Cts-Clinical and Translational Science最新文献

The onset of the global COVID-19 pandemic created an urgent need for therapeutic monoclonal antibody (mAb) development, while the rapid mutation of the SARS-CoV-2 virus and emergence of new variants presented a moving target for validation of efficacy. Since it is virtually impossible to conduct randomized controlled trials in the context of a continually evolving variant landscape, other sources of data can inform ongoing effectiveness and appropriate dosing of existing treatments against new variants. This may include data from in vitro neutralization testing, real-world studies, and clinical pharmacology studies. There are various clinical pharmacology approaches available to aid in dose selection of COVID-19 mAbs, and the approach used for initial dose selection may differ from that used to justify dose modifications in light of new variants. At present, there is no universally accepted approach that has been shown to work in all circumstances, and most of the available methods lack validation against clinical data. Here, we provide an overview of the different pharmacological approaches available for mAb dose selection or dose adjustments, outlining advantages and limitations of each as well as assumptions, data requirements, and key learnings for each method based on experiences with COVID-19 mAb development over the last 4 years. Future mAb development programs for COVID-19 or other viral infections with pandemic potential should take into consideration lessons learned from the COVID-19 pandemic and devise clinical development programs that generate data to help address new emerging variants of concern in a rapidly evolving virus landscape.

Chronic kidney disease is a progressive condition with limited therapeutic options in its advanced stages. Adipose-derived stem cell therapy has shown potential in preclinical studies for renal repair. This study evaluated the short-term stability of renal function in patients with moderate to severe chronic kidney disease who received adipose-derived stem cell therapy, using a matched control group derived from real-world clinical data for comparison. A total of 34 treated patients were matched in a one-to-five ratio with 170 control patients based on key clinical characteristics. The primary outcomes included the mean percentage change in estimated glomerular filtration rate and the incidence of renal function decline exceeding defined thresholds. To enhance the robustness of treatment effect estimation, real-world data were utilized to construct an external control group that closely resembled the clinical trial population. This approach allowed indirect treatment comparisons and strengthened the internal validity of findings in the absence of randomization. Results demonstrated that the treated group exhibited a more stable renal function trajectory and a significantly lower risk of deterioration compared to the control group, particularly in patients with more advanced disease. Among dose groups, the low-dose group showed the greatest stability in renal function. These findings support the feasibility of using real-world data to construct external comparators and suggest that stem cell therapy may offer a short-term stabilizing effect on renal function. Further research is needed to validate these findings and explore their long-term clinical implications.

Trial Registration: ClinicalTrials.gov identifier: NCT02933827 (registered October 13, 2016. https://clinicaltrials.gov/study/NCT02933827)

Janus kinase inhibitors (JAKIs) are immunomodulatory drugs used for autoimmune and inflammatory conditions. Their potential impact on pregnancy and fetal development remains a concern due to placental transfer and potential disruption of cytokine and growth factor signaling, with limited human data. This study analyzed VigiBase, the World Health Organization global pharmacovigilance database of individual case safety reports (ICSRs), to assess signals of disproportionate reporting (SDRs) for pregnancy-related adverse drug reactions (ADRs) reported with systemic JAKIs, including abrocitinib, baricitinib, deucravacitinib, fedratinib, filgotinib, itacitinib, momelotinib, pacritinib, peficitinib, ritlecitinib, ruxolitinib, tofacitinib, and upadacitinib. As of May 26, 2024, 163 ICSRs met inclusion criteria, mainly from North America (41.7%) and Europe (39.3%). The most frequently reported JAKIs were tofacitinib (44.8%) and upadacitinib (34.4%), primarily indicated for rheumatoid arthritis (29.4%). Among 213 pregnancy-related ADRs, spontaneous abortion was the most frequently reported event (47.9%) without representing an SDR compared with other drugs in the database (reporting odds ratio [ROR] 0.37, 95% confidence interval [CI] 0.30–0.46). Congenital anomalies were reported in 16.0% of ICSRs (43 events), but no specific organ-related patterns were identified. Prematurity occurred in 9.2% of ICSRs, without SDR compared to the full database (ROR 0.07, 95% CI 0.04–0.11). Current pharmacovigilance data from VigiBase do not indicate SDRs for spontaneous abortion or prematurity following JAKI exposure during pregnancy. Findings should be interpreted cautiously given the limitations of spontaneous reporting systems and the exploratory nature of the analysis. Further studies are needed to better characterize the JAKI safety in pregnancy.

