Pharmacotherapy最新文献

Background: The nephrotoxic risks of combining ceftazidime/avibactam (AVI) with vancomycin (VAN) remain underexplored, despite both agents independently being linked to acute kidney injury (AKI). This study assessed the risk of AKI associated with concurrent VAN and ceftazidime/avibactam (VAN-AVI) therapy and developed synthetic data models to enable early prediction of AKI.

Methods: We conducted a retrospective analysis using electronic health record data from hospitalized adults between 2015 and 2022. The incidence of AKI was compared among patients receiving VAN-AVI or VAN in combination with piperacillin/tazobactam (VAN-TPZ) versus VAN monotherapy. AKI was defined as a composite of de novo and recurrent AKI (i.e., patients had a prior diagnosis of AKI within the preceding 6 months and experienced a new AKI event after 7 days of VAN-AVI initiation). To address sample size imbalance, we applied inverse probability of treatment weighting (IPTW) and generated synthetic datasets using Conditional Tabular Generative Adversarial Networks (CTGAN) and Tabular Variational Autoencoders (TVAE). These synthetic datasets were subsequently used to augment machine learning (ML) models aimed at the early prediction of AKI in patients treated with VAN-AVI combination therapy.

Results: Among the 92 patients receiving VAN-AVI combination therapy, only four (4.3%) patients experienced new-onset AKI, and 66 (71.7%) patients had a recurrent AKI. After applying IPTW, VAN-AVI was associated with a higher risk of AKI Hazard Ratio (HR) = 3.47; 95% Confidence Interval (CI): 1.97-6.11, followed by VAN-TPZ (HR = 1.96; 95% CI: 1.37-2.81), compared to VAN alone. Synthetic data analyses conducted over 1000 iterations supported these findings, with mean HRs for VAN-AVI of 3.80 using TVAE and 4.45 using CTGAN. ML models augmented with synthetic data outperformed those using original data alone. For 30-day AKI prediction, F1-scores improved across all models, with the highest performance observed in the augmented XGBoost and logistic regression classifier (F1 = 0.80).

Conclusion: This study introduces a novel approach that integrates IPTW with synthetic data generation to evaluate drug-associated AKI risk in small-sample cohorts. Although our findings demonstrate a lower incidence of de novo AKI in the VAN-AVI group, the use of synthetic data and augmented ML models significantly improved early AKI prediction. These findings support the potential utility of synthetic data frameworks for scalable drug safety evaluations, although further validation is warranted.

Succinylcholine, a commonly used neuromuscular blocker, is hydrolyzed by the pseudocholinesterase (also known as butyrylcholinesterase) enzyme in the plasma to inactive metabolites. Individuals who have inherited genetic variants in the BCHE gene that result in decreased or no pseudocholinesterase enzyme activity are at increased risk of prolonged neuromuscular blockade with succinylcholine. Although succinylcholine/BCHE is one of the earliest identified pharmacogenomic drug/gene associations, clinical implementation remains the exception rather than the norm today. This review will explore the historical roots of pseudocholinesterase deficiency, its therapeutic implications for succinylcholine use, and future considerations for BCHE genetic testing to minimize the occurrence of prolonged neuromuscular blockade that can cause serious physical (i.e., apnea) and psychological (i.e., post-traumatic stress) consequences for patients. A summary and critical examination of the published literature that includes BCHE genetic testing in relation to succinylcholine response is also provided. Prolonged paralysis with succinylcholine may be prevented with preemptive BCHE genetic testing.

Background: Patients who undergo coronary artery bypass graft (CABG) surgery remain at high risk for major adverse cardiovascular events (MACE) despite contemporary preventive pharmacotherapy. Although commonly used in practice, it is uncertain whether P2Y12 inhibitors reduce MACE in patients post-CABG surgery.

Methods: This retrospective, population-based cohort study evaluated the effect of exposure to P2Y12 inhibitors, versus no exposure, on MACE using linked administrative databases that included all cardiac revascularization procedures, hospitalizations, and prescriptions for the population of British Columbia, Canada. All adults who underwent CABG surgery from 2002 to 2020 were eligible. The primary outcome was time to MACE, defined as a composite of all-cause death, nonfatal myocardial infarction, and nonfatal ischemic stroke using Cox proportional hazards models with inverse probability treatment weighting.

Results: Included were 15,439 patients. Mean age was 66 years, and 83% were male. Fifty-seven percent had a previous myocardial infarction. Sixteen percent were prescribed a P2Y12 inhibitor (of which, 83% were prescribed clopidogrel) within 30 days of CABG surgery. Median exposure time was 23 months. After probability-weighting and adjustment for relevant covariates, exposure to P2Y12 inhibitors reduced the 1- and 5-year hazard of MACE (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.27-0.55 and HR 0.65, 95% CI 0.54-0.79, respectively). Exposure to P2Y12 inhibitors was also associated with a lower hazard of all-cause death, cardiovascular death, and an extended MACE outcome that included unstable angina and percutaneous coronary intervention. Adherence to P2Y12 inhibitor therapy, based on the proportion of days covered, did not affect these outcomes.

