Background: Tuberculosis (TB) is an infectious disease transmitted through airborne, causing it highly contagious. Toll-like receptor 4 (TLR4) plays a crucial role in the pathogen destruction, including Mycobacterium tuberculosis.

Aims: This study aims to determine genotyping frequency of the TLR4 gene rs7873784 polymorphism and its impact on TB susceptibility in the healthy Thai population.

Methods: A total of 43 Thai TB patients and 54 healthy Thai control subjects were included in this study. After obtaining informed consent, 3 ml of whole blood was collected in EDTA tubes. Genomic DNA was then extracted by PureLink™ Genomic DNA Mini Kit and analyzed using QuantStudio™ 3 Real-Time PCR system. The association between TLR4 gene rs7873784 polymorphism and TB susceptibility was assessed by logistic regression analysis.

Results: The allele frequencies in TB group were approximately 85% for G and 15% for C, while in control group, they were approximately 91% for G and 9% for C. The CC genotype was associated with an approximately threefold increased risk of TB susceptibility compared to the GG genotype (wild-type carriers), although this finding was not statistically significant (p = 0.407).

Conclusions: The genetic variation of TLR4 rs7873784 may influence TB susceptibility in Thai population. Although the association was not statistically significant, the findings suggest a clinically potential link to increased TB risk in the Thai population. Future studies with larger sample sizes are warranted to confirm these finding and provide more definite conclusions.

Key words: Tuberculosis, Toll-like receptor 4, gene polymorphism, Thai population, SNPs rs7873784

Introduction: Allopurinol and its active metabolite oxypurinol is the primary treatment for gout. ATP-binding cassette subfamily G member 2 (ABCG2) functions as an efflux transporter for uric acid excretion, while human aldehyde oxidase 1 (hAOX1) is a uric acid-metabolizing enzyme sharing homology with xanthine oxidase. Genetic polymorphisms in ABCG2 rs2231142 and hAOX1 rs3731722 have been linked to variability in allopurinol response.

Aims: To investigate the relationship between ABCG2 rs2231142 and hAOX1 rs3731722 polymorphisms and plasma oxypurinol concentration to explain variability in allopurinol treatment response

Method: This cross-sectional study examined 37 gout patients from Hospital Canselor Tuanku Mukhriz. Plasma oxypurinol levels were analyzed using high-performance liquid chromatography with ultraviolet detection, while genotyping was performed through PCR-Sanger sequencing.

Results: All participants (86.5% male, mean age 58.0±14.2 years) carried the homozygous TT variant of ABCG2 rs2231142, while for hAOX1 rs3731722, 81.1% had the wild-type allele and 18.9% carried the heterozygous AG variant. No significant association was observed between hAOX1 rs3731722 and oxypurinol concentration in both unadjusted and adjusted models. However, allopurinol dose and creatinine clearance significantly influenced oxypurinol concentration (p=0.001, p=0.013). Notably, hAOX1 rs3731722 showed significant association with daily allopurinol dose (p<0.001).

Conclusion: While hAOX1 rs3731722 had no direct impact on oxypurinol concentration, its significant association with allopurinol dosing suggests potential influence on treatment requirements. The homogeneity of ABCG2 rs2231142 in our population prevented assessment of its impact on oxypurinol levels limiting our ability to evaluate its role in allopurinol therapy effectiveness

Keywords: ABCG2, hAOX1, allopurinol, oxypurinol, genetic polymorphism

Background: Mycophenolate mofetil (MMF) is widely used with other immunosuppressants to prevent organ rejection. It is hydrolyzed to its active form, mycophenolic acid (MPA), which is further metabolized into inactive mycophenolic acid glucuronide (MPAG) and active acyl-glucuronide (AcMPAG). MPA is extensively bound to albumin, and only free MPA is pharmacologically active. MPAG reflects UDP-glucuronosyltransferase activity, and AcMPAG is associated with gastrointestinal toxicity. Simultaneous quantification of free MPA and its metabolites provides comprehensive insight into MPA metabolism, potentially enhancing dose individualization to optimize immunosuppression while minimizing toxicity.

