Cts-Clinical and Translational Science最新文献

Enzalutamide and abiraterone are hormonal treatments that improve survival in metastatic castration-resistant prostate cancer. Identifying genetic variants associated with the clearance of these drugs may aid in improved dosing and outcomes. We performed genetic association studies of enzalutamide and abiraterone oral clearance in the Alliance A031201 clinical trial. Genome-wide genotyping was performed with the primary analysis limited to European-descent participants. Pharmacogene metabolic phenotypes were estimated using PyPGx and Stargazer. Associations of metabolic activity groups for CYP3A4, CYP3A5, CYP2C19 and SLCO1B1 with enzalutamide clearance (N = 706) and CYP3A4, SLCO2B1 and UGT1A4 with abiraterone clearance (N = 323) were tested by linear regression. Targeted SNP associations were assessed for abiraterone clearance at loci proximal to major metabolizing genes. Full genome-wide association studies were performed for both sets of clearance values. No significant associations were identified between metabolic phenotypes and enzalutamide or abiraterone oral clearance SNPs in the SULT2A1 5′ flanking region were significantly associated with lower abiraterone clearance, (rs296373, minor allele frequency = 0.15, β = −0.457, p = 3.2E-06). Liver protein and liver and adrenal gland gene expression QTL databases indicated significantly lower SULT2A1 expression patterns for individuals carrying associated alleles, likely explaining the lower abiraterone oral clearance. CYP2C8*3 was associated with higher enzalutamide clearance (p = 0.012), but this was not significant after correction for multiple testing. This study is the first to identify the genetic association of SULT2A1, known to be involved in the metabolism of steroids in the liver and adrenal glands, with abiraterone clearance. Genetic variation in SULT2A1 may be useful to inform personalized dosing of abiraterone.

ClinicalTrials.gov Identifier: NCT01949337

Rivaroxaban is an oral anticoagulant that requires food intake at high doses (15 and 20 mg) due to a pronounced food effect. AD-109 is a novel formulation of rivaroxaban 18 mg, designed to enhance oral bioavailability and mitigate the food effect. This study aimed to evaluate the pharmacokinetics (PKs) of AD-109 compared to the conventional formulation, Xarelto (Xarelto, rivaroxaban 20 mg) and the effect of food on the PK of AD-109. Two open-label, single-dose, two-period, two-sequence crossover studies were conducted. In Study 1, participants received a single dose of AD-109 and Xarelto under fed state, while in Study 2, participants received a single dose of AD-109 under fed and fasted state. Serial blood samples were collected up to 34 h post-dose and PK parameters were calculated by non-compartmental method. In both studies, 33 out of 36 volunteers completed the study. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for the maximum plasma concentration (C_max) and area under the curve until the last measurable concentration (AUC_0-last) of rivaroxaban for AD-109 to Xarelto were 1.0466 (0.9961–1.0996) and 0.9450 (0.9094–0.9819), falling within the bioequivalence range of 0.8–1.25. The corresponding values of AD-109 in the fed to fasted state were 1.0475 (0.9789–1.1209) and 0.9795 (0.9371–1.0238), suggesting the systemic exposure was not substantially influenced by food intake. AD-109 (rivaroxaban 18 mg) demonstrated a PK profile comparable to that of Xarelto (rivaroxaban 20 mg) and effectively minimized the food effect on drug exposure.

Photoreceptor transplantation is being studied to restore visual function in retinal diseases causing blindness, including age-related macular degeneration, hereditary eye diseases, and traumatic retinopathy. Preclinical studies often involve delivering exogenous human photoreceptor cells into animal models' retinas. A key readout in such experiments is distinguishing donor cell integration from artificial labeling secondary to material transfer of cytosolic or nuclear labels. Recognizing donor (human) versus animal photoreceptor nuclei is key, but purely immunohistology discrimination is challenging due to antigenic species overlap or intercellular antigen transfer. To address this, we sought to develop and validate a computational technique to discriminate between photoreceptor cells of different animal species based on machine learning of nuclear morphology. We aim to evaluate the feasibility of computer-assisted nuclear detection combined with random forest classification to automate species differentiation in DAPI-stained photoreceptors after xenotransplantation into mouse and pig retinas. Our models were trained on single-species samples and validated with mixed-species samples. We then transplanted human embryonic stem cell-derived retinal organoid cells into rodent and pig retinal degeneration models. The random forest model accurately determined cell identity post-xenotransplantation, validated by histological assessment using an antihuman nuclear antibody. Our results support the potential efficacy of employing machine learning image analysis and classification techniques that may promote experimental rigor, minimize observer bias, and enable high throughput semiautomated workflows for transplantation outcomes analysis. The methodological framework reported here may enable a more nuanced and precise analysis of the behavior of transplanted photoreceptors for the purposes of human retinal regeneration.

