Cts-Clinical and Translational Science最新文献

Efavirenz's effects on cytochrome P450 2C9 (CYP2C9) activity have not been formally characterized in vivo. We conducted the first clinical drug–drug interaction (DDI) study to test the effect of chronic efavirenz dosing on CYP2C9 activity, using tolbutamide as a selective probe. Healthy participants received a single oral dose of tolbutamide (250 mg) with a single 600 mg dose of efavirenz (SD) before and after 600 mg daily efavirenz for 17 days (MD). Tolbutamide, efavirenz, and their metabolites were quantified in plasma and urine samples by LC–MS/MS method. Participants were genotyped for CYP2C9*2 and *3 and for CYP2B6*4, *9, and *18. Pharmacokinetic data were valid for 71 and 59 participants for SD- and MD groups, respectively. MD efavirenz caused more than 50% increase in median tolbutamide AUC_0-∞ and C₂₄ in all subjects, and 1.42–1.46-fold increase in the paired analysis (p < 0.0001); tolbutamide/metabolite ratios were also increased (p < 0.001), while tolbutamide's CL/F/kg, metabolite formation clearance, and metabolite C_max were significantly reduced. CYP2C9 genetic variants were associated with reduced tolbutamide elimination compared to *1/*1 and *1/*2 (slowest, *3/*3; and intermediate, *1/*3, *2/*2, and *2/*3). The lowest percent change occurred in *2/*2 and *3/*3 genotypes, though small sample sizes limited reliable assessment of genotype-specific DDI effects. In conclusion, chronic efavirenz use inhibits CYP2C9 activity in vivo. This inhibition may increase the risk of adverse effects from narrow-therapeutic-index CYP2C9 substrates (e.g., warfarin, phenytoin, and sulfonylureas). Therefore, therapeutic drug monitoring and dose adjustments are warranted when efavirenz is co-administered with these medications.

Camizestrant is the next-generation oral selective estrogen receptor degrader and complete estrogen receptor antagonist in Phase 3 development for hormone receptor-positive breast cancer. To investigate the impact of manufacturing changes during pivotal Phase 3 studies, this open-label, randomized crossover study of 32 postmenopausal healthy volunteers determined the relative bioavailability of a tablet used in early clinical studies (Phase 1 tablet), a tablet designed for late-phase development (prototype Phase 3 tablet), and an oral solution. Absolute oral bioavailability in the fasted state (using a [¹⁴C] camizestrant intravenous microtracer) and effects of a high-fat meal on the prototype Phase 3 tablet were also determined. The geometric mean ratios (GMRs) of the prototype Phase 3/Phase 1 tablets (% [90% CI]) for C_max and AUC, respectively were 98.7 (87.4–111.5) and 97.4 (92.6–102.5) at 75 mg (n = 15), and 96.6 (86.9–107.5) and 100.4 (96.2–104.9) at 300 mg (n = 15). GMRs of the prototype Phase 3 tablet/oral solution for C_max and AUC were 96.2 (85.3–108.7) and 99.5 (94.6–104.6) at 75 mg (n = 15). Fed-to-fasted C_max and AUC GMRs were 106.2 (94.3–119.7) (n = 16) and 109.8 (104.4–115.5) (n = 15) at 75 mg (n = 16), and 115.9 (104.3–128.7) and 102.3 (98.0–106.8) at 300 mg (n = 15). Absolute oral bioavailability at 75 mg (n = 6) and 300 mg (n = 6) was 42.5% (36.8%–49.0%) and 55.1% (48.5%–62.5%). The formulations showed similar exposures, supporting the planned manufacturing changes. Camizestrant exhibited moderate bioavailability; exposures were similar under fasted and high-fat meal conditions, supporting its administration with or without food.

Nontuberculous mycobacteria (NTM) are emerging global pathogens. This study aimed to analyze the clinical features, species distribution, and drug resistance profiles of NTM infections in a northern Chinese hospital. A retrospective cohort study included 1769 patients with suspected mycobacterial infection from August 2023 to July 2025. PCR melting curve analysis (PCR-MCA) was used for initial screening, with confirmation by targeted next-generation sequencing (tNGS). Confirmed cases were classified as localized or disseminated disease. Among 60 confirmed NTM cases, 48 were localized (mainly pulmonary) and 12 were disseminated. The predominant species in localized disease were Mycobacterium intracellulare (35.4%) and Mycobacterium abscessus (35.4%), while disseminated cases were primarily caused by M. intracellulare, Mycobacterium avium, and Mycobacterium kansasii. Localized disease presented mainly with cough and expectoration (95.8%), whereas fever was common in disseminated infections (83.3%, p < 0.001). Key risk factors included prior tuberculosis, bronchiectasis, and immunodeficiency. Time to diagnosis was significantly longer in localized cases (10.59 ± 17.05 months) than disseminated (1.83 ± 1.47 months). Drug resistance rates varied significantly among species. The M. avium complex (MAC) predominates in NTM disease. Species identification and drug susceptibility testing are essential for guiding targeted therapy due to non-specific symptoms and species-dependent resistance patterns.