Aims: To develop and validate a multiplex liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantification of free MPA, along with MPA metabolites, in plasma and saliva.

Methods: Absolute quantification of MPA, MPAG, and AcMPAG in plasma was achieved using LC-MS/MS. Analytical validation included assessments of sensitivity, linearity, precision, recovery, matrix effects, and carryover, following clinical laboratory guidelines.

Results: The developed assay enables the simultaneous quantification of MPA, MPAG, and AcMPAG with imprecision of 3.4%, 2.2%, and 1.8% for low, mid, and high MPA QCs; 5.9%, 1.8%, and 1.7% for MPAG QCs; and 9.1%, 2.2%, and 1.8% for AcMPAG QCs. LLOQs were 0.01 mg/L for MPA and MPAG and 0.05 mg/L for AcMPAG, with linear ranges of 50 mg/L (MPA), 150 mg/L (MPAG), and 4 mg/L (AcMPAG).

Conclusions: This validated assay enables accurate monitoring of MPA and its metabolites. Further studies will assess saliva as a non-invasive alternative for TDM in transplant patients.

Keywords: Immunosuppressant, mycophenolic acid, metabolites, LC-MS/MS, therapeutic drug monitoring, saliva

Background: Therapeutic drug monitoring (TDM) of immunosuppressant drugs is a necessary component of post-transplant care to prevent graft rejection. Nevertheless, current testing modalities are limited to centralized laboratories and unavailable in point-of-care (POC) settings, including rural and underserved urban areas. This results in time and resource expenditures for patients to obtain routine tests and can be especially harmful in acute situations where fast turn-around times are essential. POC tests may alleviate these burdens and there is growing recognition of the importance of active user engagement, to increase usability, effectiveness, and enthusiastic adoption of such technologies.

Aim: Conduct stakeholder engagement meetings to identify context, attitudes, requirements, and potential unintended consequences for an immunosuppressant TDM POC test.

Methods: We conducted interviews with 9 transplant providers and 11 organ transplant recipients, including members of the community engagement committee of the Center for Innovations in Cancer & Transplant and the Transplant Recipient Advisory Council.

Results: Patients had strong interest in an accurate, quantitative POC test to reduce financial and time burdens. Providers wanted faster turn-around times than available with current modalities, especially for managing patients in remote settings. Both groups agreed that a POC test could enhance patient engagement and empowerment in healthcare, and they expressed concerns about potential increased work a POC device would create for caregivers and healthcare workers.

Conclusions: We will incorporate these findings into our POC test engineering and continue iterative stakeholder engagement to co-design a device that can transform post-transplant care.

Keywords: point-of-care, immunosuppression, expanding healthcare access, design methodologies

Background: Tacrolimus (FK506), a calcineurin inhibitor, is widely used as an immunosuppressive therapy in renal transplant patients. Voriconazole, a first-line antifungal agent for invasive fungal infections, is a potent CYP3A4/5 inhibitor known to interact significantly with tacrolimus. This study aimed to evaluate the effects of voriconazole on the pharmacokinetics of tacrolimus and develop a predictive model to guide personalized dosing.
Methods: The study included 51 renal transplant patients undergoing combination therapy with tacrolimus and voriconazole. Statistical analyses, including Spearman correlation and multivariate linear regression, were performed using SPSS 26.0 to identify factors influencing tacrolimus pharmacokinetics (Ctac, C/D, C/D/W). GraphPad Prism 10.1.2 was utilized for data visualization.
Results: Voriconazole administration significantly reduced the daily tacrolimus dose (P < 0.001) while increasing C/D and C/D/W values (P < 0.001). However, no statistically significant difference was observed in Ctac (P = 0.369).
Voriconazole concentrations were positively correlated with Ctac, C/D, and C/D/W (P < 0.001). CYP3A5 genotype had a marked influence on tacrolimus metabolism: rapid metabolizers (EM, *1/*1) exhibited the lowest C/D and C/D/W values, while slow metabolizers (PM, *3/*3) showed the highest values (P < 0.001).
Multivariate regression analysis identified tacrolimus dose (negative), voriconazole concentration, total bilirubin (TBA), red blood cell count (RBC, positive), and albumin levels (ALB, negative) as independent predictors of C/D, with an adjusted R² of 0.470.
Conclusion: This study emphasizes the critical role of CYP3A5 genotyping in guiding individualized therapy and presents a predictive model for optimizing tacrolimus dosing in clinical practice.

