Expert Review of Clinical Pharmacology最新文献

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.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes mellitus (T2DM) and obesity.

Areas covered: An electronic search was conducted in Scopus, PubMed/MEDLINE, and Google Scholar databases. Orforglipron is a novel oral non-peptide GLP-1RA. In T2DM individuals, it has led to reductions in glycated hemoglobin (HbA_1c) by up to 2.10%, in weight by up to 10.1 kg and in waist circumference by up to 8.7 cm. In studies on overweight or obesity, a weight loss up to 13.0 kg has been reported. In meta-analyses, orforglipron was the most efficient GLP-1RA in terms of weight loss. Significant decreases in systolic blood pressure have also been found in individuals with and without T2DM. Untoward effects include mild-to-moderate vomiting and nausea, particularly in those receiving high doses and after rapid-dose escalation.

Expert opinion: Orforglipron is a promising treatment option for T2DM and overweight or obesity, in terms of glucose control and weight loss. The increased frequency of adverse events, particularly in those receiving high doses and after rapid-dose escalation, requires caution before widespread use.

Background: Increased diagnoses burden is a characteristic of post-COVID sequelae. Concomitant increased polypharmacy burden is a consequence yet there are few publications on the topic. The aim of this report is to help characterize post-COVID polypharmacy in older adults.

Research design and methods: Using data from a large health system, pre- and post-COVID disease and medication burden was analyzed. Patients aged 61 years and older who were diagnosed with COVID-19 during the early variant period (March 2020-December 2021), before widespread vaccination, were followed through December 2024. Within-person difference was tested. Multiple linear regression determined predictive post-COVID increases in clinical burden. Qualitative characterization was supported by multidisciplinary literature review.

Results: In patients ≥61 years, the mean increase in diagnoses and medications per post-COVID patient was 7.37 and 13.23, respectively. The largest increase in diagnoses was seen in patients aged 71-80 and people of Black race. The largest increase in medications was in patients aged 81-90 and females. Each additional pre-covid diagnosis and medication was associated with a 0.10 unit, and 0.12 unit increase, respectively, post-COVID-19.

Conclusions: Each pre-COVID diagnoses and medication were associated with quantifiable increase post-COVID, with higher risk with advanced age, Black race and female gender. Single health system data may inhibit generalizability of our findings. Clinicians should be vigilant and prepared to manage post-COVID-19 polypharmacy.

Background: Adverse drug reactions (ADRs) in hospitalized pregnant women remain under-recognized, and no validated risk prediction tools exist. We developed and validated a tool to estimate individual ADR risk in this population.

Research design and methods: A nested case-control study was conducted within a prospective cohort of high-risk pregnant women admitted to a Brazilian hospital from September 2021 to July 2023. Patients receiving at least one medication during a hospital stay > 24 hours were eligible. ADRs were classified as 'probable' or 'definite' using the Naranjo algorithm. Multivariate logistic regression identified independent predictors. Discriminative performance was assessed by the area under the ROC curve (AUC); calibration was evaluated using the Hosmer-Lemeshow test and Brier score.

Results: Among 330 women (110 cases and 220 controls), eight independent predictors of ADRs were identified: gestational hypertensive syndrome, drug allergy, aPTT ≥27.9 seconds, hospitalization ≥7 days, blurred vision, sedation, nausea, and polypharmacy (≥5 drugs). The final score (0-100) showed good performance at a cutoff ≥34 (AUC: 0.77; 95% CI: 0.71-0.82) and satisfactory calibration (p = 0.528; Brier = 0.27).

Conclusion: PREG-ADR demonstrated strong predictive performance and may support identification of high-risk pregnant women to improve pharmacotherapy safety.

Introduction: Pediatric chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disease with multifactorial etiology. CRS is less prevalent in children than in adults, but it substantially affects the patient's quality of life with significant diagnostic and therapeutic challenges.

Areas covered: This review gives an overview of the pathophysiology, diagnostic approach, and current medical treatment strategies for pediatric CRS.

