Expert Review of Clinical Pharmacology最新文献

Introduction: Identification and monitoring of adverse drug reactions (ADRs) and interventions to reduce ADRs, is essential for patient safety in hospitals. Causality analysis (CA) is an approach that helps to determine a causal link between a medication and patient harm (i.e. an ADR). Whilst numerous CA tools exist, there is no gold standard.

Areas covered: Five online databases were searched to identify studies that evaluated the potential clinical utility of CA tools for ADRs. CA tools were mapped against the Bradford Hill (BH) criteria and included if they adhered to the first seven criteria proposed by BH. Upon the database search, 550 studies were identified, with 41 studies being selected that looked at tools mapped to BH. Thirty-four different CA tools were identified in the included studies.

Expert opinion: Naranjo and WHO-UMC were the most reported CA tools for studies examining inter-rater and intra-rater reliability. Naranjo commonly received a 'fair' agreement level while WHO-UMC received a 'substantial' agreement level between raters. Along with kappa statistics, time using the CA tool was also analyzed; with WHO-UMC being the most time-efficient. There does not appear to be one CA tool that can be applied universally to pharmacovigilance efforts in hospital in-patient settings.

Introduction: The discovery of the role of the calcitonin gene-related peptide (CGPR) in migraine pathogenesis ushered in a new era in headache medicine. This evidence led to the development of small-molecule CGRP receptor antagonists and monoclonal antibodies targeting either CGRP or its receptor.

Areas covered: We will present selected aspects of the role of CGRP in the pathogenesis of migraine, the efficacy of CGRP-targeted treatment, and the still-open questions regarding the practical application of CGRP antagonists in headache medicine.

Expert opinion: CGRP-targeting drugs represent a transformative approach to migraine treatment, offering superior efficacy and tolerability compared to traditional therapies, they are a helpful addition to the treatment arsenal but also have their flaws and require further observation. Their availability provides new hope for migraine patients, particularly those who have not responded adequately to conventional treatments. Future directions for migraine care planning, especially for chronic migraine and medication-overuse headache, should include universal access to these specific and effective forms of therapy to prevent complications from the disease and its negative effects in many aspects of a patient's life.

Tobacco use represents the leading preventable risk factor for premature deaths worldwide. A meta-analysis of 74 epidemiological studies, including 3.2 million individuals with type 2 diabetes mellitus (T2DM) from 33 countries, reported a pooled prevalence of smoking of 20.8% among individuals with T2DM. Cigarette smoking further aggravates existing deleterious vascular effects of T2DM. Namely, chronic hyperglycemia and exposure to cigarette smoke cause additive injurious effect on the endothelium, leading to an acceleration of vascular complications seen in persons with T2DM and tobacco use disorders (TUD). In a recent study, Wang and colleagues found that semaglutide use was associated with a significantly lower risk for medical encounters for TUD, when compared to other antidiabetic drug classes; indeed, this effect was strongest compared with insulins and weakest compared with other glucagon-like peptide-1 receptor agonists. Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed irrespective of the presence of obesity. Therefore, semaglutide use might be useful in terms of smoking cessation among individuals with T2DM, thus offering an additional benefit for this constantly growing population. However, those interesting findings should be confirmed through dedicated, large-scale randomized controlled trials.

Introduction: Mixed hyperlipidemia represents a substantial public health issue and a considerable burden on healthcare systems. Although the introduction of statins and LDL-cholesterol lowering agents have significantly reduced the incidence of atherosclerotic cardiovascular diseases (ASCVD), a significant portion of the population continues to exhibit ASCVD progression due to elevated triglyceride-rich lipoprotein (TRL) levels. This persistent risk has catalyzed the development of novel pharmacological interventions targeting these lipoproteins.

Areas covered: Our special report commenced with a targeted PubMed search using keywords such as 'plozasiran,' 'zodasiran,' and terms related to APOC3 and ANGPTL3. As the review progressed, emergent research questions guided further searches, allowing for the inclusion of additional relevant articles to comprehensively illustrate the linkage between TRLs and cardiovascular disease, discuss the roles of APOC3, ANGPTL3, and the pharmaceutical agents that target these proteins, and provide a comparison on the ARCHES-2 and MUIR trials.

Expert opinion: The ARCHES-2 and MUIR trials demonstrated effective triglyceride reduction by these therapies, yet it is uncertain if this correlates with significant clinical benefits. Advances in antisense oligonucleotide technology, especially the GalNAc delivery platform, show promise for personalized lipid management, though challenges such as cost and safety concerns remain.

Background: This study aimed to establish population pharmacokinetics (PPK) models of nirmatrelvir/ritonavir in critically ill Chinese patients with the coronavirus disease 2019 (COVID-19) infection, explore factors affecting the pharmacokinetics (PK) of nirmatrelvir/ritonavir.

Methods: A total of 285 serum samples and clinical data were collected from 152 patients. The PPK models of nirmatrelvir/ritonavir were analyzed using nonlinear mixed-effect modeling (NONMEM) approach. The optimal dosing regimen for patients with different renal function was determined using Monte Carlo simulations.