We assessed the predictive value of MAdCAM-1 expression on response to vedolizumab in patients with inflammatory bowel disease. This was a retrospective, single-center, cohort study including 109 patients with pretreatment inflammation who completed at least three doses of vedolizumab. We described clinical and endoscopic outcomes of patients based on MAdCAM-1 expression. There was no significant difference in MAdCAM-1 expression when stratified by histology. Patients in clinical remission at 14 weeks had significantly lower median baseline MAdCAM-1 expression (37425.3 vs. 46278.9, p < 0.015). There was no difference in pretreatment MAdCAM-1 expression among patients who later achieved endoscopic or biologic response. In the posttreatment cohort, lower MAdCAM-1 expression was associated with an increased likelihood of endoscopic or biologic response (36719.5 vs. 44229.9, p < 0.038). However, posttreatment MAdCAM-1 expression did not significantly differ when stratified for clinical remission at 14 weeks. Ultimately, MAdCAM-1 immunohistochemistry has limited utility as a predictive biomarker but may provide insights into vedolizumab-associated bowel healing.

Malnutrition implies a decline in the systemic status and organ function, which is closely related to sarcopenia, frailty, osteoporosis, and prognosis. Diabetes medications work in a multifaceted manner on various tissues, such as the pancreas, muscle, liver, and adipose tissue; these medications affect metabolism, which in turn affects nutritional status. This study aimed to determine the effect of diabetes medications on the scores of the Geriatric Nutrition Risk Index (GNRI) and Controlling Nutritional Status (CONUT) nutritional indices, both cross-sectionally and longitudinally. This cross-sectional study included 2146 individuals who were prescribed diabetes medications. Multivariate analysis showed that both GNRI and CONUT scores tended to be improved in patients using sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP4i), or biguanide (BG). Additionally, propensity score matching of nutrition-related laboratory values was performed to assess the variation in nutritional indices over time, which resulted in less deterioration of the GNRI in the SGLT2i and BG groups. In conclusion, this study suggests that SGLT2i and BG prevent the progression of malnutrition and may help in selecting drugs that consider the nutritional status of patients.

Physiologically-based pharmacokinetic (PBPK) modeling has become a major tool in drug discovery and development. Here, we describe the bottom-up PBPK modeling approaches employed at AbbVie using Simcyp Simulator and evaluate the impact of three system parameters, GI physiology, P-gp Relative Expression Factor (REF), and recombinant CYP enzyme (rCYP) intersystem extrapolation factor (ISEF), independently and in combination, on PBPK prediction performance through retrospective analysis of 8 clinical assets. Overall, the application of New GI physiology resulted in a considerable improvement in the prediction of oral absorption for most compounds compared to the Original GI physiology (C_max: 76% vs. 43% within 3-fold) when using the default P-gp REF (1.5) and adjusted ISEF. Decreasing P-gp REF to 0.5 resulted in additional improvement in the predictions of C_max for P-gp substrates (86% within 3-fold). The observed plasma exposure-time profiles and AUC_INF are better predicted using the default rCYP ISEF values instead of individually adjusted values (48% vs. 43% within 3-fold) when using the Original GI and default P-gp REF (1.5). The combination of optimized parameters (New GI physiology, P-gp REF of 0.5 and rCYP default ISEF) predicted the plasma exposures (AUC_INF and C_max) within 3-fold for 81% and 86% of the tested simulations, respectively. In conclusion, the present study proposes an optimized strategy for bottom-up PBPK model development in Simcyp Simulator. Retrospective comparison with observed clinical PK data is vital for model verification as well as further improvement in prospective predictions for future drug candidates.

This study assessed the potential risk of QT prolongation associated with the dual enhancer of zeste homolog 1/2 inhibitor valemetostat. An evaluation of the relationship between plasma valemetostat concentration and heart-rate-corrected QT (QTc) interval was performed. Time-matched plasma concentration and 12-lead electrocardiogram data were collected from the phase I studies DS3201-A-J101, in patients with relapsed/refractory B-/T-cell non-Hodgkin lymphomas (NCT02732275), and DS3201-A-U102, in patients with relapsed/refractory acute myeloid leukemia and acute lymphoblastic leukemia (NCT03110354). A prespecified linear mixed-effects model was used to assess the effect of valemetostat on change in QTc corrected by the Fridericia method (ΔQTcF). A population-specific method (ΔQTcP) was also used to remove the heart rate interval (RR) dependence. The final dataset contained 769 electrocardiogram measurements from 100 patients. Linear mixed-effects modeling found no significant demographic or clinical covariate effects. The slope versus concentration was significant (95% confidence interval [CI] of the coefficient excluded 0) in the final models for ΔQTcF, but not ΔQTcP, while the relative standard error of the slope was > 50% for both models. Baseline QTc had a negative effect on ΔQTc in all models. At the steady-state geometric mean maximum concentrations in the dose range of 100–700 mg tested in the DS3201-A-J101 and DS3201-A-U102 studies, the 90% CI upper bounds for model-predicted ΔQTcF and ΔQTcP were 1.52–8.38 ms, all of which were below the clinically significant threshold of 10 ms. The analysis supports a lack of a clinically meaningful effect on the QTc interval for valemetostat.

