Serum Concentrations Of Valproic Acid Research Articles

Metabolic Differentiation in Manic Episode of Bipolar Disorder Compared to Substance-Induced Psychosis and Substance Use Disorder Based on Serum Valproate Level

Aim: Valproic acid (VPA) is primarily used in the treatment of epilepsy but also has uses in the treatment of manic episodes in bipolar disorder and substance use disorders. Manic episodes and psychosis may also affect hepatic clearance and drug distribution volume. The aim of this study was to assess the effect of mania and psychosis compared to substance use on VPA pharmacokinetics, specifically changes in total and unbound clearance. Material and Methods: Fifty patients with a manic episode of bipolar disorder, and 51 patients with substance use disorder, 38 of whom were considered as substance-induced psychosis, were included in this retrospective study. All patients received a constant dose of 1000 mg VPA daily for at least five days, and serum VPA concentrations were measured. Results: The mean serum levels of VPA were 59.2±17.4 μg/ml in the substance use disorder group, 60.9±13.5 μg/ml in the substance-induced psychosis group, and 61.8±13.7 μg/ml in the manic episode of bipolar disorder group. No significant difference was found between the groups (p=0.840). When considering substance use disorder and substance-induced psychosis as one group, the mean VPA level of 60.5±14.4 μg/ml in this group showed no significant difference compared to 61.8±13.7 μg/ml in the manic episode of bipolar disorder (p=0.630). Conclusion: After reaching steady-state plasma levels, no significant difference in serum VPA levels was observed between the three groups. This suggests that manic episodes do not lead to a significant increase in VPA metabolism compared to substance use disorder or substance-induced psychosis.

A prospective study of drug-drug interaction between antiepileptic drugs and meropenem in patients in a tertiary hospital in China from January 2020 to March 2023.

This study aimed to determine the minimum interaction between different antiepileptic drugs (AEDs) and meropenem (MEPM) for clinical treatment. The data of 91 patients enrolled in the neurology department from January 2020 to March 2023 for clinical trials were measured and observed. Self-controlled studies were conducted to monitor the trough concentrations of valproic acid (VPA), carbamazepine (CBZ) and levotiracetam (LEV) before and after MEPM usage. Relevant indicators of liver and kidney function were also monitored. The serum VPA trough concentrations were 36.25±8.22 μg/ml at 24±12 h and 34.99±11.17 μg/ml at 96±12 h after MEPM use; the difference was significant (p<0.05). Decreased CBZ trough concentrations were also identified after MEPM usage (96±12 h), whereas LEV trough concentrations were not affected. An increased liver injury rate (χ2 =8.744, p<0.05) and a decreased kidney injury rate (χ2 =5.393, p<0.05) were found in the VPA group only. The interaction between VPA and MEPM decreased serum VPA concentrations, increased liver injury rates, and decreased kidney injury rates. In addition, the co-administration of MEPM and CBZ reduced serum CBZ concentrations. Clinicians should be aware of this potential interaction and closely monitor the relevant biochemical indices and number of seizures.

Valproic acid monitoring: Serum prediction using a machine learning framework from multicenter real-world data

BackgroundOur study employs machine learning to predict serum valproic acid (VPA) concentrations, aiming to contribute to the development of non-invasive assays for therapeutic drug monitoring. MethodsMedical records from 2002 to 2019 were obtained from the Taiwan Chang Gung Research Database. Using various machine learning algorithms, we developed predictive models to classify serum VPA concentrations into two categories (1–50 μg/ml or 51–100 μg/ml) and predicted the exact concentration value. The models were trained on 5142 samples and tested on 644 independent samples. Accuracy was the main metric used to evaluate model performance, with a tolerance of 20 μg/ml for continuous variables. Furthermore, we identified important features and developed simplified models with fewer features. ResultsThe models achieved an average accuracy of 0.80–0.86 for binary outcomes and 0.72–0.88 for continuous outcome. Ten top features associated with higher serum VPA levels included higher VPA last and daily doses, bipolar disorder or schizophrenia spectrum disorder diagnoses, elevated levels of serum albumin, calcium, and creatinine, low platelet count, low percentage of segmented white blood cells, and low red cell distribution width-coefficient of variation. The simplified models had an average accuracy of 0.82–0.86 for binary outcome and 0.70–0.86 for continuous outcome. LimitationsThe study's predictive model lacked external test data from outside the hospital for validation. ConclusionsMachine learning models have the potential to integrate real-world data and predict VPA concentrations, providing a promising tool for reducing the need for frequent monitoring of serum levels in clinical practice.

