Abstract
Background: Aripiprazole, an atypical antipsychotic, is widely prescribed for psychiatric disorders. While the relationship between its pharmacokinetic variability and genetic polymorphisms has been extensively studied in adults, the data on the genotype-guided dosing of aripiprazole in adolescents with psychiatric disorders remain scarce.

Aims: To examine the feasibility of using genotype-guided strategy to determine aripiprazole dose in adolescents with psychiatric disorders and investigate the key role of gene polymorphisms.

Methods: Data from electronic health records and opportunistic sampling of aripiprazole-treated adolescents (12~18 years) were analyzed. A genotype-guided study was conducted, including a pharmacogenetic association analysis of 13 single nucleotide polymorphism loci in genes involved in aripiprazole disposition. Associations were assessed using analysis of covariance, and population pharmacokinetic parameters were estimated via nonlinear mixed-effects modeling.

Results: A total of 175 TDM points from 134 adolescents were analyzed, in which CYP2D6 rs1135840 and rs1065852 showed closer relationship with plasma aripiprazole concentration, total plasma concentrations of aripiprazole and dehydroaripiprazole, and metabolic ratio (dehydroaripiprazole/aripiprazole). Additionally, ABCB1 rs1128503 was significantly linked to evelated plasma concentration of aripiprazole, and total plasma concentrations of aripiprazole and dehydroaripiprazole. Meanwhile, the population pharmacokinetics analysis of aripiprazole estimated a clearance of 2.32 L/h and volume of distribution of compartments of 56.9 L, in which CYP2D6 rs1065852 TT genotype especially reduced aripiprazole clearance by 24.5%.

Conclusions: This study successfully established genotype-guided dosing framework for aripiprazole in Chinese adolescents with psychiatric disorders, emphasizing the critical role of CYP2D6 and ABCB1 polymorphisms in optimizing aripiprazole therapy.

Keywords
aripiprazole; pharmacogenetics; psychiatry; adolescents; genotypes-guided dosing

Background: Fluoropyrimidine-based chemotherapy is one of the useful treatments for many cancers. On the other hand, it could cause severe side effects due to a dihydropyrimidine dehydrogenase (DPD) deficiency. Therefore, European health authorities strongly recommend screening for DPD deficiency. However, the standardization of this method has not yet been established.

Aims: The purpose is to evaluate the analytical performance and clinical performance of LC/MS/MS assay with reagent kit for confirming DPD deficiency.

Methods: Clinical evaluation by LC/MS/MS assay with reagent kit developed by Alsachim was conducted at a site in France, already routinely performing indirect DPD phenotyping with their own laboratory-developed test. Both methods are used to measure uracil and dihydrouracil concentrations using reverse-phase LC coupled to a triple quadrupole mass spectrometer. The same samples and the same equipment were used for the method comparison. A total of 229 samples were analyzed and the evaluation of the results was conducted based on CLSI EP09c, using the Bland-Altman method and Deming regression.

Results: Accuracies of calibration curves were assessed on each series and were within the acceptance criteria defined during method validation. A good correlation between methods was obtained with a limited bias for both compounds. However, it should be noted that bias evaluation can be limited as, currently, only LDTs are available as reference methods.

Conclusion: The LC/MS/MS assay with reagent kit was clinically validated to provide reliable diagnostic of DPD deficiency prior to chemotherapy with fluoropyrimidines.

Key words: DPD, phenotyping, 5-FU, chemotherapy, LC/MS/MS, clinical validation

Background and Aims: Voriconazole (VRCZ) is metabolized by hepatic cytochrome P450 (CYP) isozyme CYP2C19, with genetic polymorphisms causing variability in its efficacy and safety. Poor metabolizer alleles of CYP2C19 are more prevalent in Asian populations, which increases the risk of supratherapeutic VRCZ use in Japanese patients. This study aimed to evaluate whether CYP2C19 genotype-guided VRCZ therapy reduces toxicity.

Methods: This retrospective study included 64 patients (38 controls and 26 genotype-guided). The initial VRCZ dose in the genotype-guided group was determined using a nomogram developed at our hospital in accordance with current guidelines and literature. The primary objective was to determine whether genotype-guided dosing reduced hepatotoxicity and visual symptoms. Secondary outcomes included the percentage of patients within the therapeutic VRCZ trough concentration range (1–4 μg/mL).

