Cts-Clinical and Translational Science最新文献

Several antibiotics have nephrotoxic potential and an undeniable role in the development of acute kidney injury (AKI). The current AKI definition and operational criteria are dependent on functional biomarkers, serum creatinine and urine output, to identify and quantify kidney dysfunction and injury. However, there is a tremendous amount of research on novel kidney biomarkers that can be used in the assessment (i.e., prediction, detection, and prognosis) of AKI. This narrative review aimed to discuss different aspects of using novel kidney biomarkers in the context of AKI caused by selected anti-infectives including vancomycin, aminoglycosides, amphotericin B, and polymyxins as examples. Clinical studies on biomarker utilization have focused on diagnosis and detection. Urinary tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein-7, urine/plasma neutrophil gelatinase-associated lipocalin, and serum cystatin C are prominent novel kidney biomarkers studied in the milieu of anti-infective-induced AKI. Several practical issues should be considered in the application of novel kidney biomarkers in the context of antibiotic-induced AKI including: (1) the potential impact of non-kidney factors on biomarker results, (2) the utility of an optimal panel of biomarkers, (3) the appropriate starting time, frequency, and time intervals of urine/plasma sampling, (4) having a standard approach for urine sampling (random spot vs. 24-h or serial measurements), (5) ascertainment of clinically significant and diagnostic threshold values/concentrations for each biomarker, and (6) consideration of cost issues for routine use in clinical practice. Overall, novel kidney biomarkers have the potential to improve prediction and detection of antibiotic-induced AKI.

This study aimed to comprehensively assess the impact of administration time errors on the estimation of clearance (CL), a key pharmacokinetic (PK) parameter used to predict appropriate maintenance dosing and drug exposure. To identify general principles, we simulated 23 cases of hypothetical compounds with varying CL, volume of distribution (Vd), and elimination half-lives (t_1/2), and assumed administration time errors of 4, 8, and 12 h on the day before the last dose (Day last–1). Substantial underestimation of CL was observed for compounds with t_1/2 values in the approximate range of 2–26 h, with the largest effects seen for relatively short t_1/2 values of 4–5 h. Mean CL underestimation reached 7.1%, 17.7%, and 31.1% for the 4-, 8-, and 12-h timing errors, respectively. A two-compartment analysis using three oral drugs with distinct distribution characteristics and half-lives was performed to examine structural robustness. The results reproduced the core pattern—greater CL underestimation with larger administration time errors and attenuation with longer t_1/2. These findings suggest that the magnitude of CL estimation error is primarily determined by t_1/2, and a 12-h error can result in clinically relevant bias in CL estimation and potentially affect maintenance dose selection.

Imetelstat is a first-in-class, 13-mer oligonucleotide telomerase inhibitor approved in the United States and European Union for the treatment of certain adult patients with lower-risk myelodysplastic syndromes (LR-MDS) with red blood cell (RBC) transfusion-dependent anemia. This post hoc analysis evaluated imetelstat immunogenicity and its association with the pharmacokinetics (PK), efficacy, and safety of imetelstat in patients with LR-MDS from the phase II/III IMerge study (NCT02598661). A validated, semi-quantitative 3-tiered method evaluated anti-drug antibodies (ADAs). Graphical and descriptive analyses evaluated ADA incidence and association with clinical outcomes. Of 166 evaluable patients who received 7.1 mg/kg imetelstat via a 2-h intravenous infusion every 4 weeks, 16.9% developed imetelstat ADAs (median [range] time to onset, 38 weeks [12–109]; ~8 treatment cycles). In ADA-positive patients, peak titer was low (median [range], 30 [10–160]). Evaluations showed no association of ADA positivity with imetelstat PK, nor any negative association with efficacy responses, including ≥ 8-week RBC-transfusion independence (TI), ≥ 24-week RBC-TI, hematologic improvement-erythroid, or duration of RBC-TI response. There was no apparent relationship between the onset of ADAs and loss of RBC-TI. The rates of any-grade or grade ≥ 3 treatment-emergent adverse events (TEAEs) were similar for both ADA groups, with no reported serious TEAEs or TEAEs causing death in ADA-positive patients. Infusion-related TEAEs were more frequent in ADA-positive patients, although the sample size was small. Overall, imetelstat ADAs did not appear to impact imetelstat benefit/risk profile in the LR-MDS population of IMerge, although the analysis is limited by the low incidence of imetelstat ADAs, resulting in a small ADA-positive group.

