Clinical Pharmacology & Therapeutics最新文献

Verekitug, a novel, high-affinity, fully human monoclonal antibody targeting thymic stromal lymphopoietin receptor (TSLPR), is in development as a potential treatment for severe asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and chronic obstructive pulmonary disease (COPD). This phase 1b, double-blind, randomized, placebo-controlled, multiple ascending-dose trial assessed the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of verekitug administered subcutaneously in patients with mild–moderate asthma. Thirty-two participants were randomized in 4 placebo-controlled dosing cohorts (3 × 100-mg or 200-mg doses, once every 4 weeks; 2 × 300-mg doses, once every 12 weeks; single 25-mg dose) and observed for 32 weeks. The primary endpoint was safety; secondary endpoints were pharmacokinetics and immunogenicity. Exploratory endpoints included TSLPR occupancy and biomarker effects. Treatment-emergent adverse events were mild or moderate. Complete TSLPR occupancy was observed at the first timepoint (2 weeks post dose) and maintained for 24 weeks (doses ≥100 mg). Rapid mean reductions in fractional exhaled nitric oxide, eosinophils, and interleukin-5 (up to −54%, −65%, and −64%, respectively) were sustained up to 24 weeks (doses ≥100 mg). The mean verekitug half-life was ~20 days. Low-titer antidrug antibody response was observed in some participants, without clinically meaningful impact on pharmacokinetics, pharmacodynamics, or safety. Verekitug was generally well tolerated, with rapid, substantial, and sustained effects on asthma biomarkers. These findings support further development of verekitug for treating severe asthma, CRSwNP, and COPD.

Advancing pharmacoequity is both a public health imperative and a scientific opportunity. While policy efforts have focused largely on post-approval issues like pricing, insurance, evidence-based prescribing practices, and pharmacy access, science offers powerful tools to address inequities much earlier. This perspective outlines how clinical translational pharmacology (CTP) is uniquely positioned as a scientific discipline to advance pharmacoequity through its principles, innovation, methods, and patient-centered applications across the discovery, development, regulation, and utilization (DDRU) continuum.

A considerable number of oral antitumor therapeutics (OAT) has the potential for causing pseudo-worsening of kidney function (PW) due to inhibition of renal creatinine secretion, i.e., kidney function is unaffected, while creatinine-based calculation of glomerular filtration rate (eGFR) erroneously indicates an impaired kidney function. Nonrecognition of PW can lead to dose reductions, interruptions, or discontinuations of OAT. The extent and incidence of PW has so far not been studied for a broad set of OAT in clinical routine. In this retrospective, multicenter cohort study, 694 AMBORA patients newly started on OAT were assessed for eligibility. eGFR values were compared between baseline and within 30 days of treatment. OAT were separated into the groups unlikely causing and likely causing/with proven PW. The usage of cystatin C measurements as an alternative method for assessing kidney function was evaluated. A total of 238 patients received 38 OAT likely causing PW/with proven PW. In this group, eGFR decreased significantly (−6.8 ml/min, p < 0.001). In 17.2% of these patients, eGFR decreased by ≥20 ml/min. Significant decreases in eGFR were observed for patients receiving, for example, abemaciclib, ribociclib, and osimertinib. Cystatin C measurements were not performed in 95.8% of the patients. In the group of 67 patients receiving OAT unlikely causing PW, there was no significant change in eGFR. In clinical routine, multiple OAT associated with PW are prescribed. A very low rate of usage of creatinine-independent methods for assessing kidney function (cystatin C) indicates that further training of oncologists is required on OAT-induced PW to further improve patient safety.

