Plasma Valproic Acid Concentrations Research Articles

Combined carbapenem resulted in a 4.48-fold increase in valproic acid clearance: a population pharmacokinetic model in Chinese children and adults with epilepsy or after neurosurgery

Our study aims to explore the pharmacokinetics of valproic acid (VPA) in Chinese patients with epilepsy or after neurosurgery and establish a robust population pharmacokinetics (PPK) model. The PPK model was developed using nonlinear mixed-effects modeling, incorporating a total of 615 VPA plasma concentration data points from 443 Chinese epilepsy or after neurosurgery patients. A one-compartment model with an additive residual model was established. Forward addition and backward elimination strategies were used to assess the impact of covariates on the model parameters. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution errors were used for model validation. In the final model, the apparent clearance (CL) was estimated using the following formula: CL L/h=0.430×BW/600.787×Cr/50.3−0.253×ALB/39−0.873×egender×eCBP×eIND2 ×eηCL (gender = 0.121 when is female, otherwise = 0; CBP = 1.50 when combined with carbapenems, otherwise = 0; IND2 = 0.15 when combined with oxcarbazepine, carbamazepine, phenobarbital, or phenytoin, otherwise = 0). The volume of distribution (Vd) was estimated using the formula: Vd L=8.66×BW/600.751. Comedication with carbapenems could increase VPA clearance by 4.48 times, and comedication with oxcarbazepine could enhance VPA clearance by 116%. Besides, creatinine and albumin could affect VPA clearance. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution showed acceptable data fit, stability, and predictability of the model. In our study, a PPK model was utilized to attain a more comprehensive insight into these variables, improving the accuracy and individualization of VPA therapy in Chinese patients with epilepsy or after neurosurgery.

Joint use of population pharmacokinetics and machine learning for prediction of valproic acid plasma concentration in elderly epileptic patients

BackgroundValproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug. For elderly epileptic patients, VPA plasma concentrations have a considerable variation. We aim to establish a prediction model via a combination of machine learning and population pharmacokinetics (PPK) for VPA plasma concentration. MethodsA retrospective study was performed incorporating 43 variables, including PPK parameters. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were employed for ensemble model, and the model was interpreted by Shapley Additive exPlanations. ResultsThe inclusion of PPK parameters significantly enhances the performance of individual algorithm model. The composition of categorical boosting, light gradient boosting machine, and random forest (7:2:1) with the highest R2 (0.74) was determined as the ensemble model. The model included 11 variables after feature selection, of which the predictive performance was comparable to the model that incorporated all variables. ConclusionsOur model was specifically tailored for elderly epileptic patients, providing an efficient and cost-effective approach to predict VPA plasma concentration. The model combined classical PPK with machine learning, and underwent optimization through feature selection and algorithm integration. Our model can serve as a fundamental tool for clinicians in determining VPA plasma concentration and individualized dosing regimens accordingly.

Evaluation of CYP2C19 Genetic Variant and Its Lack of Association with Valproic Acid Plasma Concentrations Among Zhuang and Han Schizophrenia Patients in Guangxi.

To investigate the CYP2C19 genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between CYP2C19 genetic variants and standardized blood levels of Valproic Acid (VPA) in schizophrenic patients, and evaluate the effects of age, gender, and Body Mass Index (BMI) on standardized VPA blood concentrations. Between February and December 2022, 192 Zhuang and Han schizophrenia patients treated with VPA were studied. Steady-state VPA concentrations were determined using homogeneous enzyme immunoassays, and CYP2C19 *1, *2, and *3 loci via q-PCR. CYP2C19 genotype distributions between Zhuang and Han groups in Nanning were compared using chi-square tests and contrasted with other ethnicities. Non-parametric tests analyzed VPA variations, identifying critical factors through multivariate stepwise regression. The study identified five CYP2C19 genotypes at the *2 and *3 loci, with the *3/*3 genotype absent in both cohorts. The CYP2C19 distribution in Guangxi Zhuang and Han mirrors, yet diverges significantly from Hui and Kazakh groups. Among 192 subjects, VPA blood levels remained consistent across metabolic types and ages 18-60 but varied significantly by gender. Multivariate analysis revealed gender and BMI as significant factors, overshadowing CYP2C19 genotype and age. In Guangxi, CYP2C19 genetic variants in Zhuang and Han schizophrenia patients demonstrate statistically indistinguishable allelic and metabolic distributions. Gender and BMI can influence standardized VPA blood concentrations in schizophrenia patients. However, in our study cohort, the CYP2C19 genotype and age are not the primary determinants of standardized VPA blood levels.