Background:
Mitochondrial dysfunction and disrupted bioenergetic processes are critical in the pathogenesis of bipolar disorder (BD), with cognitive impairment being a prominent symptom linked to mitochondrial anomalies. The Krebs cycle, integral to mitochondrial energy production, may be implicated in this cognitive dysfunction, yet its specific association with BD remains underexplored.

Aims:
To investigate the association between Krebs cycle disruptions, mitochondrial dysfunction, and cognitive decline in first-episode, drug-naive BD patients, and to explore the potential of bioenergetic metabolites as biomarkers for BD diagnosis and therapeutic monitoring.

Methods:
In this cross-sectional study, 144 first-episode, drug-naive BD patients and 51 healthy controls were assessed. Serum Krebs cycle biomarkers were quantified using liquid chromatography-tandem mass spectrometry. Cognitive function was evaluated through the Repeatable Battery for the Assessment of Neuropsychological Status and the Stroop Color-Word Test.

Results:
BD patients exhibited significantly elevated serum levels of several Krebs cycle biomarkers compared to healthy controls, alongside lower cognitive function scores. Correlational analyses revealed that certain bioenergetic metabolites were significantly positively associated with anxiety and negatively correlated with cognitive performance in BD patients. Notably, succinic acid, α-Ketoglutaric acid, and malic acid emerged as independent risk factors for BD, with their combined profile demonstrating diagnostic utility.

Conclusions:
These findings underscore the potential of serum bioenergetic intermediates as biomarkers for BD, providing insights into the mitochondrial dysfunction underlying cognitive impairment. The study offers a basis for early diagnosis and targeted therapeutic strategies.

Key Words:
Bipolar disorder, bioenergetic metabolites, Krebs cycle, mitochondrial dysfunction, cognitive impairment, biomarkers

Objectives: The aim of this study is i) to establish a population pharmacokinetic (PPK) model and limited sampling strategies (LSSs) to estimate the area under the curve of the dosing interval (AUC0-12h) of MPA and ii) to find the covariates that significantly affect the pharmacokinetics of MPA exposure and iii) to assist dosage optimization of MPA during the perioperative period in Chinese renal transplant recipients.

Methods: Population pharmacokinetic analysis was performed using with data obtained from 120 adult patients at steady states during the perioperative period. Various demographic variables were investigated as potential covariates for PPK modeling. The LSSs were established based on multiple linear regression for estimating the AUC0-12h of MPA.

Results: A two-compartment model with first-order absorption and elimination with a lag time was chosen as the structure model in PPK modeling. Non-linear mixed-effects models were developed. The covariate analysis identified delayed graft function (DGF) as an individual factor influencing central volume of distribution and identified uric acid as individual factors influencing apparent oral clearance (CL/F) of MPA. The LSSs showed the four-point model (C0.5h, C1.5h, C2h, C8h) (R2=0.946) and the three-point model (C1.5h, C2h, C8h) (R2=0.913) were both effective in predicting MPA AUC0-12h.

Conclusion: In conclusion, this study successfully developed a PPK model and LSSs that could be applied in real clinical settings to assist TDM and dosage optimization of MPA during the perioperative period in Chinese renal transplant recipients.

