Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism

Shen, Xianhuan; Chen, Xinyi; Lu, Jieluan; Chen, Qing; Li, Wenzhou; Zhu, Jiahao; He, Yaodong; Guo, Huijuan; Xu, Chenshu; Fan, Xiaomei

doi:10.3389/fphar.2022.1037239

Cited by 8 publications

(10 citation statements)

References 64 publications

(78 reference statements)

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“…A study in a Tunisian population showed that the TT genotypes of C1236T, G2677T and C3435T were associated with DRE [25]. In addition, in our previous study, the rs3789243 variant of ABCB1 was found to have a significant effect on the pharmacokinetic variability of VPA, which was observed by establishing a population pharmacokinetic model [26].…”

Section: Introductionmentioning

confidence: 75%

“…There were no significant differences in the clinical characteristics of the patients in the persistent seizure and seizure-free groups. The selection of the two polymorphisms was based on previous reports suggesting their association with ASM responsiveness [23][24][25][26]. The polymorphism of ABCB1 rs1128503 as well as a haplotype consisting of the two SNPs were found to be associated with the efficacy of VPA.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, this study was conducted in children, which is beneficial for optimizing the development of individualized treatment plans for children. Based on previous studies [23][24][25][26]28], rs1128503 (C1236T) and rs3789243 were selected as candidate SNPs of ABCB1 to investigate their relationship with the efficacy, safety, and blood concentration of VPA in the treatment of children with epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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

Zhu,

Lu,

et al. 2023

Pharmaceuticals

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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.

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Section: Introductionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhu,

Lu,

et al. 2023

Pharmaceuticals

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“…For example, Shen et al reported pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism. 40 Thyssen et al reported population pharmacokinetics and Monte Carlo simulations demonstrated similar pharmacokinetics of risperidone in children, adolescents and adults. 41 Chen et al reported population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy.…”

Section: Discussionmentioning

confidence: 97%

Effects of Aripiprazole on Olanzapine Population Pharmacokinetics and Initial Dosage Optimization in Schizophrenia Patients

Zhang,

Jiang,

et al. 2024

NDT

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Objective Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains unclear. The purpose of this study was to explore the drug–drug interaction (DDI) of multiple drugs combined with olanzapine and to recommend the optimal administration of olanzapine in schizophrenia patients. Methods In this study, we obtained olanzapine concentrations from therapeutic drug monitoring (TDM) database. In addition, related medical information, such as physiological, biochemical indexes, and concomitant drugs was acquired using medical log. Sixty-five schizophrenia patients were enrollmented for analysis using population pharmacokinetic model by means of nonlinear mixed effect (NONMEM). Results Weight and combined use of aripiprazole significantly affected olanzapine clearance. Without aripiprazole, for once-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40–70, and 70–100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40–60, and 60–100 kg schizophrenia patients, respectively. With aripiprazole, for once-daily olanzapine administration dosages, 0.4, 0.3 mg/kg/day were recommended for 40–53, and 53–100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.4 mg/kg/day was recommended for 40–100 kg schizophrenia patients, respectively. Conclusion Aripiprazole significantly affected olanzapine clearance, and when schizophrenia patients use aripiprazole, the olanzapine dosages need adjust. Meanwhile, we firstly recommended the optimal initial dosages of olanzapine in schizophrenia patients.

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“…Excipients can enhance solubility and bioavailability, improving absorption and pharmacokinetics. Enteric coatings can protect VPA from gastric degradation, reducing gastrointestinal side effects [12] .…”

Section: Introductionsmentioning

confidence: 99%

The influence of different excipients on Valproic acid tablets in neurological disorder treatment

Sharma,

Rajput

2024

Int. J. Adv. Acad. Stud.

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Valproic acid is widely used in treating neurological disorders such as epilepsy, bipolar disorder, and migraine, yet its exact mechanisms of action remain unclear. In this review, we aim to comprehensively outline the multifaceted mechanisms underlying Valproic acid's therapeutic effects. VPA modulates neurotransmitter systems, including gamma-aminobutyric acid (GABA), glutamate, and dopamine, influencing synaptic transmission and neuronal excitability. It enhances GABAergic transmission by inhibiting GABA degradation enzymes, promoting GABA release, and inhibiting reuptake, thereby contributing to its antiepileptic and mood-stabilizing effects. Valproic acid also reduces glutamatergic transmission by inhibiting N-methyl-D-aspartate receptors, thus attenuating glutamate-induced excitotoxicity. Moreover, Valproic acid affects dopaminergic neurotransmission by enhancing dopamine release and inhibiting reuptake, aiding mood stabilization. Another critical mechanism involves Valproic acid's modulation of voltage-gated ion channels, particularly sodium and calcium. Valproic acid reduces neuronal excitability and hyperactivity by inhibiting these channels, which is particularly beneficial in epilepsy treatment. Additionally, Valproic acid inhibits histone deacetylase, increasing histone acetylation and enhancing gene transcription. This epigenetic modulation upregulates neuroprotection, synaptic plasticity, and neurotransmission genes. Furthermore, Valproic acid exhibits neuroprotective properties by attenuating excitotoxicity, oxidative stress, and apoptosis, protecting against neuronal damage. Excipients in tablet formulations play a pivotal role in modifying Valproic acid's mechanisms of action. Sustained-release formulations are essential for maintaining stable plasma concentrations, while enteric coatings protect against gastric degradation, enhancing bioavailability. Excipients can also enhance solubility and improve drug delivery. For instance, surfactants and solubilizers can enhance Valproic acid's dissolution, while disintegrants promote rapid disintegration for faster drug release, which is crucial for acute conditions like seizures. Understanding how different excipients affect Valproic acid's mechanisms provides insights into optimizing therapy and developing novel treatments for neurological disorders.

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Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism

Cited by 8 publications

References 64 publications

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

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

Effects of Aripiprazole on Olanzapine Population Pharmacokinetics and Initial Dosage Optimization in Schizophrenia Patients

The influence of different excipients on Valproic acid tablets in neurological disorder treatment

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