Retrospective Analysis of Steady-State Sodium Valproate Plasma Concentrations in Chinese Patients With Bipolar Disorder: Impact of Demographic and Clinical Characteristics.

This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes. In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study. The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01). This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy.

Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid.

This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA. We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group. The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 μg/mL) compared with that before co-administration (88.8 ± 13.6 μg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 μg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291). In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted. Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Association of Valproic Acid and Its Main Metabolites' Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring.

Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 μg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 μg/mL versus 4.83 μg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.

Interaction between valproic acid and meropenem or ertapenem in patients with epilepsy: clinical relevance and results from pharmaceutical intervention

ObjectiveThe literature has described the interaction between valproic acid and carbapenems. This interaction leads to decreases in plasma concentrations of valproic acid. The main objectives of this study were to assess its relevance in clinical practice, to identify variables associated with increased seizure episode rates, and to analyse the impact of pharmaceutical intervention on avoiding the effects of this interaction. MethodAn observational retrospective study of inpatients with epilepsy admitted between 2016 and 2020. Their pharmacological treatment throughout admission was recorded, and the presence of other interactions leading to decreased plasma concentrations of valproic acid was reviewed. The seizure rate during the year prior to admission was compared to that during the interaction period. For every episode in which the interaction was detected, an intervention was conducted by providing the prescriber with information on the interaction and suggesting a change of antibiotherapy as well as the pharmacokinetic monitoring of valproic acid. Results37 episodes were included. 58.1% of the patients were male and median age was 70 years. In total, 56.8% of the patients received meropenem and 43.2% received ertapenem. The median duration of concomitant treatment with valproic acid and carbapenem was 4 days. The incidence rate ratio was 2.60 (95% confidence interval: 1.61-4.21). Thus, this interaction was associated with a higher seizure rate. A statistically significant association was found between higher seizure rates and patients treated with more than one anti-epileptic drug. Hospital pharmacists detected 24 episodes (64.9%). In total, 17 interventions (70.8%) were accepted and 13 combinations were discontinued. Pharmacokinetic monitoring was conducted in 13 episodes (35.1%) and infratherapeutic levels were found in all of them. ConclusionsThe interaction between valproic acid and meropenem or ertapenem is clinically relevant. It is recommended that this combination should be avoided provided that a viable alternative is available. Pharmaceutical intervention may contribute to preventing seizures associated with this combination.

Distribution pattern of UGT1A6 and UGT2B7 gene polymorphism and its impact on the pharmacokinetics of valproic acid and carbamazepine: Prospective genetic association study conducted in Pakistani patients with epilepsy