Comparison of four valproic acid free fraction determination methods used in clinical practice

ObjectiveGiven that hypoalbuminemia tends to result in higher free fraction concentrations of valproic acid, different methods have been developed to determine the latter in patients with this condition. The aim of this study is to assess the reliability of these methods and, if necessary, design a new estimation method. MethodA retrospective analysis was carried out by the Pharmacy Department of Severo Ochoa University Hospital of admitted patients with at least one trough concentration of valproic acid between October 2017 and February 2019. The estimation methods used were those developed by Kodama, Hermida, Doré, as well as a new method proposed in the study. A total of 17 serum valproic acid concentrations were used to determine the free fraction of valproic acid with each method; the values obtained were compared with the results obtained following laboratory determinations. Accuracy and precision were calculated using mean error and root mean square error, respectively. ResultsThe comparison between observed and predicted free valproic acid values using the methods under investigation showed that the method proposed in this study provides the highest reliability as it presents the highest accuracy and precision. The worst results were those obtained using the Kodama method, which does not consider albuminemia, an essential variable that determines the concentration, therapeutic effect and toxicity of valproic acid. ConclusionsGiven that the method proposed in this study proved to be superior to the other methods analyzed, we believe it can be reliably used to estimate free valproic acid levels in patients with hypoalbuminemia.

Association of ABCB1 Polymorphisms with Efficacy and Adverse Drug Reactions of Valproic Acid in Children with Epilepsy.

Genetic polymorphisms in ATP-binding cassette subfamily B member 1 (ABCB1, also known as MDR1) have been reported to be possibly associated with the regulation of response to antiseizure medications. The aim of this study was to investigate the association of ABCB1 polymorphisms with the efficacy of and adverse drug reactions to valproic acid among Chinese children with epilepsy. A total of 170 children from southern China with epilepsy treated with valproic acid for more than one year were recruited, including 61 patients with persistent seizures and 109 patients who were seizure-free. Two single nucleotide polymorphisms of ABCB1, rs1128503 and rs3789243, were genotyped using the Sequenom MassArray system. The two single nucleotide polymorphisms of ABCB1 were found to be significantly associated with treatment outcomes of valproic acid in children with epilepsy. Carriers with the TT genotype of ABCB1 rs1128503 were more inclined to exhibit persistent seizures after treatment with valproic acid (p = 0.013). The CC genotype of rs3789243 was observed to be a potential protective factor for valproic acid-induced gastrointestinal adverse drug reactions (p = 0.018), but possibly increased the risk of valproic acid-induced cutaneous adverse drug reactions (p = 0.011). In contrast, the CT genotype of rs3789243 was associated with a lower risk of valproic acid-induced cutaneous adverse drug reactions (p = 0.011). Haplotype analysis showed that CC haplotype carriers tended to respond better to valproic acid treatment (p = 0.009). Additionally, no significant association was found between ABCB1 polymorphisms and serum concentrations of valproic acid. This study revealed that the polymorphisms and haplotypes of the ABCB1 gene might be associated with the treatment outcomes of valproic acid in Chinese children with epilepsy.

Prediction of systemic free and total valproic acid by off-line analysis of exhaled breath in epileptic children and adolescents.