Conclusions: In this population-based cohort study, use of P2Y12 inhibitors reduced the hazard of MACE in patients post-CABG surgery at 1 and 5 years of follow-up. These results support the use of P2Y12 inhibitors (primarily clopidogrel), in addition to other standard cardiovascular preventive therapy, in patients who undergo CABG surgery.

Background: Amiodarone (AMI) is a potent inhibitor of Cytochrome P450 (CYP) 2C9 and P-glycoprotein (P-gp), as well as a weak inhibitor of CYP3A4. Concomitant administration of AMI with digoxin (DIG), rivaroxaban (RIV), or phenytoin (PHT) can significantly increase the exposure of the victim drugs. Elevated RIV exposure raises the risk of bleeding, whereas DIG and PHT have narrow therapeutic windows, potentially leading to severe toxicity when co-administered with AMI.

Purpose: Physiologically based pharmacokinetic (PBPK) modeling was employed to simulate, validate, and predict the impact of drug-drug interactions (DDIs) between AMI and DIG, RIV, or PHT on the pharmacokinetics (PK) of victim drugs. The findings aim to provide evidence-based recommendations for optimizing combination therapy regimens.

Methods: PBPK models for AMI, RIV, and PHT were developed using PK-Sim, while the DIG model was adopted from previously published literature. DDI scenarios were simulated to assess exposure levels. Model performance was evaluated by comparing predicted plasma concentration-time (PCT) profiles and PK parameter values with clinical trial data from healthy subjects in previously published PK studies. Finally, dosing regimens for combination therapy were adjusted based on changes in exposure levels.

Results: According to model simulations, when the perpetrator drug AMI was co-administered with DIG, RIV, or PHT following label-recommended dosing regimens, the steady-state exposure of the victim drugs increased by 79%, 38%, and 59%, respectively. Compared to monotherapy, reducing the doses of DIG, RIV, and PHT by 40%, 25%, and 45%, respectively, achieved similar steady-state concentrations.

Conclusions: We have successfully developed PBPK models for AMI, RIV, and PHT. These models effectively simulate the DDIs that occur when AMI is co-administered with DIG, RIV, or PHT, thereby providing guidance for dosing regimens in clinical combination therapies.

Background: Laparoscopic cholecystectomy (LC) may cause significant pain, increasing morbidity. Granisetron, an antiemetic selective serotonin (5HT3)-antagonist, demonstrates analgesic properties through sodium channel blockade. The current study aims to assess the efficacy of adjuvant intraperitoneal granisetron in post-LC pain.

Research design and methods: In this prospective randomized controlled trial, 48 patients undergoing LC were randomized into placebo (intraperitoneal saline) and intervention (intraperitoneal granisetron) groups. Pain intensity was measured via visual analog scale (VAS) at 2-, 4-, 8-, 12-, and 24-h post-surgery, with comparative analysis of the area under the curve (AUC) of the 24-h VAS scores. Additional outcomes included sedation levels, persistent pain incidence, quality of life improvement, postoperative nausea and vomiting (PONV), time to first rescue analgesic request, total analgesic consumption, and independent mobilization.

Results: The treatment group showed significantly lower VAS at 8, 12, and 24 h (p = 0.039, 0.004, 0.030) and lower VAS score AUC (542.7 ± 260.5 vs. 767.1 ± 317.8, p = 0.011) compared to controls, respectively. No significant differences were observed in (2-4 h) pain scores, persistent pain incidence, quality of life, sedation levels, PONV, analgesic requirements, or mobilization time (p < 0.05).

Conclusions: Granisetron could improve multimodal pain control after LC, offering better outcomes while maintaining its established safety profile.

Trial registration: NCT06281418.

Background: Daptomycin is a once-daily lipopeptide antibiotic with a narrow therapeutic window. As higher doses (8-12 mg/kg) are increasingly used to treat resistant gram-positive infections, achieving therapeutic exposure while minimizing toxicity has become critical. Understanding daptomycin therapeutic drug monitoring (TDM) and what sampling strategy may be most precise and feasible are key to guiding appropriate dosing. The primary objective of this study was to ascertain the precision and bias of a mid-point sample area under the curve over 24-h (AUC₂₄) determination compared to a peak and trough sample AUC₂₄ determination using both simple calculation-based methods and a Bayesian model versus no TDM.

Methods: Adult patients receiving daptomycin with at least three steady-state concentrations (peak, mid-point, trough) were included in this analysis. A previously published one-compartment population pharmacokinetic model was applied using Bayesian estimation (Monolix Suite 2024R1). AUC₂₄ values were estimated using all three concentrations (AUC_ref), and then re-estimated using individual samples (peak, mid-point, or trough) or paired samples (peak + trough). Performance of each strategy was evaluated using regression analysis with the coefficient of determination for precision (R²) and mean bias.