This meta-analysis evaluated the risk of malignancies and major adverse cardiovascular events (MACE) associated with the use of JAK inhibitors in patients with RA through a comprehensive meta-analysis of available clinical trials. A systematic search was conducted in PubMed, EMBASE, and Web of Science from inception to February 7, 2025, to identify relevant clinical trials. Data on malignancies and MACE incidence were extracted, and pooled risk ratios (RR) were calculated using a random-effects model. A total of 18 studies (N = 111,260) met the inclusion criteria. JAK inhibitors were associated with a significantly increased risk of malignancies excluding NMSC (RR = 1.30, 95%CI: 1.05, 1.60; P = 0.016), NMSC (RR = 1.54, 95%CI: 1.23, 1.93; P < 0.01), overall malignancies (RR = 1.53, 95%CI: 1.18, 2.00; P = 0.002), lung cancer (RR = 1.52, 95%CI: 1.11, 2.08; P = 0.009), lymphoma (RR = 3.69, 95%CI: 1.19, 11.42; P = 0.024), non-small cell lung cancer (RR = 1.70, 95%CI: 1.01, 2.86; P = 0.047), cutaneous squamous cell carcinoma (RR = 2.30, 95%CI: 1.44, 3.65; P < 0.01), and thyroid cancer (RR = 7.51, 95%CI: 1.39, 40.74; P = 0.019). In contrast, JAK inhibitors did not significantly alter the risk of MACE (RR = 0.75, 95%CI: 0.38, 1.45; P = 0.390), venous thromboembolism (VTE) (RR = 1.52, 95%CI: 0.90, 2.56; P = 0.117), or deep vein thrombosis (DVT) (RR = 1.77, 95%CI: 0.84, 3.34; P = 0.079). Trial sequential analysis (TSA) confirmed data adequacy, and meta-regression indicated that sample size, treatment duration, and patient age did not influence outcomes. JAK inhibitors are associated with an elevated risk of malignancies but do not significantly affect MACE, VTE, or DVT risk in RA patients. Further large-scale post-marketing surveillance is warranted to refine the safety profile of JAK inhibitors in RA management.

Tumor necrosis factor-α inhibitors (TNFαi) and Janus kinase inhibitors (JAKi) are widely used biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatoid arthritis. We aimed to compare the risk of serious infections between TNFαi and JAKi in patients with rheumatoid arthritis. We conducted a retrospective cohort study using a nationwide Japanese claims database covering over 19 million individuals. Patients were identified using the International Classification of Diseases, 10th Revision (ICD-10) codes (M05 or M06), and new users of bDMARDs or JAKi were included. We applied overlap weighting based on propensity scores. The primary outcome was serious infection, defined as a hospitalization-associated infection accompanied by diagnostic testing or anti-infective treatment. Among 5,018 eligible rheumatoid arthritis patients (TNFαi: 4042; JAKi: 976), TNFαi use was associated with a significantly lower risk of serious infections (HR: 0.55; 95% confidence interval: 0.39-0.77). The E-value for the observed HR was 2.39, suggesting that unmeasured confounding would need to be strongly associated with both treatment assignment and infection risk to fully explain the result. Site-specific analyses showed significantly lower risks of respiratory tract infections, urogenital infections, and sepsis in the TNFαi group. Drug-specific analyses indicated an elevated infection risk with baricitinib and infliximab. In this study, TNFαi use was associated with a lower risk of serious infections than JAKi in patients with rheumatoid arthritis. These findings support the preferential use of TNFαi in infection-prone populations and highlight the importance of individualized risk assessment in rheumatoid arthritis treatment decisions.

In recent years, different national and international regulatory authorities, notably the FDA, have made their adverse event repositories publicly available, offering user-friendly dashboards. This has led to a large increase in low-quality, poorly reported research using adverse event reporting databases (e.g., FDA’s Adverse Event Reporting System [FAERS]). Such publications producing thousands of statistical associations erroneously presented as “safety signals” can create unscientifically grounded alarm with considerable impact on healthcare provider practices and patient behaviors.

Pregnancy loss after frozen embryo transfer (FET) remains an under-recognized complication in assisted reproductive technology (ART), particularly in non-Western settings. Existing prediction models rarely capture evolving hazards over gestation or externally validated. To address this, we developed and externally validated a parametric time-to-event model to predict the dynamic risks of pregnancy loss following FET using a large real-world Chinese cohort. The model incorporated routinely available clinical variables, including maternal demographics, progesterone concentration, endometrium thickness, and endometrium preparation protocols. A Gompertz distribution model captured the time-dependent hazard trajectory. Model performance was externally validated in two temporal cohorts, as well as in older women (≥40 years) and ethnic minority subgroups. Clinical utility was assessed by decision-curve analysis (DCA). Among 21,242 conceptions, 17.6% resulted in miscarriage or stillbirth, with risks peaking in the first trimester. Maternal age showed a nonlinear effect: compared with reference age 32, hazard increased by 67% at age 40 and more than doubled by age 45. Higher weight accelerated risk over time. Protective factors included greater endometrial thickness, higher progesterone levels, and use of mild- (hazard ratio, HR 0.80, 95% CI: 0.753-0862), late- (HR 0.90, 95% CI: 0.798-0.951), or modified-late stimulation (HR 0.80, 95% CI: 0.732-0.863) protocols. DCA indicated that model-guided risk-stratification strategies offered clear net benefit in older women across a broader range of risk threshold. This validated, time-resolved model supports individualized risk-stratification strategies and informed treatment decisions in FET-based ART across diverse clinical settings in China.