Therapeutic drug monitoring (TDM) of medications with a narrow therapeutic window is a common clinical practice to minimize toxic effects and maximize clinical outcomes. Routine analyses rely on the quantification of systemic blood concentrations of drugs. Alternative matrices such as exhaled breath are appealing because of their inherent non-invasive nature. This is especially the case for pediatric patients. We have recently showcased the possibility of predicting systemic concentrations of valproic acid (VPA), an anti-seizure medication by real-time breath analysis in two real clinical settings. This approach, however, comes with the limitation of the patients having to physically exhale into the mass spectrometer. This restricts the possibility of sampling from patients not capable or available to exhale into the mass spectrometer located on the hospital premises. In this work, we developed an alternative method to overcome this limitation by collecting the breath samples in customized bags and subsequently analyzing them by secondary electrospray ionization coupled to high-resolution mass spectrometry (SESI-HRMS). A total ofn= 40 patients (mean ± SD, 11.5 ± 3.5 y.o.) diagnosed with epilepsy and taking VPA were included in this study. The patients underwent three measurements: (i) serum concentrations of total and free VPA, (ii) real-time breath analysis and (iii) off-line analysis of exhaled breath collected in bags. The agreement between the real-time and the off-line breath analysis methods was evaluated using Lin's concordance correlation coefficient (CCC). CCC was computed for ten mass spectral predictors of VPA concentrations. Lin's CCC was >0.6 for all VPA-associated features, except for two low-signal intensity isotopic peaks. Finally, free and total serum VPA concentrations were predicted by cross validating the off-line data set. Support vector machine algorithms provided the most accurate predictions with a root mean square error of cross validation of 29.0 ± 7.4 mg l-1and 3.9 ± 1.4 mg l-1for total and free VPA (mean ± SD), respectively. As a secondary analysis, we explored whether exhaled metabolites previously associated with side-effects and response to medication could be rendered by the off-line analysis method. We found that five features associated with side effects showed a CCC > 0.6, whereas none of the drug response-associated peaks reached this cut-off. We conclude that the clinically relevant free fraction of VPA can be predicted by this combination of off-line breath collection with rapid SESI-HRMS analysis. This opens new possibilities for breath based TDM in clinical settings.

Case of Decreased Serum Valproic Acid Concentration During Concomitant Use of Meropenem in Patients with Traumatic Brain Injury

Case of Decreased Serum Valproic Acid Concentration During Concomitant Use of Meropenem in Patients with Traumatic Brain Injury

Effect of ANKK1 Polymorphisms on Serum Valproic Acid Concentration in Chinese Han Adult Patients in the Early Postoperative Period.

This study aimed to investigate the relationship between gene polymorphisms and clinical factors with the concentrations of valproic acid (VPA) in adult patients who underwent neurosurgery in China. A total of 531 serum concentration samples at steady state were collected from 313 patients to develop a population pharmacokinetic (PPK) model. Data analysis was performed using nonlinear mixed effects modeling. Covariates included demographic parameters, biological characteristics, and genetic polymorphism. Bootstrap evaluation showed that the final model was stable. Sensitive analysis was performed to verify the relationship between gene polymorphisms and concentrations of VPA. Linear regression was used to analyze the relationship between VPA concentration, ANKK1, and daily dosage. In the recruited patients, 17 of 25 single-nucleotide polymorphism distributions were consistent with the Hardy-Weinberg equilibrium. A one-compartment model with first-order absorption and elimination was developed for VPA injections. VPA clearance was significantly influenced by three variables: sex (17.41% higher in male than female patients), body weight, and the ANKK1 gene. Typical values for the elimination clearance and the volume of central compartment were 0.614L/min and 23.5L, respectively. The model evaluation indicated the stable and precise performance of the final model. After sensitive analysis using Kruskal-Wallis and Mann-Whitney U tests, we found that patients with AA alleles had higher VPA concentrations than those with GG and AG alleles. Linear regression models showed that gene polymorphisms of ANKK1 had little effects on VPA concentration. A PPK model of VPA in Chinese Han patients was successfully established; this can be helpful for model-informed precision-dosing approaches in clinical patient care, and for exploring the mechanism of VPA-induced weight gain.

Serum concentrations of valproic acid in people with epilepsy: Clinical implication

Context: Therapeutic drug monitoring (TDM) allows personalizing the dose of valproic acid in patients with epilepsy to optimize drug therapy, minimize adverse effects and detect interactions. Aims: To determine valproic acid concentrations in serum samples from people with epilepsy and to analyze its clinical implications. Methods: Cloned donor enzyme immunoassay; descriptive, cross-sectional, non-randomized, convenience recruitment study of 57 voluntary patients with epilepsy (n = 39 male, 68.42%; n = 18 female, 31.58%) aged between 19 and 62 years. After three months of treatment with valproic acid, a single blood sample was collected from each volunteer at a minimal concentration. Results: Serum drug concentrations 51.30-100.10 mg/L (SD 5.94) and level/dose 2.17-5.31 (SD 1.14) were observed. Association was shown between the dose ratio/dose of valproic acid (R2 = 0.8693; p&lt;0.05) and the Mann-Whitney U test (p&lt;0.05). Valproic acid monotherapy and association with carbamazepine and phenytoin are not different between treatment groups (Mann-Whitney U test: p = 0.391 &gt; α = 0.05). Conclusions: Serum valproic acid concentrations are within the therapeutic range, and there is a significant inverse linear correlation between dose ratio/dose, which must be considered to personalize the dose and optimize the pharmacotherapeutic result.