Keywords: mycophenolic acid, population pharmacokinetics, limited sampling strategy, renal transplant recipient, perioperative period, therapeutic drug monitoring

Background: Tacrolimus is cornerstone in immunosuppressive regimens for heart transplantation, with narrow therapeutic index and large inter- and intra- variabilities. Therapeutic drug monitoring is important for tacrolimus personalized dosing, but have some limitation for clinical application.
Aims: We aimed to establish and validate a population pharmacokinetic (PPK) model of tacrolimus, develop the model into a clinical decision support system (CDSS) for convenient use, and further compare the outcome of MIPD and traditional dosage.
Methods: Tacrolimus data were retrospectively collected from the records of 100 patients who received first heart transplantation. Tacrolimus PPK model was established by NONMEM. Information technology and Bayesian method are used to establish CDSS. The C0 and obtained rate for desired C0 of tacrolimus were compared between MIPD and empiric dosing.
Results: A one-compartment model with first order absorption and elimination was used to describe the disposition of tacrolimus in whole blood. Tacrolimus apparent clearance was significantly reduced in CYP3A5 nonexpressers (CYP3A5*3/*3), concomitant with azole antifungal drugs and Wuzhi capsule (WZ). Recommended dose regimens were obtained by simulations based on the established model. Based on MIPD, the percentage of achieved the therapeutic target is higher, the time to reach the target concentration is faster, and fewer dose adjustments are required.
Conclusions: MIPD for tacrolimus in heart transplantation is superior to the clinic-based dosage to achieve the therapeutic target.
Keywords: Model-Informed Precision Dosing, Tacrolimus, Heart transplantation

Introduction: Cytochromes P450 (CYP) regulate exposure to medicines and hence medicine efficacy and safety. Understanding variability in CYP abundance and activity caused by physiological and pathological factors is useful for safe and effective dosing of medicines. Liver-derived extracellular vesicles (EVs) offer a novel strategy to characterise CYP abundance and predict variability in exposure to medicines.
Aim: Investigate liver EVs as a strategy to account for variability in CYP enzyme activity associated with physiological and pathological conditions.
Methods: The abundance of 8 CYP enzymes in liver EVs and tissue homogenates prepared from eleven human livers were quantified by LCMS. Linear regression assessed EV-tissue protein correlations. CYP3A4 abundance was quantified in liver-derived EVs isolated from plasma of pregnant (n=9) and non-pregnant (n=3) females, patients with metabolic associated fatty liver disease (MAFLD; n=14) and controls (n=14).
Results: Strong correlations were observed in paired liver EVs and homogenates for all CYP (r = 0.654 to 0.962) supporting EVs as a robust surrogate of hepatic enzyme expression. CYP3A4 expression in liver EVs was significantly elevated in third-trimester pregnancy (3.2-fold, P = 0.003) compared to non-pregnant controls. CYP3A4 abundance was 30 to 70% lower in MAFLD patients, consistent with reported reduced metabolism in liver disease. The reduction in CYP3A4 abundance in MAFLD patients was associated with the severity of disease.
Conclusion: These data support liver EVs as a non-invasive liquid biopsy to characterize variability in medicine exposure cased by physiological and pathological changes. EV protein abundance may complement genotype to enable a comprehensive ADME genomic profile.

Background: Tacrolimus, an immunosuppressive agent, is widely used to treat various types of transplants, and controlling its blood concentration and therapeutic efficacy has always been a particularly critical issue of concern.

Aims: This retrospective analysis evaluated tacrolimus therapeutic drug monitoring (TDM) data to determine the optimal therapeutic window and guide treatment adjustments for transplant patients in real-world settings.

Methods: TDM data from outpatient and inpatient transplant patients (liver, kidney, cardiac, and hematopoietic stem cell transplants) at the First Affiliated Hospital of University of Science and Technology of China (Jan. 1, 2024–Dec. 31, 2024) were analyzed. Tacrolimus steady-state blood concentrations were monitored in 12,539 patients (10,718 outpatients and 1,821 inpatients).