Results: The population typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of nirmatrelvir were 2.26 L/h and 15.3 L, respectively. Notably, creatinine clearance (CrCL) significantly influenced the PK variation of nirmatrelvir. Monte Carlo simulations suggested that patients with mild-to-moderate renal impairment experienced a 22.0-59.9% increase in the area under the curve (AUC) when they were administered a standard dose of nirmatrelvir compared to those with normal renal function. The AUC in patients with severe renal impairment after administration of 150 mg q12h nirmatrelvir was similar to that in patients with normal renal function after administration of 300 mg q12h nirmatrelvir.

Conclusions: PPK modeling and simulation provided a reference for the rational clinical application of nirmatrelvir/ritonavir in critically ill Chinese patients.

Background: While the survival benefits of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are firmly established in the general population, their efficacy within patient undergoing dialysis with coronary artery disease (CAD) remains controversial.

Methods: Between January 2015 and June 2021, 1168 patients undergoing dialysis with CAD were assessed from 30 tertiary medical centers. The primary outcome was all-cause death, and the secondary outcome was cardiovascular death. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for between-group differences.

Results: Overall, ACEI or ARB were prescribed to 518 patients (44.3%) upon discharge. After a median follow-up of 22.2 months, 361 (30.9%) patients died, including 243 cardiovascular deaths. The use of ACEI or ARB was associated with a significantly lower risk of all-cause (25.3% vs 35.4%, hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.52-0.82, p < 0.001) and cardiovascular death (17.0% vs 23.8%; HR 0.64, 95% CI 0.48-0.83, p = 0.001). These findings remained consistent across IPTW and PSM analyses. Sensitivity analyses for ACEI and ARB use separately yielded similar results.

Conclusions: Our findings suggested that among patients undergoing dialysis with CAD, ACEI or ARB use was associated with a lower risk of all-cause and cardiovascular death.

Tenecteplase (TNK), as a thrombolytic treatment for acute ischemic stroke (AIS), has been found to be effective when used within 4.5 hours of symptom onset. However, the efficacy of TNK after 4.5 hours is not well established, especially in patients with large vessel occlusion and with no access to thrombectomy. In this article, we will discuss the results of the recently published TRACE-III trial. The study involved 516 patients with large vessel occlusion, either proximal middle cerebral artery or internal carotid artery, with salvageable brain tissue and no endovascular thrombectomy access. Key safety outcomes included symptomatic intracranial hemorrhage and death. TNK treatment resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment. Mortality at 90 days was 13.3% with TNK and 13.1% with standard medical treatment. The trial found that TNK treatment for Chinese patients with ischemic stroke resulted in less disability and similar survival compared to standard medical treatment. However, there was a higher incidence of symptomatic intracranial hemorrhage within 36 hours.

Introduction: Methotrexate polyglutamates (MTXPGs) are intracellular metabolites of methotrexate (MTX) that play a critical role in the drug's activity, influencing both its efficacy and toxicity. As the exact implications of MTXPGs in these processes remain a subject of debate, a comprehensive review of MTXPGs could provide valuable insights for clinicians and pharmacists, potentially minimizing adverse reactions and enhancing therapeutic outcomes.

Areas covered: A comprehensive search of relevant literature was conducted in PubMed and Web of Science databases, including studies from their inception to April 2024. Eligible studies included reviews, clinical trials, and real-world analyses. Additional manual searches and citation reviews were also performed. This review aims to explore MTXPGs with a primary focus on their pharmacokinetics, analytical methods, determinants of drug exposure, and their correlation with MTX efficacy and toxicity.

Expert opinion: MTXPGs have not yet garnered significant attention in clinical practice. However, multiple studies have demonstrated a relationship between MTXPGs and the efficacy and toxicity of MTX, suggesting a potential avenue for personalized treatment strategies. Future research should aim to further validate and refine this correlation. Additionally, attention should also be directed toward other metabolites of MTX, which may hold clinical significance.

Objectives: Percentage protein binding (%PB) of arsenic species in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide remains unclear. It can be different depending on the status of hepatic or renal function.

Methods: This study obtained steady-state blood samples from normal APL patients and those with hepatic or renal impairment. %PB of inorganic arsenic (iAs), monomethylarsonic acid (MMA^V), and dimethylarsinic acid (DMA^V) was determined by analyzing free and total plasma concentrations using ultrafiltration method by HPLC-HG-AFS.

Results: There is a linear relationship between free and total plasma concentrations for iAs (r² = 0.952), MMA^V (r² = 0.603), and DMA^V (r² = 0.945). For patients with normal hepatic and renal function, mean %PB was as follows: iAs at 26.7 ± 14.3%, MMA^V at 53.3 ± 11.9%, and DMA^V at 24.7 ± 7.8%. %PB decreased in patients with renal impairment, with MMA^V and DMA^V showing statistically significant differences (p < 0.05 for MMA^V, p < 0.01 for DMA^V). No significant differences in %PB between normal and hepatic impairment group were observed.

Conclusion: Free arsenic species fraction can be estimated by total concentration. DMA^V and iAs present low %PB, while MMA^V exhibits a relatively high %PB in plasma. Level of %PB is more likely to be affected by renal function and age.