Expert Review of Clinical Pharmacology最新文献

Introduction: Cholesterol-lowering medications (CLMs) are used globally. Cholesterol is a key stratum corneum lipid that helps maintain epidermal barrier integrity. Barrier dysfunction contribute to pathogenesis of atopic dermatitis (AD). Clarifying whether CLMs impact AD has implications for dermatology and cardiology.

Areas covered: We synthesized evidence from experimental, clinical, and genetic epidemiology through targeted literature searches and expert selections. It focuses on 1) skin barrier biology and epidermal cholesterol metabolism, and 2) potential effect of CLMs on AD. We discuss findings from experimental studies comparing topical versus systemic statins; population-based observations of AD among CLM users; and Mendelian randomization analyses of CLMs.

Expert opinion: Effect of CLMs on AD is biologically plausible but clinically unproven. Signals of concern are most consistent for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and Niemann-Pick C1-Like 1 (NPC1L1) inhibition, whereas Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition appears protective in some populations. Current studies are limited by confounding, heterogeneous outcomes and sparse ancestry-specific analyses. Until robust causal and pharmacoepidemiologic studies across ancestries are available, clinicians should prioritize established cardiovascular benefit of lipid reduction while monitoring for new or worsening dermatitis after therapy initiation. Future work should triangulate Mendelian randomization with pharmacoepidemiology designs in large, diverse datasets to deliver definitive guidance.

Introduction: Botulinum toxin (BoNT), recognized for its distinctive pharmacological properties, has become a highly effective therapeutic agent with a wide range of clinical applications. Among its serotypes, botulinum toxin A (BoNT A) is the most extensively used, with established roles in conditions such as limb spasticity, overactive bladder, and neuropathic pain. Despite its broad utility, careful consideration is required to minimize adverse outcomes, underscoring the importance of multidisciplinary collaboration to ensure patient safety.

Areas covered: This expert review is developed through the evaluation of experimental studies and systematic reviews, which were integrated to generate a practice-oriented expert perspective. Although we have provided an overview of all BoNTs, our primary focus has been BoNT A. We have particularly focused on key considerations for the use of BoNT, including immunogenicity and its utility in special populations such as pregnant patients, individuals with pulmonary compromise, older adults, and children.

Expert opinion: Despite the practical challenges of prescribing BoNT A, it is generally regarded as an effective therapy. Its use requires careful risk vs benefit evaluation and strict adherence to guidelines to reduce adverse outcomes. Non-response and immunogenicity remain important barriers, although ongoing research and engineered toxins point toward a future with more precision-based applications.

Introduction: Monitoring the safety of drugs regarding their potential for misuse falls within the scope of international conventions on narcotic and psychotropic drugs. In the U.S. a surveillance approach based on multiple sources has been implemented for decades and identified the opioid epidemic in the early 2000s. In Europe, this monitoring is carried out by the European Union Drugs Agency (EUDA) for substance abuse and by the European Medicines Agency (EMA) through pharmacovigilance activities for substances for therapeutic use.

Areas covered: Due to the hidden nature of prescription drug misuse, spontaneous pharmacovigilance reporting is rarely sufficient to quantify this complex phenomenon. This narrative review presents examples of a multisource approach based on a PubMed literature search using the terms 'pharmacovigilance' and 'addiction,' 'drug abuse,' or 'drug misuse.' These examples mainly concern the U.S. and the addictovigilance monitoring system in France.

Expert opinion: Because of the constant changes in the drug misuse phenomenon and the effectiveness of addictovigilance in addressing it, other countries should strongly consider adapting this approach (with the necessary adaptations) into their national monitoring systems and adopting the addictovigilance terminology.

Introduction: Nonalcoholic fatty liver diseases (NAFLD) and metabolic dysfunction-associated fatty liver diseases (MAFLD) are closely associated with metabolic syndrome, including obesity, dyslipidemia, and insulin resistance (IR). Thus, stains may be considered for the management of NAFLD/MAFLD. However, its efficacy and safety remain unclear in NAFLD/MAFLD.

Methods: The PubMed, EMBASE, and Cochrane library databases were searched to identify randomized controlled trials (RCTs) evaluating the efficacy and/or safety of statins in NAFLD/MAFLD. Risk ratios (RRs) and weight mean differences (WMDs) with their 95% confidence intervals (CIs) were calculated.