Results: The interquartile range (P25–P75) of tacrolimus blood concentrations was 4.60–7.31 ng/mL. The outpatient concentrations ranged from 4.60–7.10 ng/mL (66.64% compliance), whereas the inpatient concentrations ranged from 4.77–9.25 ng/mL (70.35% compliance). Patients with multiple TDM sessions had significantly higher compliance rates than those with single sessions (P < 0.01). The interquartile ranges (compliance rates) of blood concentrations varied by transplant type: kidney (4.70–7.07 ng/mL, 68.71%), liver (3.97–8.11 ng/mL, 61.30%), hematopoietic stem cell (3.60–9.20 ng/mL, 60.84%), cardiac (5.55–8.98 ng/mL, 81.71%), and lung (4.80–10.19 ng/mL, 69.76%), and the differences were significant (P < 0.05).

Conclusions: The optimal tacrolimus therapeutic window may need re-evaluation for different transplant types to improve compliance and guide precision therapy.

Key Words: Transplant; Tacrolimus; Therapeutic drug monitoring; Therapeutic window; Individualized therapy

Background:
Systemic juvenile idiopathic arthritis (sJIA) is a rare and severe subtype of juvenile idiopathic arthritis, accounting for approximately 10–20% of cases. It is characterized by systemic inflammation, high-spiking fevers, transient rash, and arthritis. In KwaZulu-Natal (KZN), sJIA is among the rarest diseases and is managed on a case-by-case basis due to limited healthcare resources. The KZN Provincial Pharmacy and Therapeutics Committee (PTC) approves nonformulary medicine requests for rare diseases, but follow-up data on treatment effectiveness remain limited.

Aim:
This study evaluates the effectiveness of tocilizumab, a nonformulary medicine approved by the KZN PTC, in managing sJIA at tertiary hospitals since January 2019.

Methods:
A retrospective case-series study was conducted at Inkosi Albert Luthuli Central Hospital. Patient records of those receiving tocilizumab through a named-patient program were reviewed. Ethical approval was obtained from the University of KwaZulu-Natal and relevant authorities.

Results:
One patient experienced resolution of joint pain, swelling, rash, and morning stiffness, with improved white blood cell (WBC), haemoglobin (Hb), and platelet counts, though red blood cell (RBC) levels remained slightly elevated. Another patient reported improved appetite and reduced muscle stiffness, with no signs of active inflammation except for persistent pain. However, C-reactive protein (CRP) levels remained high.

Conclusion:
The approval of tocilizumab for immunosuppression in sJIA was justified, demonstrating potential effectiveness in symptom management and disease control. Further research is needed to assess long-term outcomes and optimize treatment strategies.

Keywords:
Systemic juvenile idiopathic arthritis, tocilizumab, inflammation, rare diseases, KwaZulu Natal, immunosuppression.

Backgroud: Sirolimus (SRL), is widely used in transplantation but exhibits significant variability and can cause adverse effects. Reliable biomarkers are needed to predict its pharmacokinetic behavior and to optimize therapeutic outcomes as well as minimize adverse events.

Objective: To investigate the association between creatinine to cystatin C ratio (CCR) with concentration variability and safety outcomes.

Methods: A retrospective study in patients who had kidney transplantation and treated with sirolimus was conducted. The level of CCR was quantified and categorized into low and high groups based on the median value. Then we compared the sirolimus concentration variability as well as the serum level of RBC, HB, Glucose, ALT and TG between groups.

Results: A total of 294 trough SRL concentrations were included and divided into two groups based on median value of CCR. Among them, significant narrower coefficient of variation of C0/Dose was found in high CCR group (36.35%) as compared with low CCR group (61.01%). The mean glucose level (5.54±1.07 vs. 5.18±0.64, p=0.0005), mean ALT level (30.46±32.22 vs. 21.12±20.09, p=0.0031) and mean TG level (2.33±1.34 vs. 1.89±1.00, p=0.0019) were significant lower in High CCR group. On the contrary, the mean RBC level (4.46±0.96 vs. 4.76±0.72, p=0.0033) and mean HB level (122.50±25.15 vs. 131.40±18.59, p=0.0007) were significantly higher in high CCR group.