To investigate if a newly developed tadalafil oral soluble film (OSF) was bioequivalent to the approved tadalafil tablets, a clinical study was conducted in healthy Chinese male volunteers under fasting conditions. In this study, 36 volunteers were randomized into three groups and received one tadalafil tablet, one tadalafil OSF with water, or one OSF without water in each period. The dosages were all 10 mg. Blood samples were collected and centrifuged. Plasma concentrations of tadalafil were determined by liquid chromatography tandem mass spectrometry. Pharmacokinetic (PK) parameters including maximum plasma concentration (C_max), area under the concentration versus time curve (AUC) from dosing to the last sampling time (AUC_0–t), AUC from administration to infinity (AUC_0–∞), time to C_max, half-life and terminal elimination rate constant were calculated. Primary PK parameters including C_max, AUC_0–t, and AUC_0–∞ were logarithmically transformed and an analysis of variance was applied to determine the bioequivalence between the reference and test formulation, as well as bioequivalence between tadalafil OSF administered with or without water. Safety was assessed by adverse events (AEs), serious adverse events (SAEs) and results of laboratory tests and examinations. The 90% confidence intervals of geometric mean ratios of primary PK parameters were all within the bioequivalence range of 80.00%–125.00%. AEs were mild or moderate and no SAEs were reported. Under fasting conditions, the test OSF formulation was bioequivalent to the reference tablets, and the test OSF administered with water was bioequivalent to that without water. All investigational formulations were well tolerated in the study.

Trial Registration: chinadrugtrials.org.cn (CTR20181044).

Artificial Intelligence (AI) is transforming drug development and regulatory submission by enabling advanced data analytics, predictive modeling and intelligent decision support systems. Beyond efficiency gains, AI establishes a translational bridge between model-informed drug development (MIDD) and clinical implementation, turning regulatory evidence into actionable insights that enhance therapeutic precision and patient outcomes. This perspective paper explores AI's current applications, regulatory integrations, and future prospects in accelerating data-driven, patient-centered drug development.

N,N-dimethylacetamide (DMA) is an organic solvent, used in busulphan, iv-formulation, (Busulfex). DMA is metabolized primarily to N-methylacetamide (MMA) via CYP2E1. In the present study, we investigated the pharmacokinetics and toxicity of DMA and MMA in patients, mice and cell lines. In pediatric patients (6 months to 18 years) undergoing hematopoietic stem cell transplantation, the pharmacokinetics of DMA and MMA were followed during the 4-days Busulfex conditioning (3.2–4 mg/kg, b.i.d). No accumulation of DMA was found; however, a significant increase in clearance and a significant decrease (p < 0.005) in half-lives by the end of treatment were observed which might indicate CYP2E1 autoinduction. Furthermore, continuous increases in plasma concentration of MMA were observed during treatment and a terminal half-life of 15.2 ± 1.7 h was detected. Moreover, ALT was significantly (p = 0.04) increased in > 61% of the patients after conditioning. Additionally, mice were treated with either dimethyl sulfoxide (DMSO), DMA, busulphan in DMSO, Busulfex or saline for 4 days. DMA-treated mice showed elevated ALT and AST values. Interestingly, Busulfex administration did not alter mice liver enzymes. Busulphan in DMA showed higher cytotoxicity compared to busulphan in DMSO in HepG-2, Huh-7 and HL-60 cells. The combination Bu-DMA-MMA exhibited increased cytotoxicity in a concentration-dependent manner. In conclusion, Busulfex administration to pediatric patients resulted in an accumulation of MMA during the 4-days treatment. Busulfex is less toxic compared to Bu dissolved in DMA. MMA addition to Bu in DMA showed higher cytotoxicity. Therefore, MMA with a relatively long half-life may induce hepatotoxicity and/or interaction with subsequently administered drugs; thus further investigations are urgently warranted.