Gastric Signet Ring Cell Carcinoma (GSRCC) is an increasingly recognized subtype of gastric cancer, particularly prevalent in South Asian populations and regions within India. This carcinoma is distinguished by its abundant cytoplasmic mucinous cells and aggressive clinical behavior, often affecting younger individuals and leading to a poor prognosis due to its advanced-stage presentation and resistance to standard treatments. A critical factor in its progression is the tumor's uniquely immunosuppressive and stromal-rich microenvironment, characterized by dysfunctional immune infiltrates, activation of cancer-associated fibroblasts, extracellular matrix remodeling, and complement cascade dysfunction. Recent research has highlighted the significance of key biomarkers, including MSMB, AGR2, CLDN18.2, and notably GRIN2D, which play roles in tumor angiogenesis, immune evasion, and metabolic reprogramming. The interaction of these elements contributes to therapeutic resistance and immune escape, thereby reducing the effectiveness of chemotherapy and checkpoint inhibitor immunotherapies. Innovative strategies that integrate stromal-targeting agents, complement modulators, anti-CLDN18.2 antibodies, and novel GRIN2D-targeted therapies, along with precision molecular profiling, offer potential for enhancing patient outcomes. Tailored approaches that incorporate early detection and dynamic biomarker monitoring may ultimately transform GSRCC management toward personalized, evidence-based therapies and prevention.

Cannabidiol (CBD) is one of the most extensively studied cannabinoids and is used for myriad conditions. Its oral pharmacokinetics are complex, exhibiting non-linear absorption, significant food effects, and variable exposure in hepatic impairment. Existing physiologically based pharmacokinetic (PBPK) models for oral CBD have largely relied on fitted first-order absorption or fitted dissolution profiles, limiting their mechanistic and predictive capabilities and extrapolation, particularly regarding the mechanistic details of its absorption. This study developed and verified the first PBPK model for oral CBD with mechanism-based oral absorption based on our prior published PBPK model. It incorporated mechanism-based absorption using the multi-layer gut wall within the advanced dissolution, absorption, and metabolism (M-ADAM) model within Simcyp. Pharmacokinetic parameters for CBD or population parameters related to absorption were obtained from the literature or optimized. Some physiological parameters (e.g., luminal bile salt and lymph flow rate) were adjusted mechanistically to account for CBD's sesame oil formulation and meal characteristics. The model well captured the CBD concentration-time profiles and key pharmacokinetic parameters, including area under the concentration-time curve (AUC), peak concentration (C_max), and time to maximum concentration (t_max) across diverse doses, fed/fasted states, and in patients with hepatic impairment (mild, moderate, severe). Predictions were consistently within two-fold of observed data. This work offers a robust foundation for the mechanistic understanding of CBD's complex oral absorption. The verified models can optimize CBD dosing strategies, predict potential drug–drug interactions, and evaluate CBD pharmacokinetics in various specific populations, ultimately contributing to safer and more effective clinical use.

The discovery and approval of Suzetrigine (VX-548, Journavx) marks a significant breakthrough in pain management. It is the first non-opioid analgesic approved since celecoxib in 1998. Suzetrigine selectively blocks voltage-gated sodium channel Na_v1.8 and acts exclusively on peripheral nociceptors without crossing the blood–brain barrier, providing analgesia while sparing central nervous system side effects such as dependence, addiction, sedation, and respiratory depression. In vitro experiments have demonstrated that Suzetrigine is a state-dependent inhibitor with nanomolar potency against human Na_v1.8, exhibiting > 31,000-fold selectivity compared to other subtypes of sodium channels and molecular targets. Suzetrigine is rapidly absorbed following oral administration with peak plasma concentrations (T_max) in approximately 3 h under fasting conditions and an effective half-life (t_1/2) of 23.6 h. Suzetrigine is primarily eliminated via hepatic metabolism. Recent phase II and III clinical trials have validated Suzetrigine's efficacy in acute postoperative pain settings, demonstrating statistically significant reductions in pain intensity over 48 h following abdominoplasty and bunionectomy. Additionally, Suzetrigine has shown favorable safety and tolerability in broader acute pain indications and is under continued investigation for the treatment of chronic neuropathic conditions such as diabetic peripheral neuropathy. Pharmacokinetic and pharmacodynamic data support Suzetrigine's rapid oral absorption, state-dependent Na_v1.8 inhibition, and limited off-target activity as confirmed by both nonclinical and clinical safety studies. Suzetrigine received approval for use in January 2025 in the United States only. Ongoing trials are exploring novel formulations, long-term safety, and integration into multimodal regimens for surgical and non-surgical pain.