Expert Review of Clinical Pharmacology最新文献

Introduction: 27.1 million adults in the United States have alcohol use disorder (AUD). However, current medications for AUD have mixed efficacy. As such, a shift in treatment approach and the development of novel pharmacotherapies for AUD is imperative.

Areas covered: This review addresses novel insights on treating AUD through precision medicine that identifies subgroups of individuals most responsive to existing single or combination pharmacotherapies for AUD. In parallel, this review synthesizes the emergence of pharmacological agents for AUD that are on the treatment horizon. These include glucagon-like peptide 1 receptor agonists, classic psychedelics, ketamine, immune modulators, and cannabinoids. Data reviewed were culled from searches of the PubMed database and clinicaltrials.gov registry.

Expert opinion: Adopting a precision medicine approach and investigating novel compounds for AUD treatment requires a shift in systems of care. Precision medicine navigates away from the traditional 'one size fits all' health care model to emphasize the individual, leading to long-term cost-effectiveness and improved patient outcomes. Moreover, novel pharmacotherapies face challenges in the scale of their distribution throughout healthcare settings. The developments reviewed in this paper elucidate a paradigm shift necessary to facilitate the integration of precision medicine and the adoption of novel pharmacotherapies within the AUD field.

Background: Piperacillin population pharmacokinetic models reportedly perform poorly for critically ill females compared to males. We aimed to explore potential methods that may better adjust for female data during model development.

Research design and methods: Total piperacillin concentrations were used from a prospective observational study in NONMEM v7.5.1. Two models were developed following different approaches: classic stepwise approach and sex-specific approach. Relationship between covariates and estimated parameters were explored by statistically and graphically assessing their performance on males and females separately. Dosing regimen simulations were also performed separately by sex.

Results: A one-compartment model based on data from 70 critically ill patients (49/21 males/females) with 233 concentrations best fit the data with both approaches. Creatinine clearance was the most significant covariate for the classic approach model, while creatinine clearance was best for male patients and estimated glomerular filtration rate was best for female patients with the sex-specific approach. Dosing recommendations were different between male and female patients with the sex-specific model.

Conclusion: This study is the first to consider sex-specific covariates during the modeling process for piperacillin in critically ill patients. This approach may help reduce differences in model predictions between males and females in model-informed precision dosing strategies.

Introduction: Non - clear cell renal cell carcinoma (nccRCC) encompasses a heterogeneous group of rare malignancies, representing approximately 20-25% of all renal cancers. Unlike clear cell RCC (ccRCC), these subtypes - papillary, chromophobe, collecting duct, translocation, molecularly defined variants and others - display distinct biological behaviors, genetic profiles, and therapeutic sensitivities, which preclude a uniform treatment approach.

Areas covered: This review provides an updated overview of systemic therapy for nccRCC, integrating evidence from prospective trials, retrospective series, and translational research. For most of these histologies, immune checkpoint inhibitor (ICI) - based combinations (e.g. pembrolizumab - lenvatinib, nivolumab - cabozantinib or nivolumab-ipilimumab) have demonstrated the best activity. In chromophobe RCC (chRCC), also mechanistic target of rapamycin (mTOR) inhibition appears particularly relevant, whereas in collecting duct carcinoma and renal medullary carcinoma platinum-based chemotherapy continue to have an important role, with cabozantinib showing encouraging results. Novel biomarker-driven approaches are emerging for selected molecular subsets.

Expert opinion: Although remarkable progress has been achieved, the optimal therapeutic strategy for nccRCC remains undefined. Future efforts should focus on histology- and biomarker-driven clinical trials, molecular stratification, to optimize efficacy across subtypes. International collaboration is crucial to overcome the challenges posed by the rarity and biological heterogeneity of these tumors.

Introduction: In patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), long-term dual antiplatelet therapy (DAPT) is the current standard of care. However, recent evidence suggests that shortening DAPT duration in favor of single antiplatelet therapy (SAPT) can optimize the overall clinical benefit, as it can prevent bleeding without significant tradeoff in ischemic events.

Areas covered: In this narrative review, we synthesize current evidence from PubMed and SCOPUS on SAPT vs DAPT regimens in CAD patients undergoing PCI, including pharmacodynamic and clinical outcomes data, and we propose an algorithm for appropriate antiplatelet regimen selection depending on the ischemic and bleeding risk profile of the individual patient.

Expert opinion: The landscape of antiplatelet treatment regimens has significantly evolved over time, with the current trend being toward a tailored approach based on risk profile, aiming to reduce the risk of bleeding while maintaining ischemic protection. The accurate evaluation of each patient's ischemic and bleeding risk profile is of utmost importance. Dedicated tools have been developed to optimize patient risk profiling and help guide the selection of the antiplatelet regimen. Based on risk estimation, several strategies can be used to reduce the overall risk, including the selection and duration of the antiplatelet regimen.