Comparative effectiveness of valproic acid in different serum concentrations for maintenance treatment of bipolar disorder: A retrospective cohort study using target trial emulation framework.

SummaryBackgroundThere is a lack of consensus on the optimal serum valproic acid (VPA) concentration for maintenance therapy in bipolar disorder (BD). We aimed to investigate the association between serum VPA levels and risk of mood episode recurrence.MethodsWe enrolled patients with BD from multiple medical institutions in Taiwan between January 1, 2001 and December 31, 2019. Patients were divided into three groups according to their serum VPA concentrations (< 50 μg/ml, 50–74 μg/ml, and 75–104 μg/ml). Adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) compared times to mood episode recurrence using the < 50 μg/ml group as reference. A systematic review found relevant articles published before February 2022 (PROSPERO: CRD42022309661), and corresponding results were compared.FindingsThis cohort included 896 patients for an intention-to-treat analysis. Compared with the < 50 μg/ml group, a non-significantly lower risk of mood episode recurrence was found in the 50–74 μg/ml (aHR, 95% CI: 0·86, 0·71–1·05) and 75–104 μg/ml (0·91, 0·71–1·18) groups. A per-protocol analysis of 481 patients found a significant risk reduction in the 50–74 μg/ml group (0·76, 0·60–0·97), with inconclusive results in the ≥ 75 μg/ml group (1·03, 0·73–1·46). A meta-analysis including two studies (254 patients) and our cohort found a similar significantly lower risk of mood episode recurrence in the 50–74 μg/ml group (HR, 95% CI: 0·83, 0·69–0·99), while risk reduction in the 75–99 μg/ml group (0·62, 0·26–1·48) did not differ significantly from that in the < 50 μg/ml group or the 50–74 μg/ml group.InterpretationThe combined results of this cohort and previous studies suggest that VPA between 50–74 μg/ml may be a more effective concentration to prevent acute mood episodes during maintenance therapy in patients with BD compared with VPA < 50 μg/ml.FundingMinistry of Science and Technology, Taiwan, and Chang Gung Medical Research Project.

Published population pharmacokinetic models of valproic acid in adult patients: a systematic review and external validation in a Chinese sample of inpatients with bipolar disorder

ABSTRACT Background This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to determine predictive performance. Methods Thirteen published PPK models (labeled with letters A to M) not restricted to children were identified in PubMed, Embase, and Web of Science databases. They were evaluated in a sample totaling 411 serum concentrations from 146 adult inpatients diagnosed with bipolar disorder in a Chinese hospital. Serum concentrations of VPA were analyzed by validated ultra-performance liquid chromatography-tandem mass spectrometry. Performance was assessed by four tests (prediction-based diagnostics, visual predictive checks, normalized prediction distribution error, and Bayesian forecasting). Results Models K and L, developed in large samples of Chinese and Thai patients, showed good performance in our Chinese dataset. Models H and J demonstrated good performance in 2 and 3 of the 4 tests, respectively. Another seven models exhibited intermediate performance. The models with the worst performance, F and M, could not be improved by Bayesian forecasting. Conclusion In our validation study, the most important factors contributing to good performance were absence of children, Asian ethnicity, one-compartment models, and inclusion of body weight and VPA dose in previously published models.

Valproic Acid Serum Concentration and Incidence of Toxicity in Pediatric Patients.

In certain pediatric patients on valproic acid, therapeutic range (50-100 μg/mL) is maximized or exceeded to achieve better seizure control. This study compared incidence of common valproic acid adverse effects (thrombocytopenia, hepatotoxicity, and hyperammonemia) across maintenance concentration and age group. One hundred twenty-four children on maintenance valproic acid between January 2013 and January 2021 were eligible for inclusion. Fifty-six patients were maintained in concentration range 50 to 80 μg/mL, an additional 44 between 80 and 100 μg/mL and 24 between 100 and 120 μg/mL. Forty-one patients were prepubescent, 57 pubescent, and 26 postpubescent. There were no statistically significant differences observed in the primary endpoint of thrombocytopenia across serum concentration range (P = .093) or age group (P = .628). No significant differences in hepatic dysfunction (P = .099) or hyperammonemia (P = .548) were observed in serum concentration groups. Similarly, age group analysis observed no difference in hepatic dysfunction (P = .615) or hyperammonemia (P = .369). Serum valproic acid levels >100 μg/mL can be considered in select pediatric patients based on this study.