Conclusion: CCR is a valuable prognostic biomarker for sirolimus concentration variability and safety outcomes in kidney transplant patients.

Keywords: Sirolimus; therapeutic drug monitoring; concentration variability; creatinine to cystatin C ratio; kidney transplant patients

Background: Tacrolimus is one of few immunosuppressants used in pregnancy. Therapeutic drug monitoring often prompts dose increases due to decreasing trough blood concentrations (BC0) throughout pregnancy. Given high erythrocyte-binding, decreasing BC0 may reflect changes in haematocrit, rather than clearance.

Aims: To investigate relationships between BC0, trough plasma concentrations (PC0) and pregnancy outcomes.

Methods: BC0 and PC0 were measured by LC-MS/MS. Biochemistry and outcomes were obtained from clinical records. Relationships between BC0 and PC0 were investigated by linear mixed effect models adjusting for repeated measures and confounders. Effects of BC0 and PC0 on neonatal birth weight, gestational age and maternal plasma creatinine were investigated by linear regression or mixed effects models.

Results: In 9 participants (6 kidney transplant, 3 lupus nephritis) median BC0 and PC0 were 5.4ng/mL (1.6-23.1ng/mL, n=97) and 0.88ng/mL (0.28-4.27ng/mL, n=88). BC0 and PC0 were moderately correlated (R2=0.51; P<0.0001). The PC0/BC0 ratio increased during pregnancy (P<0.01) and with higher albumin (P<0.05). Maternal creatinine increased during third trimester (P<0.001) and with higher dose (P<0.05). 6/8 neonates were <37 weeks gestation, 5/6 weighed <2.5kg. Weight was inversely associated with BC0 (P<0.0001, Padj<0.0004). For every 100ng/L increase in BC0, weight decreased by 60g (95%CI: -90, -30).

Conclusions: BC0 were highly variable in pregnancy and often subtherapeutic. However, routinely increasing dose may be unwarranted given the only moderate relationship between BC0 and PC0, and our preliminary observation of a relationship between high dose, BC0 and poor outcomes (decreased maternal renal function and neonatal weight), which warrants further investigation.

Key words: tacrolimus, pregnancy, immunosuppression

Background: DPYD genotype screening for targeted variants prior to fluoropyrimidine treatment represents a critical advancement in personalised chemotherapy. Despite availability of pre-emptive genetic testing to identify individuals with dihydropyrimidine dehydrogenase enzyme deficiency, clinical implementation remains limited within Australia.

Aims: To evaluate integration of a pre-emptive DPYD genotyping service in real-world clinical practice, including utility of DPYD genotype-based fluoropyrimidine dosing strategies and impact on short-term patient clinical outcomes.

Methods: Targeted DPYD genotype testing was implemented in a tertiary hospital, from which service and short-term patient outcomes were examined. Data collected included administered fluoropyrimidine doses, toxicity, patient and disease characteristics. Toxicity was assessed using the Common Terminology Criteria for Adverse Events. Clinical dosing of fluoropyrimidines was evaluated against recommendations from the CPIC guideline.

Results: Between 1 June 2022 and 31 December 2023, a total of 225 patients were screened, of whom 20 (8.89%) patients were DPYD variant carriers. Of the 20 patients, 19 were heterozygous carriers and received fluoropyrimidine chemotherapy; one patient was a homozygous c.1236G>A/HapB3 carrier and received alternate treatment. Initial (Cycle 1) dose reductions were reported in 17/19 variant carriers; however, significant variation in dose intensities was observed. Most variant carriers did not report grade ≥3 toxicity and completed their planned treatment.