Results: Hepatotoxicity (grade ≥2) and visual symptoms were significantly lower in the genotype-guided group (42.1% vs. 11.5%, P=0.008 and 44.7% vs. 7.7%, P=0.001, respectively). VRCZ discontinuation due to adverse events occurred in 9 patients (23.7%) in the control group and in 1 patient (3.8%) in the genotype-guided group (P=0.039). A higher proportion of patients in the genotype-guided group achieved therapeutic range of trough concentrations on 3–5 days after VRCZ initiation (37% vs. 77%, P=0.002).

Conclusion: CYP2C19 genotyping can reduce VRCZ adverse effects while maintaining therapeutic efficacy. Genotype-guided dosing can also facilitate the achievement of the therapeutic range. These results indicate the necessity of CYP2C19 genotyping in VRCZ treatment for Japanese patients.

Keywords: Voriconazole, CYP2C19, Pharmacogenetics, Genotype-guided, Precision medicine

Background
CYP1A2 activity varies significantly among individuals, highlighting its importance in personalized medicine. Currently, caffeine clearance (CLCA) and the paraxanthine/caffeine ratio (PX/CA) are used to access CYP1A2 activity. However, these methods require caffeine intake restrictions and multiple blood samples, making them inconvenient. We developed a novel method to assess CYP1A2 activity—melatonin partial metabolic clearance (CLm(MEL))—based on endogenous melatonin (MEL) and its CYP1A2-mediated metabolite, 6-hydroxymelatonin (6-O-MEL). However, it has not yet been evaluated.

Aims
This study aimed to establish a new CLm(MEL) method by examining its correlation with CLCA and PX/CA.

Methods
Blood samples were collected at 4, 6, 24, and 26 h after caffeine ingestion. Urine samples were collected over 2-hour periods at 4–6 hours and 24–26 hours from 18 healthy participants who provided informed consent. Plasma MEL, CA, PX, and urinary 6-O-MEL concentrations were analyzed using LC−MS/MS. CLCA was calculated from the plasma CA concentrations, while CLm(MEL) was determined by dividing urinary 6-O-MEL excretion by plasma MEL AUC.

Results
CLCA ranged from 1.38 to 12.32 L/h, and PX/CA from 0.41 to 4.55. CLm(MEL) varied between 25.81 and 83.09 L/h. The correlation coefficients of CLm(MEL) with CLCA and PX/CA were 0.72 and 0.60, respectively, indicating the validity of the new assessment method.

Conclusions
The new CLm(MEL) method provides a simple and effective approach to assessing CYP1A2 activity and can be applied in clinical practice for personalized dosing.

Keywords
CYP1A2, 6-hydroxymelatonin, LC–MS/MS, phenotyping, caffeine clearance

Background: To explore the clinical significance of CYP2C19 polymorphisms in therapeutic drug monitoring of voriconazole.
Objective: To investigate the relationship between CYP2C19 polymorphisms and the trough concentration of voriconazole.
Methods: A retrospective, single-center study was conducted, collecting data from patients who underwent voriconazole polymorphism testing and therapeutic drug monitoring between 2023.1 and 2024.5. The primary endpoint was whether the trough concentration of voriconazole was within the normal range. Data from enrolled patients were analyzed using multivariate logistic regression.
Results: A total of 65 patients were included. Single-factor regression included 15 variables, and multivariate logistic regression revealed significant differences in total bilirubin and alcohol history (P = 0.039, P = 0.023).
Conclusion: The single-center retrospective analysis did not find a significant effect of voriconazole genetic polymorphisms on patients' blood drug concentrations. A history of alcohol consumption and abnormal baseline total bilirubin levels may be key factors influencing voriconazole blood concentrations.

Background: Tacrolimus exhibits significant pharmacokinetic variability, requires precise dosing to balance efficacy and toxicity. Its blood levels are influenced by differences in absorption and metabolism. This study explores alternative strategies for individualized dose adjustments to optimize therapeutic outcomes.

Aims: To establish a personalized tacrolimus dosing strategy by integrating pharmacogenomic testing with pharmacokinetic analysis.

Methods: 57 kidney transplant recipients were studied, with pharmacogenomic testing performed on 23 patients. Tacrolimus pharmacokinetics were assessed via blood concentrations at five time points (C0, C1, C2, C4, C8). CYP3A5 and ABCB1 polymorphisms were analyzed.