BackgroundEthnic variation is one of the important factors in clinical practice that may affect the pharmacokinetics of drugs. The present study aims to determine the distribution pattern of UGT1A6 and UGT2B7 gene polymorphism and its possible impact on the metabolism of valproic acid (VPA) and carbamazepine (CBZ) in patients with epilepsy from Khyber Pakhtunkhwa region of Pakistan. Methods: After the enrollment of targeted patients, blood was collected for genotype analysis through Sanger sequencing. Plasma concentrations of VPA and CBZ were determined by reversed-phase high-performance liquid chromatography (HPLC) at the follow-up visit of third month from the initiation of therapy. The drug plasma levels were correlated with different genotypes of UGT1A6 and UGT2B7 to determine the impact of genetic polymorphism on the drug metabolism. Results: Of the total 178 epileptic patients, 120 subjects were prescribed VPA monotherapy while 58 subjects were given CBZ monotherapy. The mean age of the subjects was recorded as 26.1 ± 13.5 years with a predominance of the male gender. Generalized tonic-clonic (GTC) was the most prevalent type of seizure (82%) followed by partial seizure. Genotype analysis revealed that the frequency of homozygous and heterozygous variants of the targeted UGT genes were exceptionally high in the Khyber Pakhtunkhwa population compared to the ethnic groups of other countries. In UGT1A6-A552C and UGT1A6-A541G, AC and AG were the most prevalent genotypes with respective frequencies of 43.2% and 41.1% whereas, in UGT2B7-T161C and UGT2B7-G211T, TC and GG were the most prevalent genotypes with respective frequencies of 42.7% and 99.4%. In the VPA-treated group, the homozygous and heterozygous variants of UGT1A6-A552C and UGT1A6-A541G were significantly associated with lower drug plasma concentrations (p < 0.05). However, none of the genotypes of UGT2B7-T161C revealed any significant association with VPA plasma concentration (p greater than 0.05). In the CBZ-treated group, UGT gene polymorphisms were not recognized to cause alteration in the drug plasma concentrations (p greater than 0.05). Conclusion: The genetic polymorphisms of UGT1A6, but not UGT2B7 significantly affected the plasma levels of valproic acid. The chosen SNPs did not reveal a role in determining the plasma levels of carbamazepine.

Effects of UGT1A, CYP2C9/19 and ABAT polymorphisms on plasma concentration of valproic acid in Chinese epilepsy patients.

Aim: To evaluate the association between genetic polymorphisms and plasma concentration-to-dose ratio of valproic acid (CDRV) in Chinese epileptic patients. Methods: A total of 46 epileptic patients treatedwith valproic acid therapy were enrolled. 18 SNPs in nine genes related to valproic acid were directly sequenced with Sanger methods. Results: Patients carrying UGT1A6 heterozygous genotypes had significantly lower CDRV than those carrying the wild-type genotypes. In contrast, patients with the homozygote genotypes of CYP2C9 and ABAT had higher CDRV than those with the wild-type genotypes and patients with the heterozygous genotypes of CYP2C19 had higher CDRV. Conclusion: Detection of genetic polymorphism in these genes might facilitate an appropriate dose of valproic acid for epileptic patients. Further studies with larger cohorts are necessary to underpin these observations.

Therapeutic drug monitoring of phenytoin and valproic acid in critically ill patients at Windhoek Central Hospital, Namibia.

BackgroundPhenytoin and valproic acid, anticonvulsants, have a low therapeutic index and are highly plasma protein bound, mainly to albumin. Hypoalbuminaemia is common in critically ill patients and increases the unbound drug concentration. Thus, monitoring unbound rather than total plasma drug concentrations is recommended to optimise the dosing of these drugs.ObjectiveThis retrospective study determined unbound plasma concentrations of phenytoin and valproic as a more accurate value of drug levels than total plasma drug concentrations.MethodsTotal plasma concentrations were retrieved for 56 Intensive Care Unit patients for phenytoin and 93 for valproic acid. Total drug concentrations were converted to unbound concentrations using a serum albumin-based normalising equation.ResultsTotal phenytoin plasma concentration was below (41.1% of patients), within (46.4%) or above (12.5%) the therapeutic range (10 μg/mL – 20 μg/mL). However, the predicted unbound plasma concentration of phenytoin was above the therapeutic range (1 μg/mL – 2 μg/mL) in the majority of patients (57.1%). For valproic acid, the total plasma concentration of most patients (87.1%) was below the therapeutic range (50 μg/mL – 100 μg/mL); among remaining patients (12.9%), it was within the therapeutic range. In the majority of patients (91.4%), the predicted unbound plasma concentration of valproic acid was between 2.5 μg/mL and 20 μg/mL.ConclusionThe usefulness of monitoring the total phenytoin or valproic acid levels for dose optimisation is limited as it is an inaccurate indicator of a patient’s drug therapeutic state. Thus, the unbound plasma drug concentrations should be quantified experimentally or predicted in resource-limited settings.