Conclusions: The clinical integration of DPYD genotype-based dosing to personalise fluoropyrimidine chemotherapy was successful. However, given the heterogeneity in dosing requirements, additional strategies such as expanded DPYD testing and/or quantification of fluoropyrimidine exposure may be required to comprehensively inform personalised dosing for fluoropyrimidines.

Keywords: pharmacogenomics, DPYD genotyping, fluoropyrimidine

Background: CYP3A4 is an important drug-metabolizing enzyme, and its genetic variants may affect drug metabolism and drug-drug interactions. Imatinib is a commonly used anti-cancer drug, and CYP3A4 polymorphisms may influence its metabolism.

Aims: To investigate the catalytic activity of 26 CYP3A4 variants on imatinib metabolism and their drug interactions.

Methods: Ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used to measure the concentration of imatinib's metabolite N-desmethyl imatinib. The study was conducted using an appropriate incubation system under constant temperature water to evaluate the impacts of CYP3A4 genetic polymorphisms and drug interactions on imatinib metabolism.

Results: Compared to CYP3A4.1, the intrinsic clearance (CLint) values of the 26 variants varied significantly, ranging from 2.34% to 120.57%. CYP3A4.14 showed an increase in CLint compared to CYP3A4.1, while the remaining 24 variants exhibited decreased catalytic activity for imatinib metabolism. Additionally, the metabolism of imatinib was inhibited to varying degrees by ketoconazole, itraconazole, and fluconazole in both CYP3A4.1 and CYP3A4.18. Most CYP3A4 variants showed similar enzyme activity patterns with different substrates, imatinib and cabozantinib, except for six variants (CYP3A4.3, .4, .10, .15, .29, and .31).

Conclusions: This study is the first to investigate the effects of 26 CYP3A4 variants on imatinib metabolism. The findings will contribute to the clinical evaluation of imatinib and assist in the personalization of therapy in clinical practice.

Key Words: Imatinib, CYP3A4 variants, metabolism , cabozantinib, microsomes

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: Cytomegalovirus (CMV) disease is a life-threatening complication after lung transplantation. Valganciclovir (VGCV) is safe and highly effective in prophylaxis of CMV infection. However, early cessation by VGCV-induced myelosuppression leads to serious CMV disease. Recently, Nudix hydrolase (NUDT) 15 was identified as a key metabolic enzyme in the active metabolite of VGCV. Although genetic polymorphisms in NUDT15 are prevalent in East Asians, the impact of these polymorphisms on VGCV-induced myelosuppression remains to be unclear.

Aims: This study aims to assess the effect of NUDT15 single nucleotide polymorphisms on the incidence of neutropenia and valganciclovir cessation in lung transplant recipients.

Methods: We recruited 28 lung transplant patients with VGCV prophylaxis therapy. Genotyping in exon1–3 of NUDT15 was performed by Sanger sequencing. The cumulative incidence of neutropenia (neutrophil count < 1,500 /mm³) and neutropenia-related cessation within the one-year follow-up period were assessed in the wild-type group and the reduced-function group, which consisted of patients with NUDT15 single nucleotide polymorphisms.

Results: Of 28 patients, 9 (32.1%) were identified as carrying NUDT15 reduced-function polymorphisms. The nadir of the neutrophil count within the one-month observation period following treatment initiation was significantly lower in the reduced-function group (median, WT 4.01/mm³; reduced-function group 2.60/mm³). In the analysis of covariance using GCV trough levels as a covariate, the NUDT15 polymorphism was found to have a significant effect on the nadir of the neutrophil count (p<0.05).

Conclusions: NUDT15 polymorphisms increase the risk of neutropenia due to VGCV prophylaxis in lung transplant recipients.

Keywords: NUDT15, valganciclovir, lung transplantation

Background:Lung cancer is the leading cause of cancer-related deaths in China, with 19% of deaths, totaling 3.62 million cases. Non-small cell lung cancer (NSCLC) accounts for 85% of cases. ABCB1 gene polymorphism (rs1045642) may influence chemotherapy efficacy in NSCLC, particularly with platinum-based treatments, yet studies are limited, especially in Chinese populations.