Results: CYP3A5 polymorphisms influenced tacrolimus clearance, with *1/*1 carriers exhibiting a faster metabolism and requiring higher doses to achieve therapeutic levels. In contrast, *3/*3 carriers more frequently reached the therapeutic range at standard dosing. When using the area under the concentration-time curve (AUC) calculated from cumulative blood sampling points, *3/*3 carriers were more likely to achieve an AUC >100 ng*hour/mL, whereas *1/*1 and *1/*3 carriers were more likely to remain below this threshold. Further analysis of individual blood concentrations revealed that C4 and C8 levels were strongly correlated with AUC and were significantly associated with CYP3A5 genotype. Additionally, ABCB1 mutations, which influence P-glycoprotein function, may alter tacrolimus absorption and impact drug exposure. However, analysis of blood concentrations at absorption-phase (C1 and C2) did not show a significant correlation with genotype.
Conclusions: Pharmacogenomic testing optimizes tacrolimus dosing: *1/*1 (0.2 mg/kg/day), *1/*3 (0.15 mg/kg/day), *3/*3 (0.1 mg/kg/day). C4 and C8 concentration serve as a valuable marker for drug exposure and genotype prediction.

Background: Tacrolimus, a potent immunosuppressant, is widely used in solid organ transplantation (SOT).  Despite its effectiveness, highly variable pharmacokinetics lead to inadequate drug concentrations leading to under- or over-dosing, increasing risks of early acute rejection, de novo donor-specific antibody formation and graft loss, as well as toxicities including infection and malignancy, respectively. While genotype-informed and Bayesian dosing has shown to improve outcomes in adults, paediatric data is limited.

Aim: To evaluate the effectiveness of genotype-informed Bayesian dosing of tacrolimus in paediatric SOT compared to standard weight-based dosing.

Methods: A serial cohort study, with single prospective intervention arm, will assess feasibility and benefit of genotype-informed Bayesian dosing of tacrolimus in a paediatric SOT cohort. Participants (n=45) will receive initial dosing informed by CYP3A4 and CYP3A5 genetic variants. From day 4 post-transplant, Bayesian estimation using NextDose will inform dose adjustments.

Results: The effectiveness of the intervention will be assessed by comparing the proportion of participants with therapeutic tacrolimus concentrations to a retrospective cohort who received standard weight-based dosing. Specifically, we will compare the proportion with therapeutic concentrations at day 4 (initial dose prediction) and at weeks 3 and 8 (Bayesian-adapted dosing). Secondary outcomes will include time within therapeutic range over the 8-week period.

Conclusions: BRUNO-PIC will assess the benefits of a precision dosing strategy; combining genotype-informed dosing, Bayesian dose adjustment, and exposure-target dosing on improving tacrolimus concentrations and clinical outcomes in the initial 8 weeks post-transplant, across all SOT procedures in our young patients. 

Key Words: Genotype, Pharmacogenomics, Bayesian Prediction, Transplant, Paediatrics.

Background: antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia (aml) is recommended to reduce the risk of invasive fungal infections (ifi). a few studies described the clinical impact of suboptimal posaconazole exposure during prophylaxis, other than pharmacogenetics, in this clinical setting.

Aims: to analyze if posaconazole exposure and genetics could impact on the ifi onset in patients with aml.

Methods: posaconazole plasma concentrations (cut-off 0.7 mg/l) were evaluated weekly (7/14/21/28 days) through chromatography, whereas polymorphisms of genes encoding enzymes, transporters and transcription factors through real-time pcr.

Results: 100 patients were analyzed (4 were excluded for missing clinical data): 56(58%) were women and median age was 66 years. ifi developed in 18 patients: 5 at 7, 5 at 14 and 8 at 21 days. posaconazole concentrations at 14 days influenced ifi development, when considered as linear variable (p=0.031), whereas at 7 (p=0.015) and 14 (p=0.049) days, when considered lower than 0.7 mg/l.
regarding pharmacogenetics, car540tt was associated with posaconazole trough concentrations>0.7 mg/l at every analzyed timing and ugt1a1829tt with ifi development.
an algorithm for the clinical routine including car540tt and ugt1a1829tt analysis before starting therapy (in order to understand which patients are at high risk of having posaconazole exposure<0.7 mg/l or ifi development) has been proposed.

Conclusions: this is the first study reporting a useful tool helping clinicians to identify patients with a higher risk for under-effective posaconazole exposure and it can be used to improve antifungal stewardship approach in this setting.

Keywords: therapeutic drug monitoring, genetic variants, antifungals.