The impact of ibuprofen on valproic acid plasma concentration in pediatric patients

The combination of valproic acid (VPA) and ibuprofen is common in children with epilepsy. Three case reports investigated that ibuprofen might decrease plasma concentration of VPA, however, no cohort study was published to evaluate the interaction of ibuprofen on VPA plasma concentration in pediatric patients. Data from patients with measured VPA trough concentrations (C0) were retrospectively collected in a Chinese teaching and tertiary Children’s Hospital from January 2017 to June 2019. The samples measured within 6 weeks of the last ibuprofen administration were considered as ibuprofen combination samples. Patients with paired samples before and after ibuprofen administration were additionally analyzed. The effects of ibuprofen on the VPA trough concentration to dose (C0/D) ratio were investigated. The proportion of samples with achieved target concentrations of VPA (50–100 mg/L) and the corresponding required dosage were compared. Moreover, subgroup analysis according to the interval between the last ibuprofen dosage and C0 measurement was performed. A total of 616 samples from 434 patients, of whom 16 had paired samples, were included. VPA C0/D decreased when ibuprofen was administered by 7.5% and 30.6% of the total samples and paired samples, respectively. The interaction was significant within 1 week of the last ibuprofen dose. No significant differences were observed in the proportion of target concentration achieved and VPA dose requirement when ibuprofen was combined. A moderate effect of ibuprofen on VPA C0/D was observed within 1 week of ibuprofen administration; the target concentration and required doses of VPA were comparable.

Determination of Free Valproic Acid Concentration in 569 Clinical Samples by LC-MS/MS After Hollow Fiber Centrifugal Ultrafiltration Treatment.

To perform therapeutic drug monitoring of total and free plasma valproic acid (VPA) concentrations in clinical samples and to analyze the related factors. The total VPA concentration in plasma was determined by ultrahigh-performance liquid chromatography with precolumn derivatization with α-bromoacetophenone, and the free VPA concentration was determined by liquid chromatography-tandem mass spectrometry after the plasma was treated by hollow fiber centrifugal ultrafiltration. Regression analysis was performed to examine the associations between free plasma VPA, total plasma VPA, and the plasma protein binding rate. The impact of individual situations, outpatient or inpatient factors, and drug combinations on VPA concentrations were examined. Of the 569 clinical samples, 268 were inpatients and 301 were outpatients, and the total VPA concentration in 138 cases (24.2%) was lower than the effective treatment concentration range; the total and free VPA concentrations in outpatient samples were 11.0% and 26.1% higher than those of inpatients, respectively. There was no linear relationship between the free and total VPA concentrations. The relationship equation between the plasma protein binding rate and free VPA concentrations was as follows: Y = 0.0255X2 - 1.1357X + 97.429 (r = 0.8011). The total and free VPA concentrations were significantly decreased after the coadministration of phenobarbital (83.7% and 64.3% of the control group, P < 0.05) or carbapenem antibiotics (32.0% and 32.7% of the control group, P < 0.05). The total VPA concentrations in patients with epilepsy at our hospital was lower than the effective treatment concentration range, which was inadequate for epilepsy control; the total VPA concentrations of outpatients were higher than those of inpatients; as phenobarbital affects VPA metabolism, therapeutic drug monitoring is recommended. Carbapenem antibiotic coadministration with VPA should be avoided because carbapenem antibiotics can lead to the failure of VPA antiepileptic treatment.

Switching Between LC-ESI-MS/MS and EMIT Methods for Routine TDM of Valproic Acid in Pediatric Patients With Epilepsy: What Clinicians and Researchers Need to Know.

