Pharmacotherapy最新文献

Background: Drug safety has historically been understudied in pediatric populations, rendering them "therapeutic orphans." Pediatric drug indications and dosages are often inferred by extrapolating safety, efficacy, and dosing data from adult studies, leading to widespread off-label use. However, this approach fails to account for age-specific differences in disease pathophysiology and developmental pharmacokinetics (PK). Despite evidence that adverse drug events (ADEs) manifest with greater severity in pediatric populations than in adults, fewer than 50% of drugs have been systematically studied for pediatric use. The lack of robust drug safety data may result in suboptimal or harmful treatment strategies.

Methods: We used a data-driven approach that integrated three databases -including Merative MarketScan claims, the Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledgebase (including 670,185 pediatric pharmacoepidemiology, PK, and clinical trial publications on 5062 drugs), the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, a postmarketing safety surveillance database), and FDA drug label data- to identify high-impact target. High-impact targets were defined as drugs that have a high prescription volume, limited safety evidence and high risk of serious ADEs.

Results: With 229,550 prescriptions in MarketScan, only 9 studies, and almost 50 high risk serious ADEs benzonatate was identified as a high-impact drug of concern. Serious ADEs included seizure, death, and arrhythmia with proportional reportion ratios (PRRs) ranging from 4.3 to 477.8.

Conclusion: Approved in 1958, Benzonatate, a nonnarcotic antitussive agent has a limited safety evidence with only nine PE/PK publications in six decades. Moreover, it is frequently prescribed off-label for cough relief despite questionable effectiveness, and high-risk of serious ADEs. Our findings reveal a disconnect between clinical practice and suppporting safety evidence. As such, there is critical need to study the safety of this drug using emerging real-world data for real-world evidence. In summary, this study presents an approach that is systematic, objective, reproducible, and data driven to identify and prioritize drug-ADE combinations with limited evidence.

Background: Omeprazole, a widely used proton pump inhibitor, has been associated with rare but serious adverse events such as myopathy. Previous research suggests that concurrent use of omeprazole with fluconazole, a potent cytochrome P450 (CYP) 2C19/3A4 inhibitor, may increase the risk of myopathy. However, the contribution of genetic polymorphisms in CYP enzymes remains unclear.

Aims: This study leveraged electronic health record (EHR) and biobank data to validate an interaction between omeprazole and fluconazole and to explore drug-gene interactions (DGIs) between omeprazole and polymorphisms in CYP enzymes.

Materials and methods: A nested case-control design with incidence-density matching was used. Cases were defined as patients who developed myopathy during ongoing omeprazole therapy. For each case, up to four controls were selected from patients who had not developed myopathy by the time the case was diagnosed. Conditional logistic regression models, adjusting for relevant covariates, evaluated (i) the association between concomitant fluconazole use and myopathy and (ii) genotype-stratified myopathy risk.

Results: Among 902 cases and 3608 controls, the combined use of omeprazole and fluconazole was linked to an increased risk of myopathy (adjusted odds ratio [AOR] = 1.75, 95% confidence interval [CI]: 1.17-2.63, p = 0.007). In the DGI analysis, which included 862 cases and 3448 controls, individuals classified as CYP2C19 poor metabolizers paired with CYP3A4 extensive metabolizers showed a significantly higher myopathy risk (AOR = 1.62, 95% CI: 1.03-2.55, p = 0.036); those with CYP2C19 poor metabolizer/CYP3A4 intermediate metabolizer had an even greater risk (AOR = 4.77, 95% CI: 1.74-13.1, p = 0.002).

Discussion: These findings not only confirm previously reported drug-drug interactions (DDIs) between omeprazole and fluconazole but also reveal the emerging clinical implications of DGIs.

Conclusion: By integrating EHR and genetic data, the study showcases how informatics tools can translate DDI findings into DGI hypotheses, effectively bridging genetic insights and clinical outcomes.

Lecanemab is an amyloid-targeted antibody indicated for treating patients with amyloid-confirmed early Alzheimer's Disease in mild dementia or mild cognitive impairment stages. We report here a case of a subject with early stage of Alzheimer's Disease dementia, amyloid positive, who developed severe acute urinary retention following his first dose of intravenous lecanemab. His urinary retention resolved after a week but recurred following the second intravenous dose 2 weeks later. Lecanemab was discontinued, but the urinary retention has persisted for 8 months indicating possible permanent adverse impact on the bladder. The Naranjo causality probability score was 6. The incidence of urinary retention with intravenous lecanemab is not known but given that elderly patients with dementia may have multiple risks for bladder dysfunction, clinicians should remain vigilant. It is hoped that newer formulations, such as subcutaneous lecanemab, may prove safer in such patients.

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.