocytes using oral VPA. Oral VPA can be administered to CRPC patients with resultant PSA responses. However, oral VPA cannot be administered reliably to achieve consistent levels or duration to be useful in the treatment of CRPC patients. It is unlikely that PSA responses from oral VPA are related to histone deacetylase inhibition. Development of oral VPA in prostate cancers is not recommended using an oral formulation. An intensive biomarker strategy is useful to develop clinical hypotheses in patients with CRPCs in small numbers of patients.

Determination of valproic acid in human serum by high-performance liquid chromatography with fluorescence detection.

A simple and highly sensitive high-performance liquid chromatographic method is described for the determination of valproic acid in human serum. The method is based on the direct derivatization of serum sample with 6,7-methylenedioxy-1-methyl-2-oxo-1,2-dihydroquinoxaline-3-ylpr opionohydrazide. The derivatization reaction proceeds in aqueous solution in the presence of pyridine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide at 37 degrees C. The resulting derivatives were separated on a reversed-phase column (YMC Pack ODS-A) with isocratic elution and were fluorimetrically detected at 440 nm with excitation at 365 nm. The detection limit (signal-to-noise ratio=3) for valproic acid added to serum sample was 0.1 microg (700 fmol)/ml serum sample (2.3 fmol on column). The method was applied to determine the unbound- and total-valproic acid levels in the serum obtained from three healthy volunteers after oral administration of the drug (600 mg).

Determination of Free Valproic Acid

Valproic Acid (VPA) is an important drug for the treatment of several types of seizures because it has a wide spectrum of activity. Since VPA has an unusual nonlinear binding characteristic and a wide interindividual variation, monitoring of its free concentration can be helpful in patient management. The determination of unbound VPA is more difficult because an extra sample preparation step is needed and the concentration of free VPA is low. Free drug monitoring can assume a more important role if there is a refinement in the technology. A high-performance liquid chromatography (HPLC) method with isocratic elution has been established for the analysis of the 4-bromomethyl-7-methoxycoumarin (BrMMC) derivative of free VPA. This method has a better sensitivity, linearity, and precision than enzyme immunoassay (EIA). Ultrafiltration with the Centrifree system was evaluated for the sample preparation. The influence of centrifuge times, relative centrifugal forces, and the starting sample amounts on the final results of the ultrafiltration were investigated. There was a satisfactory correlation between the free VPA levels determined by the HPLC method and the concentrations obtained by EIA. The total and free VPA were determined on 100 samples from 36 patients. The total VPA levels were in a range of 25 to 208 micrograms/ml, free VPA concentrations ranged from 1.92 to 55.75 micrograms/ml with the free fractions from 7 to 37%.

てんかん患者の遊離型バルプロ酸濃度に及ぼす血清中アルブミンと年齢の影響

The serum protein binding of valproic acid (VPA) was examined with samples collected front 88 epileptic patients whose ages ranged from 3 to 78 years.Blood samples were usually collected within one to six hours after a dose in the morning.The free fraction of VPA was obtained with a microultrafiltration devices (Molcut II®) which was developed by Nihon Millipore Ltd., Tokyo, Japan.The free and total VPA levels in serum were determined by fluorescence polarization immunoassay (TDX®).The serum albumin levels were determined by the procedure of ionophoresis.Total VPA levels were positively correlated with free fraction (Y=0.13X+6.39, n=88, r=0.67), and a negative correlation between serum albumin levels and free fraction of VPA (Y=-6.99X+48.49, n=88, r=0.54) was observed in the epileptic patients.We found that the serum albumin levels were decreased with the aging, and the total VPA levels were higher in younger children.The increases of free fraction in the children (8 patients in Lennox Syndrom) and the elderly (11 patients in Hypoalbuminemia) might be results from the protein binding saturation.

Valproic acid disposition in rabbits during chronic treatment with Escherichia coli endotoxin.

The disposition of valproic acid (VPA) in rabbits was studied after chronic treatment with Escherichia coli endotoxin. Endotoxin (1-2 micrograms/kg) was administered daily to 10 male New Zealand white rabbits for 5 days. On day 5, 50 mg/kg of VPA was given iv during the time of the peak febrile response. Blood samples were drawn at appropriate time intervals and analyzed for free and total VPA levels as well as plasma proteins and free fatty acids. The data were compared with similar control experiments performed 2 weeks before and after endotoxin treatment. Pharmacokinetic analysis indicated that the changes in free VPA clearance after endotoxin were related to the change in the febrile response during chronic treatment (r = 0.77; p less than 0.05); that is, animals which developed tolerance to the febrile response showed elevated drug clearance, whereas nontolerant animals showed decreased clearance of VPA.

Differential transplacental binding of valproic acid: influence of free fatty acids.

The unbound fraction of valproic acid (VPA) was found to be significantly lower in cord serum (6.0 +/- 0.8%) than in maternal serum collected before oxytocin (12.2 +/- 2.7%) or after delivery (9.9 +/- 2.3%). The difference was probably due to the concentration of free fatty acids (acting as displacing agents) being higher in maternal serum. The transplacental binding gradient explains the clinical observation that total VPA levels at delivery are higher in the newborn than in the mother.

Determination of Serum Free Valproic Acid by Ultrafiltration Method

The assay of free form of valproic acid (VPA) in serum was made on 71 serum specimens of epileptic patients. For the isolation of free VPA, ultrafiltration using micropartition system MPS-1 (Amicon Corp.) was applied and it was confirmed that this system was good in utility. For the lower levels of VPA as in ultrafiltrates, a modified single dilution technique was developed in EMIT assay instead of the standard double dilution procedure. The results were compared with those determined by the gas-liquid chromatography. Results determined by the above two methods were correlated well (r=0.982) and the regression line was y=1.023x-0.143. Ultrafiltration using MPS-1 is very simple and practical, because it requires small amount of serum sample. In 20 serum specimens from patients treated with VPA alone, the mean percentage of free VPA was 12.5±3.9%. The percentage of free VPA and total VPA levels showed a positive correlation (r=0.808).