Background: Dual antiplatelet therapy with aspirin and P2Y12 inhibitors is the first antiplatelet of choice for acute myocardial infarction (AMI), but alternatives are needed for patients at high bleeding risk or with aspirin intolerance/hypersensitivity. This observational study investigated the efficacy and safety of indobufen, a reversible COX-1 inhibitor, among AMI patients compared to those receiving aspirin.

Methods: We retrospectively enrolled 907 consecutive AMI patients treated between June 2021 and June 2024. The primary endpoints were GUSTO bleeding and MACE between aspirin and indobufen.

Results: Patients receiving indobufen were older and had higher rates of comorbidities such as type 2 diabetes, gastritis, and peptic ulcers (all p < 0.05). Over a median follow-up of 462 days, aspirin was associated with a higher incidence of GUSTO mild bleeding (23.8% vs. 8.6%, p < 0.001), with no significant differences in moderate/severe bleeding, re-infarction, stroke, heart failure, rehospitalization, or MACE (all p > 0.05). Multivariate regression confirmed indobufen independently reduced GUSTO mild bleeding risk. Boruta and SHAP analyses identified antiplatelet therapy, particularly aspirin, as a predictor of GUSTO mild bleeding.

Conclusions: Indobufen may be considered an alternative antiplatelet therapy for AMI patients with a high bleeding risk and/or aspirin intolerance/hypersensitivity, however, prospective studies are needed to confirm these findings.

Introduction: Medicine-related harm associated with polypharmacy is a pertinent global health challenge. Deprescribing (reducing or stopping) medicines that cause more potential harm than benefit could mitigate the risk of medicine-related harm. However, the existing deprescribing research-to-practice gap threatens the long-term sustainability and scalability of deprescribing efforts.

Research design and methods: To address this, key stakeholders including healthcare practitioners, academics, policymakers and representatives of peak professional organizations, gathered at a World Café workshop to reflect on progress achieved in the deprescribing research and practice landscape while exploring the top future priorities for deprescribing.

Results: Thirty participants agreed on three top priorities: improving the clinical management of deprescribing; engaging consumers and gaining their perspectives; and raising awareness to enhance communication. Emerging themes and related barriers and catalysts were derived and mapped to a socio-ecological model offering a bird-eye's view of these factors on an individual, interpersonal, organizational, and societal level.

Conclusions: Our World Cafe' highlights opportunities for future deprescribing research and practice. To promote the uptake of deprescribing in practice, catalysts could include leveraging new technology, promoting deprescribing via social media and optimizing workforce staff and knowledge. Ultimately, this knowledge may motivate deprescribing efforts and bridge the research-to-practice gap.

Introduction: Traditional therapeutic drug monitoring (TDM) faces limitations in accuracy and adaptability, often failing to optimize therapy for complex patients. Machine learning (ML) is emerging as a powerful tool to overcome these challenges, offering a data-driven paradigm to enhance therapeutic outcomes and minimize toxicity for drugs with narrow therapeutic indices.

Areas covered: This review synthesizes the evolution of ML in TDM. We cover foundational models that predict drug exposure from sparse data using either real-world or simulation-based training. We then explore the extension of these techniques to proactive first-dose optimization and the recent development of hybrid models, which integrate the physiological interpretability of population pharmacokinetic frameworks with the corrective power of ML.

Expert opinion: The future of TDM lies not in replacing mechanistic models, but in their convergence with ML. While promising, clinical translation requires overcoming critical barriers in data access, model interpretability, and workflow integration. The long-term trajectory points toward dynamic Digital Twins capable of forecasting patient-specific benefit-risk profiles. Ultimately, validated hybrid tools embedded in clinical decision support systems could establish proactive, individualized dosing as the new standard of care in personalized pharmacotherapy.

Introduction: Alzheimer's disease (AD) remains a major public health challenge, with growing prevalence and limited treatment options that modify disease progression. Recent advances have led to the development and approval of Anti-amyloid-β (Aβ) monoclonal antibodies, which represent a paradigm shift from symptomatic management to targeted disease modification.

Areas ccovered: Agents such as lecanemab and donanemab selectively bind aggregated forms of Aβ and have demonstrated modest but statistically significant slowing of cognitive and functional decline in early AD. However, these therapies are associated with amyloid-related imaging abnormalities (ARIA), particularly in individuals carrying the APOE ε4 allele, necessitating close monitoring and individualized risk assessment. Implementation challenges, including high treatment burden, cost, and real-world applicability, have limited broad clinical adoption. This review examines the mechanistic differences, clinical trial outcomes, and safety considerations of Aβ monoclonal antibodies, while also highlighting emerging therapies and the need for inclusive, precision-guided approaches.

Expert opinion: As research continues to evolve, balancing clinical benefits with safety and accessibility will be critical in defining the role of anti-amyloid-β therapies within the broader landscape of AD care.