HYPERAMMONAEMIA AND COGNITIVE IMPAIRMENT IN EPILEPSY PATIENTS TREATED WITH VALPROIC ACID - PRELIMINARY STUDY.

The aim: To determine whether VPA pharmacotherapy, mainly in the group of patients using subtherapeutic doses of VPA, could contribute to the occurrence of cognitive impairment. Materials and methods: The study involved 14 patients: six women and eight men, aged 24 - 77 years (mean SD ± - 52.36±13.71) diagnosed with epilepsy in accordance with the ILAE criteria (International League Against Epilepsy), in whom the main clinical complaint, in addition to poor control of epileptic seizures, were impaired concentration, attention and memory impairment. Results: Mild cognitive impairment - MCI was diagnosed in 4 patients (28.57%) (3 with elevated ammonia levels, 1 without), in 1 patient (7.14%) there was a mild level of dementia. In only one MCI case, elevated serum concentrations of valproic acid were also recorded. It is very important to highlight that cognitive impairment has never been diagnosed before (prior to VPA therapy) in this group. Of these 5 patients, in four cases, after discontinuation of the drug, an improvement in the clinical condition was achieved. In a patient with mild level dementia, the termination of therapy did not give a similar effect. This proves the possibility of other mechanisms responsible for generating these sometimes irreversible disorders. Conclusions: Regardless of the dose and concentration of ammonia in blood serum of patients diagnosed with epilepsy, VPA therapy may cause various, significant dysfunctions that significantly impair quality of life.

Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia

Valproic acid is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproic acid augmentation therapy in schizophrenia. Interindividual variability in valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between serum concentrations of valproic acid and single nucleotide polymorphisms of the cytochrome P450 (CYP) 2C19 gene in patients with schizophrenia. All patients had been receiving fixed dose of valproic acid for at least 2 weeks. The daily doses were 0.5–1.5 g. No other drugs except olanzapine were coadministered. Serum concentrations of valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The CYP2C19 (CYP2C19*2 G681A rs4244285 and CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of valproic acid were significantly higher in patients with CYP2C19 *1/*2 genotype (P < 0.01) or CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 – β) = 0.8486 at type I level of 0.05) to support the observed significant associations for CYP2C19 SNPs and serum C/D ratios of valproic acid. The findings of this study suggest that the genetic polymorphisms of CYP2C19 significantly affect the steady-state serum concentrations of valproic acid in Chinese Han population. The determination of the CYP2C19 genotypes may be useful for dosing adjustment in schizophrenia patients on valproic acid therapy.

Evaluation of Factors Impacting the Efficacy of Single or Combination Therapies of Valproic Acid, Carbamazepine, and Oxcarbazepine: A Longitudinal Observation Study.

Objective: This study aimed to determine the efficacy and clinical factors related to the pharmacodynamics of single or combination therapies of valproic acid (VPA), carbamazepine (CBZ), and oxcarbazepine (OXC), three commonly used anti-epileptic drugs (AEDs) in China. Methods: The study evaluated the records of 2027 outpatients in a Changsha hospital, located in China, from December 23, 2015 to October 28, 2019. The baseline seizure frequency was assessed during the first visit. AED efficacy was determined based on the reduction in seizures from baseline at the subsequent visits. Multivariable ordinal regression analysis was used to determine the association between the clinical factors (demographic characteristics, clinical features, and medication situation) and AED efficacy. For validation, the clinical efficacies of AEDs were compared as both single agents and in combinations. Differences in adverse effect (AEs) categories were analyzed by Chi-square between AED groups. Results: Records of patients receiving VPA, CBZ, and OXC were evaluated. Serum concentrations of VPA and CBZ is significantly correlated with efficacy (OR 1.030 [1.024–1.037], p < 0 0.0001; OR 1.250 [1.146–1.63], p < 0.0001, respectively) and OXC efficacy correlated to the serum concentration of the metabolite 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) serum concentrations (OR 1.060 [1.031–1.089], p < 0.0001). Significant differences existed between females and males in VPA efficacy (OR 1.318 [1.033–1.682], p = 0.027). After validation, VPA, in combination with OXC (OR 1.93 [1.38–2.70], p<0.001), or with VGB (Vigabatrin) (OR 2.36 [1.38–2.70], p = 0.002), showed significantly better efficacy than as a single agent. OXC efficacy was also affected by the duration of epilepsy (OR 0.965 [0.946–0.984], p < 0.001). Additionally, the efficacies of OXC and VPA were also affected by the seizure type. Seizure reduction improved significantly with an increasing number of pharmacists’ educations in the first three visits period. There were no differences in AEs incidence among these 3 AEDs except for Psychiatric (0.02) and nervous system disorders (0.0001). Conclusion: Serum concentrations of VPA and CBZ may positively affect their efficacies, while OXC efficacies are correlated to MHD serum concentrations. The efficacy of VPA was higher in females compared to males. VPA-OXC and VPA-VGB combinations had higher efficacies compared to monotherapy. Besides, OXC efficacy is probably reducing by the duration of epilepsy. Additionally, VPA efficacy for focal or generalized seizures is superior to mixed-type seizures. OXC was more effective for focal seizures compared to mixed-type ones. Education provided by pharmacists improved the seizures to some extent, and there were no significant differences between most categories of adverse effects for the investigated AEDs.