Thiopurine drugs are the cornerstone treatment for many diseases such as acute lymphoblastic leukemia (ALL), organ rejection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and other autoimmune diseases. However, their clinical use faces limitations due to the drug-induced adverse effects, including myelosuppression. Several genetic associations have been evaluated for their association with these adverse drug reactions. TPMT and NUDT15 polymorphisms have emerged as important clinical markers for predicting and optimizing the safety and effectiveness of thiopurine drugs. The bench-to-bedside approach of exploring and assessing the genetic associations of TPMT and NUDT15 variants and the new LC-MS/MS methods for evaluating TPMT is a step forward in the advancement of precision medicine of thiopurine drugs. In Thailand, TPMT and NUDT are routinely genotyped in some hospitals to guide the prescription of thiopurine drugs for optimizing the safety or effectiveness of these drugs. However, the composite effects of these genetic variants remain unexplored at the global scale. Proper large-scale studies with multi-ethnic patients can provide a clear understanding of the TPMT/NUDT15 association and would pave the way towards the optimization of thiopurine drugs to achieve precision medicine.

Maternal cell contamination (MCC) in fetal specimens poses a major risk for misdiagnosis in prenatal genetic testing. Standard variable number tandem repeat (VNTR) analysis of the thyroid peroxidase (TPO) gene intron 10 is informative for MCC detection but traditionally requires DNA extraction, limiting its use in resource-limited laboratories. This study aimed to develop and validate a direct PCR-based VNTR assay for MCC detection without DNA extraction. Leftover whole blood and amniotic fluid specimens from 90 families undergoing prenatal diagnosis for severe thalassemia were analyzed, with white blood cell and amniotic fluid pellets directly subjected to PCR amplification of the TPO intron 10 VNTR locus using a high-pH buffer to overcome PCR inhibitors. The direct PCR results were compared with standard DNA-based VNTR analysis in a blinded study, and VNTR heterozygosity at the TPO locus was also assessed in 148 unrelated Thai individuals to evaluate marker informativeness. Among 253 specimens, informative VNTR patterns were observed in 65 families (72.2%), with MCC ruled out in 64 families (71.1%) and detected in 1 family (1.1%). Uninformative VNTR patterns occurred in 25 families (27.8%) due to maternal homozygosity or similarity between maternal and fetal VNTRs. Direct PCR showed 100% concordance with standard DNA-based VNTR analysis. The heterozygosity rate of the TPO intron 10 VNTR was 87.8% among unrelated Thai individuals, supporting its suitability for routine MCC screening. The developed direct PCR protocol is a practical, rapid, and reliable tool for MCC detection, streamlining laboratory workflows and ensuring accurate prenatal diagnosis in low-resource settings.

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide, and identifying accessible blood-based biomarkers is therefore a clinical priority. Given the involvement of oxidative stress and immune cell dysfunction in atherosclerosis, we investigated whether mitochondrial reactive oxygen species (mROS) production in peripheral blood mononuclear cells (PBMCs) is associated with CAD. This exploratory study analyzed PBMCs from 40 BioHEART-CT participants with or without CT-defined CAD using MitoSOX-based flow cytometry. In parallel, single-cell RNA sequencing (scRNA-seq) was conducted in the same individuals to investigate differential expression of CCBE1, a recently implicated gene in cardiovascular disease, across PBMC populations. Overall, mROS levels in PBMCs and their major cellular subtypes did not show consistent or meaningful associations with CAD status or with modifiable cardiovascular risk factors. Small, subgroup-specific signals—such as moderate association between lymphocyte mROS and coronary artery calcium score in males, and a modest inverse association between monocyte mROS and hypertension—were exploratory and not uniform across analyses. scRNA-seq analysis did not identify a distinct CCBE1 expression signature in PBMCs. These findings indicate that PBMC-derived mROS is unlikely to serve as a useful cross-sectional biomarker of CAD in stable populations.

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate (ADC) composed of the DM4 payload conjugated to a folate receptor α (FRα)-targeting antibody via the cleavable sulfo-SPDB linker. MIRV targets and binds to FRα with high affinity and specificity, releasing the DM4 payload intracellularly following MIRV-FRα complex internalization and degradation. DM4 and its metabolite S-methyl-DM4 suppress microtubule dynamic instability, which triggers cell cycle arrest and apoptosis. Selective FRα-overexpression in ≥ 90% of epithelial ovarian tumor cells and its ability to internalize large molecules make it a highly attractive ADC target for epithelial ovarian cancers (including primary peritoneal and fallopian tube cancers). Although up to 80% of patients initially respond to platinum-based therapies, the majority of tumors will recur and become platinum-resistant. Unfortunately, platinum-resistant ovarian cancer (PROC) carries a poor prognosis with an overall survival of 12–14 months from the time of platinum-resistance, and prior to MIRV approval in 2022, little had changed in treatment options for decades. The MIRV Phase 3 registrational trial (MIRASOL) showed superiority of MIRV vs. chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) in patients with high (≥ 75%) FRα-expression PROC, showing an objective response rate of 42% versus 16%, a median progression-free survival of 5.6 versus 4.0 months, and an overall survival of 16.5 versus 12.8 months. Here, we briefly review MIRV mechanism of action, pharmacokinetics, pharmacodynamics, and key clinical efficacy and safety data.