Background: Valproic acid (VPA) is a widely used antiseizure medication and its dosing needs to be tailored individually through therapeutic drug monitoring (TDM) to avoid or prevent toxicity. Currently, immune-enzymatic assays such as Enzyme Multiplied Immunoassay Technique (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Electrospray Ionization Tandem Mass Spectrometry (LC–ESI-MS/MS), resulting a potential lack of concordance between laboratories. Methods: In this study, plasma VPA concentrations were determined for 711 pediatric patients with epilepsy by a routine EMIT assay and by a validated in-house LC-ESI-MS/MS method on the same group of samples, aimed to address the aforementioned concern. Consistency between two assays was evaluated using linear regression and Bland-Altman analysis. Results: The calibration curve was linear in the range of 5.00–300 μg/ml for LC-ESI-MS/MS method and 1.00–150 μg/ml for EMIT assay, respectively. The two methods were proven to be accurate with quality control samples. As a result, a significant correlation between two methods was obtained with a regression equation described as (r 2 = 0.9281). Bland-Altman plot showed a mean bias of 14.5 μg/ml (95% confidence interval (CI) (−0.2, 29.2) and a mean increase of 27.8% (95% CI (3.3, 52.4) measured by EMIT assay more than that measured by LC-ESI-MS/MS method. Conclusion: In conclusion, two methods were closely correlated, but EMIT assay overestimate VPA levels in human plasma compared with LC-ESI-MS/MS method. Due to the observed significant discordance between the tested methods, switching from immunoassays to LC-based techniques for TDM of VPA deserves close attention and therapeutic range of 35.0–75.0 μg/ml may be feasible. However, further studies are needed to evaluate the eligibility of this alternative range in the clinical practice. Clinicians should be informed when switching the VPA quantitation methods during the clinical practice.

Influence of UGT2B7 and UGT1A6 polymorphisms on plasma concentration to dose ratio of valproic acid in Chinese epileptic children

We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of valproic acid (VPA) in paediatric epilepsy patients. Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined. Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related to the metabolising enzymes and transporters of VPA were identified, and their influences on CDRVPA (a logarithmic transformation was performed if abnormally distributed) were evaluated. UGT2B7 rs7668258 (C>T) TT genotype was associated with a decrease in lnCDRVPA among epileptic children receiving VPA monotherapy (β=–0.191, p = 0.036). Significantly lower lnCDRVPA was also observed in paediatric patients with UGT1A6 rs2070959 (A>G) GG genotype compared to those AA genotype (β=–0.270, p = 0.021). This research indicated that UGT2B7 rs7668258 (C>T) and UGT1A6 rs2070959 (A>G) polymorphisms may be correlated to the normalised plasma concentrations of VPA in Chinese epileptic children. The associations could be abolished after Bonferroni's correction and our findings need to be validated in further and larger investigations.

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.

The association of adjusted plasma valproic acid concentration with CYP2C9 gene polymorphism in patients with epilepsy: a systematic review and meta-analysis.

BackgroundValproic acid (VPA) is a common antiepileptic drug used to treat both generalized and partial epilepsy. Although there is increasing evidence to suggest that CYP2C9 gene polymorphisms are associated with interindividual variability of VPA metabolism, the results are debatable. Therefore, in the present study, we conducted a meta-analysis to evaluate the correlation between CYP2C9 gene polymorphisms and adjusted plasma VPA concentration.MethodsThe EMBASE, MEDLINE, and Cochrane Library databases were searched to obtain relevant studies. Eligible articles were reviewed, and data extraction was performed. We calculated 95% confidence intervals (CIs) and mean differences (MDs) to assess the strength of the relationship of CYP2C9 gene polymorphisms with adjusted plasma VPA concentration.ResultsThe meta-analysis included 6 studies involving 847 patients with epilepsy. The pooled analysis showed that the CYP2C9 A1075C (AA vs. AC) polymorphism was related to the adjusted plasma concentration of VPA (P=0.02, I2= 82%). Additionally, the AC phenotype statistically significantly increased the adjusted plasma VPA concentration in children compared with the mixed age subgroup (P=0.04, I2= 48%). A similar association was observed between the AC phenotype for Asians (P<0.00001, I2=0%) but not for Caucasians (P=0.34, I2=87%).DiscussionAge might be a crucial covariate influencing the dosage-adjusted VPA concentration in patients with epilepsy. A reduced VPA dosage may be recommendable for children, particularly Asian children, who are CYP2C9 A1075C AC carriers. Further studies could provide high-quality evidence to confirm the correlation between VPA pharmacokinetics and CYP2C9 A1075C polymorphisms.

CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy.

PurposeTo perform therapeutic drug monitoring (TDM) of total and free plasma valproic acid (VPA) concentrations in pediatric patients with epilepsy and to analyze related factors.Patients and MethodsPediatric epileptic patients treated in 2015–2019 in our hospital were assessed. Total and free plasma VPA concentrations were obtained by UPLC and LC-MS/MS, respectively. Regression analysis was performed to examine the associations of free plasma VPA with total plasma VPA and plasma protein binding rate. The impacts of individual situation, CYP2C9 genotype, and drug combination on VPA concentration were examined.ResultsOf the 251 patients, 81 had lower total concentrations than effective therapeutic levels; 86 and 31 patients had infections and central nervous system dysplasia, respectively. VPA’s daily doses and free drug concentrations were significantly lower in the CYP2C9 *3/*3 genotype group versus the CYP2C9 *1/*3 and CYP2C9 *1/*1 groups (P<0.05). Free and total VPA concentrations were linked by Y = 0.0004 X2 + 0.042 X + 0.3035 (r=0.6981); VPA plasma protein binding rate and free VPA concentration were related by Y = 0.0003 X2 - 0.0127 X + 0.9777 (r=0.8136). Both total and free VPA concentrations were significantly decreased in patients simultaneously administered phenobarbital, meropenem and biapenem (P<0.05), with therapeutic failure after meropenem/biapenem co-administration.ConclusionFree VPA amounts have nonlinear relationships with total VPA amounts and plasma protein binding rate in epileptic children. Additionally, CYP2C9 *3/*3 expression affects VPA metabolism. Since phenobarbital affects VPA metabolism, TDM is recommended. Meanwhile, carbapenem-co-administration with VPA should be prohibited.

Evaluation of the Appropriateness of Valproic Acid-Levels Monitoring in Mexican Pediatric Patients

In Mexico, plasma drug quantitation is utilized to check dose titration, compliance, and toxicity in treatment with antiepileptic drugs like valproic acid (VPA), but without considering the pharmacokinetic principles due to the absence of clinical pharmacists in the Health System. This study analyzed the within-patient relationship between dosage and plasma VPA concentrations in different age groups, to evaluate the effect of enzyme-inducing co-medication, and to evaluate the efficiency of the m

Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model.

ObjectiveThis prospective study aimed to establish the valproic acid (VPA) population pharmacokinetic model in Chinese patients and realise personalised medication on the basis of population pharmacokinetics.MethodsThe patients’ clinical information and VPA plasma concentrations were collected from The General Hospital of Taiyuan Iron & Steel (Group) Corporation (TISCO). Nonlinear mixed-effect modelling was used to build the population pharmacokinetic model. To characterise the pharmacokinetic data, a one-compartment pharmacokinetic model with first-order absorption and elimination was used. The first-order conditional estimation with η-ε interaction was applied throughout the model-developing procedure. The absorption rate constant (Ka) was fixed at 2.38 hour−1, and the impact of covariates on clearance and apparent volume of distribution were also explored. Medical records of 60 inpatients were reviewed prospectively and the objective function value (OFV) of the base model and final model were 851.813 and 817.622, respectively.ResultsGender was identified as the covariate that had a significant impact on the volume of distribution, and albumin and CYP2C19 genotypes influenced clearance.ConclusionBootstrap and VPC indicated that a reliable model had been developed that was based on the simulation results, and a simple-to-use dosage regimen table was created to guide clinicians for VPA drug dosing.