Prognostic assessment of chronic thromboembolic pulmonary hypertension (CTEPH) remains challenging. Stress hyperglycemia, a condition where glucose metabolism is regulated during stress, has been regarded as an indicator of acute hyperglycemia. The stress hyperglycemia ratio (SHR) serves as a more precise marker for this state. This research intended to investigate the prognostic function of SHR in CTEPH, as its link to poor outcomes is uncertain. Clinical deterioration events were the primary endpoint. LASSO regression was utilized for variable selection and dimensionality reduction to identify key features and mitigate overfitting. Kaplan–Meier analysis, multivariable Cox regression, and restricted cubic splines were primarily used to investigate the link between SHR and adverse clinical outcomes. Internal validation was performed using bootstrap resampling. Sensitivity analysis was performed to assess the robustness of the findings. The study included a sum of 451 patients with CTEPH; over a median follow-up of 21 months, 89 (19.7%) patients encountered adverse outcomes. Kaplan–Meier analysis indicated that patients having elevated SHR levels exhibited a markedly higher overall incidence of adverse events. Restricted cubic spline analysis showed a linear relationship between SHR and adverse events. Multivariable Cox regression analysis indicated that higher SHR independently predicts adverse outcomes, whether treated as continuous (hazard ratio, 1.541; 95% confidence interval, 1.252–1.896, p < 0.001) or categorical (hazard ratio, 2.419; 95% confidence interval, 1.268–4.616, p = 0.007). Internal validation demonstrated that the original C-index was 0.693, with a bias-corrected C-index of 0.675 after bootstrap validation. In patients with CTEPH, higher SHR is independently associated with clinical worsening. The prognostic significance of SHR remained robust across internal validation and multiple sensitivity analyses.

There has been growing interest in precision dosing of beta-lactam antibiotics in recent years. At our institution, a quaternary children's hospital, we launched a new PK consult service utilizing a model-informed precision dosing (MIPD) approach to provide personalized dosing recommendations for cefepime. This consult service leveraged the infrastructure of an existing PK consult service at our institution for other drugs, such as immunosuppressants. In this manuscript, we describe the challenges in the development of a beta-lactam PK consult service due to fundamental differences between the new service and the existing PK consult service, such as varying levels of evidence for target goals for beta-lactam antibiotics versus immunosuppressants, and how they were addressed. We then present the workflow and infrastructure of our beta-lactam PK consult service to provide guidance for other institutions who may be interested in launching a similar service. Lessons learned throughout the process of building the service, including the importance of engaging multiple, diverse stakeholders early on and starting with one drug at a time, are provided.

Proteomics can identify pharmacodynamic (PD) biomarkers by detecting protein changes in response to drug treatment, providing insights into drug mechanism and biological effects. In this study, we profiled over 7000 plasma proteins to identify potential PD biomarkers for the interleukin-5 (IL-5) inhibitors mepolizumab and reslizumab, which are approved for treating eosinophilic asthma. We used longitudinal plasma samples from healthy participants treated with a single dose of mepolizumab (n = 8, 24 mg) or reslizumab (n = 8, 0.8 mg/kg), or placebo (n = 8) to identify differentially expressed proteins. We then characterized PD biomarker candidates by their magnitude of response, area under the effect curve (AUEC), dose–response, variability, and replication of response at a lower dose for mepolizumab (n = 8, 12 mg) or reslizumab (n = 8, 0.4 mg/kg) compared to placebo. Eosinophil major basic protein (EMBP) and proteoglycan-3 (PRG3) were differentially expressed in response to mepolizumab and reslizumab, respectively, achieving Bonferroni-adjusted statistical significance (p-value < 6.86E-06) and nominal significance (p-value < 5.0E-05) with the other IL-5 inhibitor. EMBP showed a > 20% fold change difference with mepolizumab (24 mg) versus placebo at peak time, and PRG3 demonstrated a > 20% fold change with reslizumab (0.8 mg/kg) versus placebo at peak time. Both proteins had significant AUEC with both drug doses, with EMBP AUEC only significant (absolute AUEC high > low dose) at the higher mepolizumab dose. Both biomarkers showed dose–response trends and comparable variability to placebo. Our study identified EMBP and PRG3 as promising plasma PD biomarkers for IL-5 inhibitors, warranting further validation for early phase trials and biosimilar development programs.