European Journal of Clinical Pharmacology最新文献

Background and purpose: There is a paucity of available clinical tools with which to accurately predict the risk of tigecycline-associated hypofibrinogenemia, an adverse reaction with a high incidence and serious consequences. This study aimed to developed an optimal machine-learning model for predicting tigecycline-associated hypofibrinogenemia and to facilitate its clinical application.

Methods: A total of 896 inpatients who received tigecycline treatment in a large tertiary teaching hospital between 2016 and 2022 were included in the model development cohort. Subsequent temporal external validation of the models was performed on 313 patients admitted in 2023. Three robust machine-learning algorithms, including LASSO, Boruta, and VSURF were integrated to identify predictors. These features were then utilized to construct nine machine-learning models. The optimal one was identified through model evaluation and validation and was interpreted based on the SHAP method.

Results: The three algorithms identified five predictors, including age, treatment duration, pre-dose fibrinogen level, D-dimer level, and activated partial thromboplastin time. The XGboost model was identified as the most suitable due to its stability and excellent discrimination, calibration, and clinical utility. The area under the receiver operating characteristic curve for the model were 0.823 (0.794-0.853), 0.810 (0.746-0.873), and 0.773 (0.721-0.825) in the training, internal validation, and temporal external validation cohorts, respectively.

Conclusions: Machine-learning models are promising in solving the classification prediction problem of tigecycline-associated hypofibrinogenemia. Model interpretation based on SHAP enables clinicians to visualize individualized risk and tailor prophylactic strategies, potentially improving patient safety and treatment outcomes.

Purpose: Renal function significantly influences the pharmacokinetics of imipenem/cilastatin/relebactam (IMI/REL). The standardized single-dose packaging commonly leads to considerable drug wastage when the medication is administered to patients with renal impairment. This investigation aimed to develop and assess alternative dosage regimens that optimize drug utilization and minimize waste.

Methods: Through Monte Carlo simulations, we evaluated alternative regimens involving extended dosage intervals and prolonged infusion times across patients with various levels of renal impairment. We assessed probabilities of target attainment (PTA) against established pharmacokinetic/pharmacodynamic (PK/PD) targets and minimum inhibitory concentration (MIC) breakpoints, and evaluated the risk of drug overexposure. Additionally, we compared the alternative dosage regimens with standard regimens in terms of dose wastage and cost savings.

Results: The findings suggest that administering full doses of IMI/REL every 8-12 h with prolonged infusion achieves satisfactory PTAs without significant overexposure risks. These alternative regimens are anticipated to reduce direct medical costs by $335.84 to $671.68 daily compared to standard dosages.

Conclusion: Alternative dosing regimens for IMI/REL in patients with renal impairment can optimize drug utilization, minimize waste, and provide significant cost savings. However, further clinical studies are necessary to validate the effectiveness and safety of these regimens.

Objective: This study aimed to evaluate the efficacy and safety of secukinumab, an Interleukin-17A (IL-17A) inhibitor, in patients with recurrent spontaneous abortion (RSA) associated with T helper 17 cells / T regulatory cells (Th17/Treg) imbalance.

Methods: This retrospective cohort study evaluated 108 RSA patients with confirmed Th17/Treg imbalance (Th17/Treg ≥ 0.6 or IL-17A > 4.74 pg/mL) at a single center. Patients were divided into secukinumab (n = 54; 3 mg/kg subcutaneously plus standard therapy) and control (n = 54; standard therapy alone) groups. Primary outcomes included live birth rate and immunological parameters (Th17/Treg ratio, IL-17A levels), with secondary assessments of neonatal outcomes and safety.

Results: The secukinumab group demonstrated significantly higher live birth rates (83.33% [45/54] vs 64.81% [35/54]; P = 0.047), with an odds ratio (OR) of 2.71 (95% Confidence Interval (CI): 1.10-6.73), and greater reductions in Th17/Treg ratios (P = 0.010) and IL-17A levels (P = 0.001) compared to controls. No congenital anomalies, maternal or neonatal infections, or treatment-related serious adverse events were observed in either group.

Conclusion: For RSA characterized by Th17/Treg imbalance, secukinumab demonstrates both clinical efficacy and an acceptable safety profile, suggesting its therapeutic utility.

Purpose: We conducted a comprehensive analysis of esketamine-related adverse events (AE) on the FDA Adverse Event Reporting System (FAERS) database, taking into account for the first time drug-drug interaction signals.

Methods: We conducted a retrospective case/non-case study of esketamine-related AEs reported in the FAERS database up to the last quarter (Q4) of 2024. Potential signals were detected using the reporting odds ratio (ROR) and confidence intervals (CI), while drug-drug interactions were studied using different metrics such as lift, conviction and the combination risk ratio detection algorithm. An analysis of sex differences was also performed using the relative ROR and CI.

Results: The analysis of 7,790 reports in which esketamine was a primary or secondary suspect identified potential safety signals for 173 AEs. Novel signals include homicidal ideation (ROR = 5.30, 95% CI: 2.38-11.82) and substance use disorder (ROR = 6.12, 95% CI: 2.54-14.73). Women showed a longer time to onset than men (p = 0.003). In addition, we detected sex differences in 23 AEs, seven of which were more likely to be reported in women, while 16 in men. Among these, four were significant exclusively in women (oxygen saturation decreased, abnormal behaviour, unresponsive to stimuli and aggression) and two in men (vision blurred and bradycardia). Potential signals of additive and multiplicative drug-drug interactions were detected for antidepressants (venlafaxine for"dizziness" and bupropion for "agitation") and antipsychotics (risperidone for "vertigo").

Conclusions: Our results increase knowledge on potential risks related to esketamine AEs and potential drug-drug interaction signals in a real-world setting.