Results: Seven studies involving 993 patients with NAFLD/MAFLD were included. Statins were significantly associated with reductions in alanine aminotransferase (ALT, WMD = -9.76 U/L, 95%CI: -17.28, -2.24, p  = 0.010), aspartate aminotransferase (AST, WMD = -4.46 U/L, 95%CI: -9.03, 0.11, p  = 0.060), gamma-glutamyl-transpeptidase (GGT, WMD = -10.18 U/L, 95%CI: -13.65, -6.70, p  < 0.001), low-density lipoprotein (LDL, WMD = -0.86 mmol/L, 95%CI: -1.06, -0.66, p  < 0.001), total cholesterol (TC, WMD = -0.88 mmol/L, 95%CI: -1.14, -0.61, p  < 0.001), and triglyceride (TG, WMD = -0.32 mmol/L, 95%CI: -0.45, -0.19, p  < 0.001) levels. Additionally, statins did not increase the risk of myalgia (RR = 0.96, 95%CI: 0.10, 9.00, p  = 0.970).

Conclusions: Statins could improve liver function and lipid profiles in NAFLD/MAFLD. No myalgia was reported as AEs in the studies we included and the overall safety was favorable.Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD42025630809.

Introduction: Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes for cancer patients. However, TKIs have a narrow therapeutic window, impact a high-risk population, and are frequently combined with additional medications, each of which increases the risk of drug-drug interactions (DDIs). As polypharmacy becomes more common, especially in older and higher-risk groups that are prescribed TKIs, there is an increased risk for harmful DDIs.

Areas covered: TKI-related DDIs can lead to toxicity or reduced efficacy, which worsens patient outcomes and quality of life. In this review, we utilized the Drug Interaction Database (DIDB), FDA labels, and PubMed TKI DDI/ADME queries to outline the mechanisms underlying both pharmacokinetic (PK) and pharmacodynamic (PD) DDIs with TKIs. Pharmacokinetic DDIs involve changes in the absorption, distribution, metabolism, and excretion (ADME) of a molecule (victim) caused by another drug (perpetrator). These DDIs may involve direct inhibition, post-translational modification, or transcriptional regulation. Pharmacodynamic DDIs involve overlapping mechanisms resulting in additive, synergistic, or antagonistic effects when two medications are combined.

Expert opinion: Understanding the mechanisms underlying DDIs facilitates a better grasp of TKI clinical pharmacology and will help in the development of strategies to optimize drug dosing and avoid DDIs.

Background: Risperidone ISM® does not require loading dose or oral supplementation. Dopamine D2 Receptor Occupancy (D2RO) profiles between Risperidone ISM® versus oral risperidone (OR) and monthly paliperidone palmitate (PP1M) were compared.

Methods: D2RO time profiles were simulated using population pharmacokinetic models in conjunction with an Emax model relating D2RO with plasma levels.

Results: The median time <65% D2RO threshold was predicted to be 0 days for 100 mg Risperidone ISM® versus 5 and 13 days for 8 mg OR, if an intermediate or poor adherence.A D2RO of more than 65% was predicted to be reached within 1 day after the first injection of Risperidone ISM®. Less than 1% of patients treated with Risperidone ISM were predicted to remain below 65% D2RO, while ranged 7-17% on treated with 150 PP1M would be below this threshold for the 28 day-period along the 4 months studied.

Conclusions: Risperidone ISM® achieves threshold D2RO on the first injection day and predicts higher median time above 65% D2RO than high OR doses in real clinical practice. A much faster onset of action and better D2RO coverage during the dosing interval was predicted for Risperidone ISM® versus PP1M. Simulations suggest that Risperidone ISM® compares favorably with high doses of OR and PP1M, making it an effective therapeutic strategy for rapid and sustained symptom reduction.

Introduction: The goal of treatment in older patients (≥60 years) with acute myeloid leukemia (AML) has recently switched from only improving quality of life to achieving long-term survival via prolonged therapy. Novel therapeutic drugs have indeed recently been approved and tested in combination therapy. In this setting, the combination of venetoclax with a hypomethylating agent (HMA) has emerged as a new standard of care in this patient population.

Areas covered: This review summarizes promising emerging strategies combining target-directed agents for the treatment of older patients with AML. A comprehensive search was made on pubmed.ncbi.nlm.nih.gov, ashpublications.org, library.ehaweb.org, and clinicaltrials.gov to look for efficacy and safety of emerging therapeutic agents.