Poisoning among older adults poses unique challenges due to age-related physiological changes, polypharmacy, and comorbidities. As Thailand transitions to a super-aged society, this study characterizes poisoning patterns in Thai older adults to inform prevention strategies. This retrospective, cross-sectional study analyzed poisoning cases involving patients ≥ 60 years reported to the Siriraj Poison Control Center from 2020 to 2023. Data included demographics, comorbidities, exposure characteristics, clinical features, and outcomes. Among 5146 poisoning cases, 682 (13.3%) involved older adults (median age: 68.5 years). Females accounted for 50.4%, and the 60–69 age group was most affected (53.8%). Comorbidities, primarily cardiovascular diseases, were present in 58.9% of patients. Most exposures were unintentional (74.6%), with nonpharmaceutical agents (54.2%) slightly exceeding pharmaceuticals (45.8%). Common nonpharmaceutical exposures included venomous animals (15.8%), household products (10.2%), and insecticides or rodenticides (7.4%). The most common scenario for unintentional exposure to nonpharmaceuticals was “accidental ingestion of nonedible substances” (41%). Among pharmaceutical exposures, antipsychotics (12.5%), analgesics (8.4%), and cardiovascular agents (5.3%) were most frequent. Unintentional pharmaceutical poisonings (73%) often resulted from adverse drug reactions or interactions (56.8%) or wrong administration route (20.8%). The proportion of fatal cases declined from 2020 to 2023; however, this trend should be interpreted cautiously due to potential confounding factors. Overall, poisoning in Thai older adults is primarily unintentional and often linked to complex medication use and comorbid conditions. These descriptive findings provide baseline information to support future efforts in medication safety, environmental awareness, and mental health promotion for Thailand's aging population.

D-2570 selectively binds to the pseudokinase domain of tyrosine kinase 2, which mediates the downstream cytokine signaling pathways involved in immune regulation. The safety, tolerability, pharmacokinetics, and pharmacodynamics of D-2570 were evaluated in a randomized, double-blind, placebo-controlled phase I study conducted in healthy Chinese subjects. The study consisted of three parts: single ascending dose (D-2570: 3–48 mg once daily) study, multiple ascending dose (D-2570: 6–36 mg once daily for 10 days) study, and food effect (D-2570: 9 mg) study. D-2570 was rapidly absorbed, with peak plasma concentration at around 4 h and exposure increased sub-proportional across the dose groups. Following multiple dosing, mean terminal elimination half-lives at steady state ranged from 22.22 to 33.86 h, with modest area under curve accumulation (1.74- to 2.08-fold) showing no dose dependence. A high-fat meal increased area under the concentration time curve from time zero extrapolated to infinite time and maximum plasma concentration by 33% and 15% for the 9-mg dose, with no significant effect on median time to maximum concentration. The inhibitory effect of D-2570 on the release of interferon-gamma induced by interleukin-12/interleukin-18 increased dose-dependently in the range of 6–36 mg. No deaths or serious treatment-emergent adverse events occurred, and all the adverse events were Grade 1 or 2 in severity. D-2570 was well tolerated in healthy Chinese subjects, and its pharmacokinetic profile was characterized. These results provide the rationale for dose selection in future clinical trials and support advancing D-2570 as a potential treatment option for autoimmune diseases mediated by tyrosine kinase 2.

Trial Registration: Chinadrugtrials.org.cn (CTR20222168)

Clinical genomics and pharmacogenomics have largely remained separate fields, though some genetic variants have overlapping disease risk and drug implications. However, the extent of this overlap is not well studied. To explore this gap, we cross-referenced genes from the American College of Medical Genetics Secondary Findings v3.2 list with genomic databases and drug labeling to identify gene-phenotype pairs with overlapping clinical genomics and pharmacogenomic implications. We searched GeneReviews and PharmGKB (now called ClinPGx) for each gene-phenotype pair and reviewed the FDALabel database contraindications or warnings. Targeted therapies for specific germline/somatic variants were excluded. PGx-trained pharmacists and a genetic counselor classified gene-phenotype pairs into three levels: Level 1 (Food and Drug Administration's or guideline-driven recommendations), Level 2 (potential pharmacotherapy implication), and Level 3 (no/weak interactions). Among 97 gene-phenotype pairs reviewed, 22 (23%) were Level 1, 31 (32%) were Level 2, and 44 (45%) were Level 3. Pharmacotherapy implications included risks inferred by disease pathology (e.g., anticoagulants and hereditary hemorrhagic telangiectasia) and less obvious associations (e.g., Marfan syndrome and fluoroquinolones). Unrecognized medication implications may pose patient safety risks. Greater research, information consolidation and dissemination, and multidisciplinary collaboration among clinical genomics specialists, pharmacogenomic specialists, and other practitioners are essential as genetic testing becomes routine in clinical care.