Objective:To explore the correlation between the ABCB1 rs1045642 genotype and the progression-free survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-containing treatment regimens. 

Methods: Clinical data such as age, gender, tumor metastasis, etc. of newly - diagnosed patients with stage IIIB - IV lung cancer admitted to the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital) between August 2020 and April 2022 were collected and the patients were followed up. The genotyping of ABCB1 rs1045642 polymorphism was performed using a fluorescence-based detection method. Kaplan-Meier survival analysis and COX proportional-hazards regression model were employed to analyze the influencing factors of prognosis. 

Results:Patients with the CC genotype of ABCB1 rs1045642 (n=34) exhibited a significantly better median progression-free survival (PFS) compared to those with the CT/TT genotype (n=49) (P=0.032). The ABCB1 rs1045642 genotype was identified as an independent factor affecting PFS in lung cancer patients treated with platinum-based regimens (P=0.018).
Conclusion:The ABCB1 rs1045642 genotype can be used to predict the efficacy of platinum-containing treatment regimens in patients with stage IIIB-IV lung cancer, providing a reference for the personalized administration of platinum-based drugs.

Key words:Non-small cell lung cancer; ABCB1 rs1045642; Platinum resistance

Background: Tuberculosis remains a high-burden disease in Thailand, with immunocompromised individuals, particularly those with diabetes mellitus, being at increased risk. Previous studies have suggested that the TLR4 variants rs11536889 and rs7873784 may be associated with TB susceptibility in diabetic patients. However, the available research is limited and inconclusive.

Aims: To determine the association between the genotype frequencies of rs11536889 and rs7873784 in the TLR4 gene and the risk of developing TB in Thai diabetic patients.

Methods: Diabetic patients were divided into two groups: Group 1 (without TB), and Group 2 (with TB). Blood samples were collected and processed using PureLink™ Genomic DNA Mini Kit for DNA extraction. Genotyping was performed by RT-PCR, and the associations were analyzed using logistic regression.

Results: Although statistical significance was not observed, carriers of CC genotype for rs11536889 had a 1.6-fold higher risk compared to wild-type carriers (p=0.633). For rs7873784, the CC genotype was absent in the TB group, so the association could not be analyzed. Meanwhile, the CG genotype was associated with decreased risk, but this finding was not statistically significant in either SNP.

Conclusions: Although the results were not statistically significant, they suggest a potential protective effect of the CC genotype for rs11536889. Further studies with larger sample sizes are needed to establish a reliable association and support the development of genetic screening measures for early intervention in diabetic patients in Thailand.

Key Words: TLR4, Diabetes mellitus, Tuberculosis, SNPs, Thai population

Objective: This study aimed to evaluate the safety and efficacy of antiplatelet therapy based on CYP2C19 genotype selection of different P2Y12 receptor antagonists in patients with intracranial aneurysms (IA) after stent-assisted coil embolization (SAC).
Methods: The study retrospectively analyzed the data of 332 IA patients who underwent SAC at the Second Affiliated Hospital of Zhejiang University School of Medicine in 2022, with an average age of 58.9 years.
Results: Patients were divided into five groups based on CYP2C19 genotype and received different antiplatelet treatment regimens. The results showed that 25 patients experienced intracranial ischemic events and 8 experienced hemorrhagic events. The incidence of hemorrhagic events in the intermediate metabolizer group treated with clopidogrel was significantly higher than that in the normal/fast metabolizer group; while in the slow metabolizer group, the risk of ischemic events in the clopidogrel group was higher than that in the ticagrelor group.
Conclusion: Antiplatelet treatment regimens guided by CYP2C19 gene testing can optimize efficacy and safety. Selecting regimens based on different metabolic types of patients helps balance the risk of ischemia and hemorrhage.