Expert opinion: Over the last 5 years, the landscape of AML therapy in older patients with AML has moved from uniform approaches toward more personalized therapy based on molecularly defined subtypes that benefit from target-directed therapy. Favorable results obtained with the synergistic combination venetoclax/HMA are currently opening a new active treatment research era by adding other specific drugs to this backbone regimen.

Introduction: Polypharmacy and potentially inappropriate medications (PIMs) contribute to adverse outcomes. Deprescribing, the supervised withdrawal of PIMs, is a key strategy to reduce these risks. Identifying the most targeted PIMs and commonly used tools for deprescribing remains essential. The aim of this systematic review was to identify the medication classes targeted by deprescribing tools, stratified by tool type and frequency and to evaluate the availability of medication-specific tools.

Methods: A systematic search of Embase, PubMed, Scopus, and Medline (2010-2023) identified observational and experimental studies using polypharmacy and deprescribing terms. The Newcastle-Ottawa Scale (NOS) and the revised Cochrane risk-of-bias tool (RoB 2) were used for quality assessment. Medication classes and tools/interventions were summarized in the TOTALLY TARGETED List.

Results: Eighty-two studies identified 44 deprescribing tools targeting 77 medication classes. The top PIMs were benzodiazepines, antipsychotics, alpha-receptor blockers, proton pump inhibitors, and Z-hypnotics. The most used tools were Screening Tool of Older People's Prescriptions (STOPP) Frail, American Geriatric Society (AGS) Beers Criteria, STOPP Criteria, and STOPPFall. Several medication-specific tools (e.g. PIMs in cognitively impaired patients) were also identified.

Conclusion: This review identified the most targeted medication classes and deprescribing tools, emphasizing the need for medication-specific and patient-centered approaches to improve safety and outcomes.

Protocol registration: https://www.crd.york.ac.uk/prospero//CRD42023442654.

Introduction: Biliary tract cancer (BTC) is an aggressive cancer arising from biliary epithelial cells. The combination of immune checkpoint inhibitors (ICIs) with other anticancer therapies has recently emerged as a new approach for BTC, and combinatorial strategies including chemotherapy plus immunotherapy are the current first-line standard in the metastatic setting. However, these combinations are effective only for a niche of patients and long-term responses are rare.

Areas covered: This review will focus on available data and ongoing clinical trials aimed at addressing the resistance mechanisms in BTC patients receiving ICIs that frequently experience primary resistance or short-term responses.

Expert opinion: The integration of immunotherapy with chemotherapy has established itself as a new standard treatment, while innovative approaches including dual immunotherapy, pairing ICIs with targeted therapies and combining ICIs with locoregional therapies have shown encouraging synergy. Nonetheless, issues like primary and secondary resistance, the immunosuppressive TME of BTC, and the lack of reliable biomarkers of response remain major challenges.

Background: Gabapentinoids are commonly used for neuropathic pain but are increasingly linked with misuse/mortality. In 2019, the UK reclassified them as Schedule 3 controlled drugs. The onset of the COVID-19 pandemic created additional uncertainty regarding their utilization. We aimed to examine the impact of reclassification and COVID-19 on gabapentinoid utilization and related mortality in Scotland and Northern Ireland (NI).

Research design/methods: A population-based, cross-national study was conducted using prescribing datasets (April/2018-February/2025). Utilization was measured as total items dispensed per 1,000 inhabitants and defined daily doses per 1,000 inhabitants/day. Gabapentinoid-related mortality data were analyzed in parallel. Segmented regression assessed changes in trends following the 2019 reclassification and two COVID-19 lockdowns.

Results: Overall utilization was higher in Scotland than NI. In Scotland, pregabalin prescribing significantly increased over the study period, while NI demonstrated a decline, largely attributable to formulary restrictions. Neither reclassification nor pandemic lockdowns were associated with statistically significant changes in prescribing patterns. Mortality rates showed no significant correlation with utilization in either country.

Conclusions: Gabapentinoid utilization does not appear to have been significantly affected by the reclassification or by COVID-19. Cross-national differences underscore the influence of formulary guidance, highlighting the need for harmonized policies/patient-level research to inform safe prescribing.