Results: The cohort included 210 patients (60% male) with a mean (range) age of 66 (18-91) years, body weight 78 (41-140) kg, and BMI 27 (14-51) kg/m². A total of 880 daptomycin concentrations were analyzed in patients receiving a mean (range) daptomycin dose of 9 (5-17) mg/kg. The mean (range) AUC₂₄ was 869 (385-1692) mg·h/L; only 45.7% of patients achieved the target range of 666 to 939 mg·h/L. A single mid-point sample had similar correlation to AUC₂₄ (R² = 0.57) as trough-only (R² = 0.55), and greater precision than peak-only (R² = 0.44). Bayesian estimation with two samples (peak + trough) provided the highest accuracy (R² = 0.87) and lowest bias.

Conclusions: A mid-interval sampling strategy offers a practical alternative to traditional TDM for daptomycin, enabling more consistent AUC estimation when full sampling is not feasible. A two-sample Bayesian approach remains the most accurate, supporting broader implementation of individualized daptomycin dosing.

Objective: To evaluate patterns in disease-modifying antirheumatic drugs (DMARDs) initiations between 2001 and 2021 among adults with Rheumatoid Arthritis (RA) in the United States METHODS: This retrospective cohort study used a US commercial claims database (2001-2021) to identify patients (≥ 18 years) with RA newly initiating a DMARD. We calculated the annual proportion of initiations for 22 DMARDs, categorized as conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic (tsDMARDs). Secondary analyses examined trends in first-line non-csDMARD initiation and biosimilar uptake.

Results: We identified 407,728 DMARD initiation episodes among 229,365 unique patients with RA (median age: 50 years [IQR], 44-58 years; 79.4% female). There were shifts in DMARD initiations, with csDMARD initiation declining from 79.9% of initiations in 2001 to 54.7% by 2021 (p < 0.001 for trend). Meanwhile, bDMARDs and tsDMARDs initiations increased from 20.3% in 2001 to 33.1% in 2021 (p < 0.001) and from 0.1% in 2012 to 12.2% in 2021 (p = 0.171), respectively. Methotrexate remained the most initiated DMARD over the 21-year study period, albeit declining from 28.7% to 15.0% of initiations over the study period (p < 0.001). Adalimumab was the most frequently initiated bDMARD (13.3% in 2003 and 12.2% in 2021; p = 0.05). Among tsDMARDs, tofacitinib initiation peaked at 8.9% in 2019 and declined to 4.4% in 2021, while upadacitinib initiation increased from 1.2% to 7.6% during the same period (p < 0.001). For secondary analyses, adalimumab was the predominant first-line b/tsDMARD initiated (> 40%). Biosimilar uptake stayed below 1%.

Conclusion: Expanded DMARD options over the last two decades have led to decreased csDMARD initiations and increased b/tsDMARD initiations, reflecting patient- and system-level factors.

First-line therapeutic approaches for Crohn's disease include immunosuppressants, aminosalicylates, and corticosteroids. However, more than one-third of patients are resistant to these treatments and require second-line therapies. Our goal was to synthesize the evidence on the efficacy and safety of biologics and small molecules for inducing remission in patients with moderate-to-severe Crohn's disease. A systematic review was conducted by searching for randomized controlled trials on the target population in PubMed, Scopus, and Web of Science (March 2025). Data synthesis for the outcomes of remission, health-related quality of life (HRQoL), and safety was performed using network meta-analyses and surface under the cumulative rating curve (SUCRA) analyses. The results were presented as risk ratios with 95% credible intervals. We included 55 trials (n = 16,113 patients) evaluating 26 biological drugs across 83 doses and six small molecules across 15 doses. Similar results were obtained in the sensitivity analyses conducted across different measurement time points. Alongside infliximab 5 mg/kg (SUCRA 98.6%), 10 mg/kg (92%), and 20 mg/kg intravenous (91.8%), the recently approved drugs guselkumab 1200 mg (83.2%), 600 mg (89.2%), and 200 mg intravenous (90.1%), as well as mirikizumab 600 mg (91.5%) and 1000 mg intravenous (82.4%) presented higher probabilities of disease remission and were associated with increased HRQoL. Drugs such as certolizumab, andecaliximab, fontolizumab, abatacept, and etanercept ranked low for remission (SUCRA < 40%) and presented high probabilities of serious adverse events (over 60%). Small molecules presented an intermediate profile. Inhibitors of interleukin-23 appear to be promising alternatives for the treatment of moderate-to-severe Crohn's disease. Given their safety profile, some anti-TNF drugs should be avoided in practice. Trial Registration: PROSPERO: CRD42024519150.