Expert Review of Clinical Pharmacology最新文献

Introduction: Access to quality-assured medicines remains unequal between high-income and low-income countries. To bridge this gap, product development and supply in low- and middle-income countries (LMICs) should follow World Health Organization (WHO)'s policies and recommendations whilst aligning with international standards.

Areas covered: We reviewed two cases on oxytocin access for postpartum hemorrhage (PPH), a condition that disproportionately affects mothers in low-income countries. The first case examines the challenges in ensuring quality-assured oxytocin injections in LMICs. International technical guidelines allow different storage conditions for oxytocin, which can cause confusion in countries with weak regulatory oversight. WHO and partners recommend a common storage and management of oxytocin to resolve this issue. The second case explores the design of clinical studies for inhaled oxytocin, a promising candidate for PPH aiming for rapid registration and inclusion in WHO's therapeutic recommendations. Aligning scientific, regulatory, and WHO policy requirements early in the development process can expedite access to new effective medicines in LMICs, and we described the potential clinical challenges in meeting this.

Expert opinion: Robust partnerships between stakeholders, to streamline medicine development and regulatory approval, are essential to close access gaps and ultimately prevent unnecessary deaths due to PPH in LMICs.

Introduction: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by rapidly enlarging, painful ulcers with undermined borders. The management of PG is challenging due to the lack of standardized evidence-based treatments.

Areas covered: This review examines recent efforts to establish standardized outcomes for clinical trials to facilitate the drug development process for PG. It explores new therapeutics in development and evaluates advanced options for wound and pain management. Literature available on the pathogenesis, treatment, and pain management of PG from database inception to April 2024 was searched in PubMed, Embase, and Cochrane. ClinicalTrials.gov and the EU Clinical Trials Register were searched for clinical trials on PG.

Expert opinion: New therapeutics such as interleukin 36 inhibitor and complement component C5a inhibitor more specifically target key pathways in the pathogenesis of PG have shown promise and can greatly benefit patients with PG, which still lacks an FDA-approved treatment. In addition to systemic therapy, local wound care and pain management should be carried out simultaneously to achieve successful wound healing.

Background: The cardioselective β-1 receptor antagonist metoprolol is used to treat heart failure. It is metabolized in the liver, primarily by cytochrome 2D6.

Research design and methods: In this study, trough serum concentrations of metoprolol and its metabolite α-hydroxymetoprolol were measured in patients with heart failure with reduced ejection fraction.

Results: Concentrations were 1.3-122.9 µg/L for metoprolol and 1.3-125.7 µg/L for α-hydroxymetoprolol, metabolic ratios were 0.11-98.32. The median weight-adjusted apparent clearance of metoprolol was 53.07 (range 3.24-500.0). Metoprolol and α-hydroxymetoprolol concentrations correlated with both daily dose and dose per kilogram of body weight. However, metoprolol concentrations at the same daily dose showed a wide variability. Patients taking 100 mg/day had significantly lower NT-proBNP values than those taking 25 or 50 mg/day. Patients with LVEF ≤ 35% versus > 35% used significantly lower daily doses and doses per kilogram of body weight, although metoprolol concentrations did not differ. A poor cytochrome 2D6 metabolizer phenotype was detected in two patients.

Conclusions: Metoprolol concentrations showed a wide interindividual variability at the same daily dose. Simultaneous determination of metoprolol and α-hydroxymetoprolol concentrations could identify patients at risk of possible accumulation of metoprolol leading to intoxication or, conversely, patients at risk of underdosing.

Introduction: Colorectal cancer is the second leading cause of cancer-related deaths worldwide. The impact of proton pump inhibitors (PPIs) on patients taking capecitabine, an oral fluoropyrimidine, remains uncertain, despite their use by 20 to 55% of cancer patients. We investigated how PPIs affect the effectiveness of capecitabine in treating colorectal cancer.

Methods: We searched PubMed, Embase, and Web of Science databases for studies that investigated the use of PPI with capecitabine versus capecitabine alone. We used random-effects models for all endpoints. Heterogeneity was assessed using I² statistics.

Results: We included 676 patients receiving capecitabine monotherapy. The overall progression/disease-free survival favored the PPI non-users (HR 2.1372; 95% CI 1.4591-3.1306; p < 0.001). Our results show that there seems to be no difference between users of PPIs and capecitabine in the colorectal cancer patients (HR 1.5922; 95% CI 0.9718-2.6086; p = 0.065). However, after sensitivity-adjusted analysis, PPI use was negatively associated with PPI use (HR 2.14; 95% CI 1.14-4.01; p < 0.001).

Conclusion: Patients with colorectal cancer undergoing oral chemotherapy, specifically capecitabine, should be monitored for the use of PPIs. Therefore, the use of PPIs should be discouraged in clinical practice in these cases.

Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD42024498240.

Introduction: Atopic dermatitis (AD) is diagnosed based on clinical signs and symptoms as well as on a clinical course lacking distinct laboratory or histological features; however, the recent appearance of molecularly targeted drugs against AD urges us to try to discover and develop biomarkers useful for treating AD patients.

Areas covered: This article commenced with a targeted PubMed search using 'atopic dermatitis' and 'biomarker' as keywords. We combined the findings from the B-PAD study that we have recently published and summarized data, particularly those recently published.

Expert opinion: Many cells and molecules are listed as potential biomarkers of AD, most of which are type 2 mediators. Among them, CCL17/TARC is now thought to be the most reliable biomarker of AD. During the B-PAD study, we recently found that three biomarkers - squamous cell carcinoma antigen 2 (SCCA2), CCL26/eotaxin-3, and lactose dehydrogenase (LDH) - are better able than CCL17/TARC to assess the clinical severity and disease activity of AD. Moreover, although several biomarkers showed good ability to monitor the efficacy of molecularly targeted drugs against AD. More studies on the discovery and development of biomarkers of AD are awaited to refine treatments for AD patients.

Introduction: Belzutifan is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor. It targets the von Hippel-Lindau protein (pVHL)-HIF-vascular endothelial growth factor (VEGF) pathway, which is crucial in cellular responses to hypoxia. By inhibiting HIF-2α, belzutifan disrupts the transcription of genes involved in tumor growth and angiogenesis.

Areas covered: In this review, we describe the pVHL-HIF-VEGF pathway and how it led to the development of HIF inhibitors, including belzutifan. A search was conducted for trials involving Belzutifan, including phase I-III trials. We describe the relevant toxicity, with emphasis on hypoxia and anemia.

Expert opinion: Belzutifan is a relatively safe drug, with manageable adverse events, including anemia and hypoxia as on-target toxicity. Ongoing trials are studying its benefit in overall survival for RCC in first-line treatment and its potential in other malignancies. The LITESPARK-005 trial reported the benefit of belzutifan in progression-free survival (PFS) compared to everolimus in later lines of treatment, with improvement in quality-of-life outcomes. Given its different mechanism of action to currently available treatments, belzutifan is expected to play a prominent role in the treatment of clear cell renal carcinoma and other cancers.