Interaction between valproic acid and carbapenems: decreased plasma concentration of valproic acid and liver injury.

Several case reports and retrospective studies have indicated that carbapenems decrease the plasma concentration of valproic acid (VPA). This retrospective study examines the effect of carbapenems on VPA levels, and explores whether the drug-drug interaction can influence the liver function of patients. The data of 141 patients were collected from the Department of Neurosurgery at Shanxi Bethune Hospital from January 2018 to December 2019. We compared the VPA levels between the VPA monotherapy group and VPA + carbapenem group to evaluate the influence of carbapenem antibiotics on the plasma concentration of VPA. We also compared the liver injury rate of the VPA monotherapy group, VPA + meropenem group, and VPA + imipenem group to evaluate the influence of concomitant use of VPA with carbapenem antibiotics on liver function. The VPA serum concentration in the VPA + meropenem group was 22.32±21.77 µg/mL, which was markedly lower than that in the VPA monotherapy group (i.e., without carbapenems) (65.17±21.49 µg/mL) (P<0.01). The rate of liver injury was significantly different between the VPA monotherapy, VPA + meropenem, and VPA + imipenem groups (χ2=30.13, P<0.01). Further comparisons showed that the liver injury rate of the VPA + meropenem group (35.42%) was higher than that of the VPA + imipenem (3.7%) and VPA monotherapy (1.52%) groups (P<0.01). Although no significant differences in liver injury rate were observed between the VPA + imipenem (3.7%) and VPA monotherapy (1.52%) groups, the alanine aminotransferase (ALT) value of the VPA + imipenem group after co-administration (65.22±48.01 U/L) was notably higher than before (40.48±24.97 U/L) (P<0.01). In this study, the interaction between VPA and carbapenems resulted in decreased plasma concentrations of VPA as well as possible liver injury. Clinicians should be aware of this potential interaction, and closely monitor VPA concentrations and liver function. Different carbapenems combined with VPA showed different effects on both VPA concentration and liver function, indicating that the mechanisms of these two effects might be related.

Simple determination of valproic acid serum concentrations using BioSPME followed by gas chromatography-mass spectrometric analysis

Valproic acid (VA) is a drug widely used on the treatment of epilepsy and bipolar affective disorders, with stablished therapeutic concentration ranges in serum. The measurement of VA serum concentrations using chromatographic methods requires a sample preparation step. In this context, this study aims to describe the development and validation of an assay for VA measurement in serum using a new microextraction strategy, known as BioSPME, followed by GC–MS analysis. The extraction procedure was very simple based on direct immersion of the BioSPME tips on acidified serum, followed by agitation and desorption in methanol. The methanolic extracts were directly injected into the chromatograph. Extraction yield was 95.6 to 101.3%. The assay was linear from 10 to 150 mg L−1. Precision, accuracy and stability assays were acceptable according to bioanalytical validation guidelines. The method was applied to 41 clinical serum samples also tested with a previously GC–MS validated assay, which used liquid-liquid extraction as sample preparation. Measurements obtained with both methods were comparable. This study is the first description of the use of BioSPME tips for a therapeutic drug. BioSPME is a promising alternative for the preparation of biological specimens prior to the determination of therapeutic drugs by GC–MS.

Interactions between carbapenems and valproic acid among the patients in the intensive care units.