Expert opinion: As a first-line medical treatment, standard management includes intranasal corticosteroids and saline irrigation. Short-course antibiotics or systemic corticosteroids are prescribed only when clearly indicated and limited to selected cases. Target therapies as monoclonal antibodies, are considered salvage options for children who do not respond adequately to standard medical or surgical treatments. Dupilumab and tezepelumab are currently the only biologics approved for adolescents with CRS, while other monoclonal antibodies are still under consideration in pediatric CRS. Regulatory approvals are largely based on results extrapolated from adults or from clinical studies conducted in other respiratory diseases. Data on the efficacy and safety of novel therapies are still limited, because pediatric-specific randomized clinical trials are limited. Future studies should focus on the early identification of comorbidities, the development of personalized treatment strategies, and improved safety.

Introduction: Patients with cancer are frequently exposed to polypharmacy, carrying a high risk of drug-drug interactions (DDIs). Given their substantial risk for thrombosis and atrial fibrillation, anticoagulants are commonly prescribed in this population. Anticoagulants can be associated with relevant pharmacokinetic and pharmacodynamic DDIs, yet their clinical significance remains undetermined.

Areas covered: A literature search of preclinical and clinical studies was performed to identify DDIs between anticoagulation and anticancer treatment, with an emphasis on pharmacokinetic and pharmacodynamic mechanisms. This narrative review summarizes the general principles of DDIs involving anticoagulation in patients with cancer. A comprehensive review of DDIs between anticoagulants and different classes of anticancer therapies is provided, including recent outcome studies evaluating their impact on mortality, clinically relevant bleeding, and thrombosis.

Expert opinion: Based on available data, we propose a practical approach to DDI assessment and clinical interpretation to support decision-making in patients with cancer requiring anticoagulation. This includes systematic screening for DDIs, tailoring anticoagulants during both initial and long-term treatment (primarily in the context of venous thromboembolism), providing patient counseling based on available evidence, and involving the pharmacy team in complex cases.

Introduction: Janus kinase inhibitors (JAKIs) emerged as novel therapies for a wide range of autoimmune and myeloproliferative neoplasms. JAKIs have remarkable clinical effectiveness, but emerging safety concerns have sparked interest in precision dosing approaches and the role of therapeutic drug monitoring (TDM) remains largely unexplored.

Areas covered: This review summarizes the mechanisms of action, indications and adverse effects of approved JAKIs in Switzerland, namely, abrocitinib, baricitinib, momelotinib, ritlecitinib, ruxolitinib, tofacitinib, and upadacitinib. We discussed factors that impact the pharmacokinetics of JAKIs, as well as exposure-efficacy and toxicity relationships, to evaluate whether JAKIs are suitable candidates for TDM. Regulatory documents and a PubMed search using the terms 'drug monitoring,' 'pharmacokinetics,' and 'JAKIs (incl. abrocitinib, baricitinib, momelotinib, ritlecitinib, ruxolitinib, tofacitinib, and upadacitinib)' were used to compile data until March 2025.

Expert opinion: JAKIs meet the criteria for TDM as they have marked inter-individual pharmacokinetic variability, narrow therapeutic margins and exposure-response relationships. Implementing TDM in clinical practice requires to establish target concentration ranges associated with efficacy and toxicity, along with a better understanding of the pharmacokinetics of JAKIs in real-life settings.

Introduction: In the last few years, interest is growing around the topic of possible therapeutic properties of substances classified as psychedelic, especially for the treatment of mental disorders. Ayahuasca is a classic psychedelic with a complex composition, which has been used in traditional contexts for centuries.

Areas covered: In this review, we explore the current evidence and limitations around ayahuasca use for the treatment of depression, anxiety, posttraumatic stress and substance use disorders, with a focus on clinical and observation studies.

Expert opinion: Similar to what happens with other psychedelics, there is an ongoing debate on subjective experience contribution to overall therapeutic mechanisms, which can depend on the targeted conditions. There are very few evidences from controlled studies, limiting the conclusions on safety and efficacy. On top of that, ayahuasca highly variable composition posits another challenge, and studies using isolated compounds are being developed.