The kidney benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients receiving contrast media remain unclear. This Taiwanese cohort study investigated the short- and long-term effects of SGLT2i on adverse kidney outcomes in patients receiving contrast media between January 1, 2016 and December 31, 2018. Patients who had used SGLT2i in the 90 days prior to receiving contrast media were matched with non-users. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for the composite kidney outcome, which included acute kidney injury (AKI), acute kidney disease (AKD), and a sustained ≥ 30% reduction in estimated glomerular filtration rate (eGFR) confirmed after 3 months. The absolute mean change in eGFR over time was compared using a linear mixed-effects model. The final analysis included 1032 patients (SGLT2i: 344; control: 688). During follow-up, the overall composite adverse kidney event rate was 32.8%. Although the SGLT2i group had a lower event rate (29.94%) than the non-SGLT2i group (34.3%), this difference was not statistically significant (HR, 0.95; 95% CI, 0.75–1.20). Crucially, SGLT2i demonstrated a significant protective effect on long-term kidney function: the hazard for a ≥ 30% eGFR reduction was significantly lower in SGLT2i users (HR, 0.48; 95% CI, 0.29–0.81). Exploratory analyses showed that this benefit—a slower rate of kidney function deterioration—was consistent across subgroups, including men, patients under 65 years, individuals with baseline eGFR < 60 mL/min/1.73 m², and patients with diabetes. While SGLT2i showed no significant short-term protection against AKI or AKD, these findings strongly suggest that SGLT2i confers significant long-term reno-protective benefits for patients receiving contrast media.

Breast cancer is among the most common cancers in U.S. women. Epidermal growth factor receptor inhibitors (EGFRIs) target pathways driving tumor growth but frequently cause dermatologic toxicities that impact quality of life and treatment adherence. This review summarizes the clinical features, mechanisms, and management of EGFRI-related skin adverse effects. A comprehensive PubMed search yielded 134 studies that discussed EGFRI treatment in breast cancer patients. Studies were included if they published over the past 10 years (between 2014 and 2024), reported data on females treated with EGFRI for active breast cancer, and included cutaneous side effects. Ninety articles met this inclusion criteria. Findings indicate that the severity of skin toxicity is influenced by patient-specific factors such as age, nutrition, lifestyle, genetics and ethnicity, as well as treatment-related factors including drug dosage and combination therapies. Common toxicities include papulopustular rashes, xerosis, pruritus, alopecia, and severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The specific type of EGFRI (monoclonal antibodies or tyrosine kinase inhibitors) also affects the nature of dermatological reactions. Management strategies include prophylactic skin care, symptomatic treatments, and emerging therapies such as laser therapy. Chemotherapy-induced skin toxicities from EGFRI in breast cancer treatment significantly impact patient quality of life and treatment adherence. This study underscores the need for proactive management as well as conversations with patients regarding the cutaneous adverse effects prior to starting EGFR treatment to enhance patient awareness.

Cell and gene therapies (CGTs) are transforming medicine by offering potential cures for diseases previously considered untreatable. Despite rapid advancements, challenges remain in optimizing efficacy and safety and ensuring patient accessibility and preference due to high costs and clinical uncertainties, particularly for rare diseases and one-time administration. The American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a CGT satellite conference in 2025, titled “Cell and Gene Therapy: Transforming Treatment Paradigms for Patient-Centric Care.” This manuscript summarizes the conference, covering gene therapies and T-cell immunotherapies from scientific, clinical, and patient-centered perspectives. Key topics on gene therapy included “platformization” to streamline development, lessons from adeno-associated virus-based gene therapies for hemophilia from patient and clinical perspectives, clinical pharmacology, and model-informed drug development (MIDD) considerations. The conference also highlighted T-cell immunotherapies including chimeric antigen receptor T therapy (CAR T), focusing on factors affecting cellular kinetics, efficacy, and safety, as well as emerging allogeneic CAR T for autoimmune diseases and MIDD strategies to optimize therapy design and clinical outcomes.

This first-in-human study investigated the safety, pharmacokinetics, and pharmacodynamics of the long-acting fibroblast growth factor 21 (FGF21) analog zalfermin. Healthy male participants (n = 56) with body mass index 25.0–34.9 kg/m² were randomized to single ascending doses (2, 6, 12, 24, 48, 96, and 180 mg) of subcutaneous zalfermin or placebo. In a second study, a single dose of 12, 30, or 96 mg was administered to Japanese (n = 24) and non-Asian (n = 18) healthy males to confirm a consistent safety and pharmacokinetic profile across ethnicity. Overall, 98 participants were enrolled across both studies and followed for 36 days. Blood samples were obtained for safety and for pharmacokinetic and pharmacodynamic assessments. The primary endpoint for both studies was the number of adverse events from treatment initiation to the end of follow-up, which was greater in the highest zalfermin dose cohorts in both studies. Adverse events were non-serious, mainly gastrointestinal-related, and mostly mild to moderate in severity; no deaths occurred. In both studies, dose proportionality was established for maximum serum concentration and area under the curve from time 0 to infinity. Time to maximum serum concentration ranged from 24 to 54 h. The serum half-life of zalfermin was ~120 h in both studies, compatible with once-weekly dosing. Significant improvements in plasma lipids were observed. Zalfermin had an acceptable safety profile across all single ascending doses, consistent with the FGF21 class. Further investigations into multiple ascending doses of zalfermin and treatment duration are warranted to assess the potential treatment of steatohepatitis and cardiometabolic disease.

Trial Registration: ClinicalTrials.gov (NCT03015207 and NCT04722653)

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.