To evaluate risk factors for epileptic seizures or status epilepticus (SE) in patients concomitantly receiving valproic acid (VPA) and carbapenems. Adult patients in the intensive care units (ICUs) who concomitantly received VPA and carbapenems from 2007 to 2017 were included. The impacts of different carbapenems on serum concentration of VPA were compared. Among 162 patients included, 104 (64.2%) and 45 (27.8%) developed epileptic seizures and SE, respectively. The risk factors for epileptic seizures were age (per year increase, adjusted odds ratio [aOR], 1.03), initial antiepileptic regimen (monotherapy and polytherapy, aOR, 0.43 and 0.18, respectively), and VPA serum concentration after concomitant carbapenem administration (per 1μg/mL increase, aOR, 0.96). VPA serum concentration after concomitant carbapenem administration was an independent risk factor for SE (per μg/mL increase, aOR, 0.98). Concomitant imipenem/cilastatin administration did not significantly decrease VPA serum concentration compared to that by meropenem or ertapenem. The length of stay and number of days on ventilation after concomitant carbapenem administration in the ICUs were significantly more in those with epileptic seizures or SE. Carbapenems decreased VPA serum concentration and increased the risk of epileptic seizures and SE, which led to increased length of ICU stay.

Impact of Age and Genotype on Serum Concentrations of Valproic Acid and Its Hepatotoxic Metabolites in Chinese Pediatric Patients With Epilepsy

The aim of the study was to investigate how age and genetic polymorphisms of UGT1A6 and UGT2B7 contribute to the concentrations of valproic acid (VPA) and its hepatotoxic metabolites in Chinese pediatric patients with epilepsy. A total of 122 children with epilepsy were genotyped at 19T>G, 541A>G, and 552A>C in UGT1A6 and -161C>T and 802C>T in UGT2B7 using the polymerase chain reaction-restriction fragment length polymorphism method or direct sequencing method. The concentrations of VPA, 4-ene-VPA, and 2,4-diene-VPA were simultaneously determined using ultra-performance liquid chromatography-tandem mass spectrometry. Significant association was observed between the UGT2B7 802C>T genotype and dose-adjusted concentrations of VPA, 4-ene-VPA, and 2,4-diene-VPA. The younger children had increased concentrations of the hepatotoxic metabolites and decreased levels of VPA. The allele status of UGT2B7 802C>T had no influence on the metabolite ratios within age groups, but showed a significant difference among the age groups. The present study suggests that UGT2B7 802C>T polymorphism and age are factors affecting the concentrations of dose-adjusted VPA and its metabolites. No genotype-related differences were noted in the metabolite ratios of 4-ene-VPA and 2,4-diene-VPA within age-assigned groups. Therefore, careful administration is particularly necessary for younger patients who are UGT2B7 802C>T poor metabolizers.

Safety range of free valproic acid serum concentration in adult patients

BackgroundTherapeutic drug monitoring (TDM) is recommended during valproic acid (VPA) use, and total serum concentration has been widely adopted. However, the free form of VPA is responsible for its pharmacologic and toxic effects, and the total and free concentrations are highly discordant because of VPA’s highly protein bound and saturable binding characteristics. Therefore, free VPA monitoring is increasingly advocated. Nevertheless, the correlation between free VPA concentration and associated adverse effects remains unknown.ObjectiveTo determine the optimal safety range of free VPA concentration in adult patients.Materials and methodsThis prospective cohort study enrolled adult patients undergoing VPA therapy with TDM. Patient characteristics, VPA use, and adverse effects (thrombocytopenia, hyperammonemia, and hepatotoxicity) were recorded. A multivariate logistic regression model was applied to identify the predictors of adverse effects, and the receiver operating characteristic curve was applied to locate the cutoff point of free VPA concentration.ResultsA total of 98 free serum concentrations from 51 patients were included for final analysis. In total, 31 (31.6%), 27 (27.6%), and 4 (4.1%) episodes of hyperammonemia, thrombocytopenia, and hepatotoxicity were observed, respectively. Free VPA concentration was a predicting factor for thrombocytopenia but not for hyperammonemia. A free VPA concentration of >14.67 mcg/mL had the greatest discriminating power (area under the curve = 0.77) for the occurrence of thrombocytopenia.ConclusionsA free VPA serum concentration of 14.67 mcg/mL had the optimal discriminating power for the occurrence of thrombocytopenia. Ammonemia should be monitored even if free VPA concentration is within the safety range.