Objective: The drug‐refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy.Methods: This single‐center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. Ninety plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non‐responders with VPA polytherapy (NR group) were collected. Non‐targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value >1, fold change >1.2 or <0.8, and p‐value <0.05 were regarded as statistically different substances.Results: A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well‐established partial least squares‐discriminant analysis (PLS‐DA) revealed a good separation of the RE from the NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine laboratory tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L‐thyroxine, but with an increased level of glucose and 2‐oxoglutarate. The top two enriched metabolic pathways involved in the DRE condition were biosynthesis of unsaturated FAs and linoleic acid metabolism.Significance: The results of this study suggested an association between metabolism of FAs and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high‐priority strategies for DRE management.

Objective: This study aimed to investigate the efficacy and tolerability of perampanel (PER) therapy and to optimize a specific plasma reference range for PER in children. Another major aim was to evaluate the potential determinators of PER concentration.Methods: Concentrations obtained from 80 children were analyzed for routine therapeutic drug monitoring (TDM) between 2021 and 2022. We retrospectively reviewed the clinical data of these patients and assessed the efficacy at 3 months after treatment initiation. Trough concentration‐to‐dose ratio (C₀/Dose ratio) of PER was compared among patients on various potential influencing factors.Results: A 3‐month PER therapy produced a ≥50% reduction in seizure frequency in 58.8% of patients. Twelve patients reported at least one adverse effect (AE), mainly dizziness. The monitoring data showed that the median C₀ was 325.5 ng/mL. Under maintenance dosages, approximately 75% of the C₀ values were 180.0‐610.0 ng/mL. The C₀/Dose ratio in patients aged 1 to <4 was significantly lower by twofold than in those aged 4 to ≤12 years (P = 0.001). Enzyme‐inducing ASMs (EIASMs) decreased the C₀/Dose ratio of PER by 25.9% (P = 0.165). In addition, seizure frequency reduction in responders was achieved at a median PER C₀ value of 357 ng/mL, which was similar to the value of 314 ng/mL found in nonresponders (P = 0.288). No significant difference was found in PER C₀ values between patients with and without AEs (P = 0.082).Significance: In this study, PER treatment showed acceptable efficacy and tolerance in Chinese children with epilepsy. Contributing factors like age to variable C₀/Dose ratios were identified, and complex PER‐ASMs interactions were observed. Notably, the reference range, that is, 180.0‐610.0 ng/mL, for routine PER monitoring may be more applicable for them. Routine TDM should be considered a positive attempt to manage the effectiveness and safety of PER.

The Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines for personalized atomoxetine therapy are based on the CYP2D6 genotype information and the peak plasma concentrations of atomoxetine. Therefore, a highly rapid, sensitive, and reproducible method is critical for the clinical implementation of the guidelines. In this study, an LC-MS/MS approach was developed and validated for the determination of atomoxetine levels in human plasma using atomoxetine-d3 as the internal standard. Samples were prepared by simple protein precipitation method with MeOH. The analyte was separated using a Kinetex C18 column (2.1 mm × 50 mm, 2.6 μm, Phenomenex) with a flow rate of 0.25 mL min⁻¹, using a gradient elution. A MeOH and water solution containing 5 mM ammonium acetate and 0.1 mM formic acid (pH 6.26) was used as the mobile phase and successfully solved the problem of inconsistent retention time between the plasma samples and the solution samples of atomoxetine. Detection was performed under positive-electrospray-ion multiple reaction-monitoring mode using the 256.4 → 43.8 and 259.3 → 47.0 transitions for atomoxetine and atomoxetine-d3, respectively. Linearity was achieved using an extremely wide range, from 0.500 to 2000 ng mL⁻¹ in plasma. The intra- and inter-batch precision and accuracy, dilution accuracy, recovery, and stability of the method were all within the acceptable limits and no matrix effect was observed. With a complex needle wash solution containing ACN : MeOH : isopropanol : H₂O (4 : 4:1 : 1, v/v/v/v), carryover contamination was eliminated successfully. This method was successfully implemented on pediatric patients with attention-deficit/hyperactivity disorder and provided valuable information to enable clinicians to do dose selection and titration.

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and 60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.