Expert Review of Clinical Pharmacology最新文献

Introduction: Drug-resistant epilepsy (DRE) affects 30% of epilepsy patients and represents a major therapeutic challenge. Understanding its genetic determinants is crucial for the development of effective precision medicine strategies.

Areas covered: This review comprehensively evaluates genetic factors in DRE, including polymorphisms in pharmacokinetic (e.g. ABCB1) and pharmacodynamic (e.g. SCN1A), findings from genome-wide association studies (GWAS) that recently identified a significant locus at 1q42.11-q42.12 (CNIH3/WDR26) for focal DRE, the critical role of rare variants (e.g. in SCN1A, KCNQ2) and copy number variations (CNVs) in severe epileptic encephalopathies, and the emerging fields of epigenetics and polygenic risk scores (PRS).

Expert opinion: Methodological limitations, including modest sample sizes and phenotypic heterogeneity, hamper genetic research on DRE. While common variants show little impact, rare variants, including CNVs, and epigenetic alterations offer promising opportunities. Future priorities include functional studies to clarify the impact of gene variants, the integration of multi-omics data and the development of advanced analytical techniques, such as machine learning and network approaches, to translate genetic discoveries into clinically actionable precision medicine and ultimately improve outcomes for DRE patients.

Background: The increasing complexity of biologic and targeted therapies for inflammatory rheumatic diseases necessitates robust, real-world evidence to guide clinical decision-making. Scotland's newly established Homecare dataset, capturing ~ 90% of secondary care disease-modifying antirheumatic drugs (DMARDs) prescribing, offers a unique national resource to evaluate treatment patterns.

Research design and methods: We conducted a retrospective cohort study using Public Health Scotland's Homecare dataset (2019-2023), including 17,695 patients treated for rheumatoid arthritis, psoriatic arthritis, spondyloarthritis (SpA), juvenile idiopathic arthritis (JIA), and related conditions. We analysed DMARD utilisation, treatment sequencing, and persistence using descriptive statistics and pathway mapping.

Results: A total of 260,054 prescriptions were analysed, with biologic DMARDs comprising 90% of homecare supplies. Adalimumab and etanercept were the predominant agents. TNF inhibitors dominated first-line use, with high persistence rates (78.6%-97.1%), particularly in JIA and SpA. Among switchers, median time on initial therapy was 10.7 months (IQR: 4.2-23.3), decreasing with each subsequent treatment, highlighting the challenges in managing multi-refractory patients.

Conclusion: This is the first national study to characterise real-world DMARD prescribing in Scotland using comprehensive Homecare data. Findings provide critical benchmarks for therapeutic optimisation, inform guideline development, and support sustainable planning for high-cost medicines delivery in rheumatology.

Introduction: The mainstay of treatment for gynecologic cancers includes surgical debulking followed in a subset of patients by chemotherapy, radiation, hormonal therapy, and immunotherapy. In the last 10 years, antibody-drug conjugates (ADCs) have provided new therapeutic options and significant promise for the treatment of patients with recurrent gynecologic tumors.

Areas covered: Information for this review article was obtained by literature review on PUBMED using phrases such as 'antibody drug conjugates in gynecologic cancers,' 'FDA approval for antibody drug conjugates in gynecologic cancers,' 'tisotumab vedotin,' 'mirvetuximab soravtansine,' 'trastuzumab deruxitcan,' 'sacituzumab govitecan,' 'datopotamab deruxtecan,' and 'sacituzumab tirumotecan.'

Expert opinion: ADCs represent a new frontier for the treatment of gynecologic malignancies. The few ADCs currently approved by the FDA for the treatment of gynecologic cancers demonstrated higher clinical activity and better tolerability when compared to standard investigator choice chemotherapy. Streamlined pathologic tissue testing of tumor samples is required for widespread use of ADCs, and future prospective studies are needed to ascertain whether ADCs can be introduced in first-line treatment for patients with advanced gynecologic malignancies.

Introduction: Long-chain fatty acid oxidation disorders (LC-FAODs) are rare inherited metabolic defects that present across the lifespan with skeletal, cardiac, and hepatic complications due to deficiency of energy production. Historically, medium-chain triglycerides (MCT) were used in their management of LC-FAODs, but individuals still developed symptoms due to depletion of tricarboxylic acid (TCA) cycle substrates.

Areas covered: This review covers the pathophysiology of LC-FAODs, highlighting the rationale for the use of triheptanoin (Dojolvi®), an MCT consisting of three 7-carbon fatty acids, in the nutritional management of LC-FAODs.

Expert opinion: Triheptanoin is an anaplerotic source of calories for treatment of LC-FAODs, providing a source of substrates to sustain the TCA cycle, gluconeogenesis, and energy production. Use of triheptanoin prior to its regulatory approval demonstrated significant clinical benefit. Clinical benefit was thereafter demonstrated in clinical trials, with a positive cardiac effect in a double-blinded, randomized controlled comparison to MCT, and improvement in major clinical events in open-label extension studies. Side effects of triheptanoin are primarily GI intolerance similar to conventional MCT oil. Use prior to onset of symptoms in severe disease is recommended. Its use is not limited to LC-FAODs with active studies looking at its potential benefit in other conditions.

Introduction: Pincus and his group's initial research on hormonal contraception focused on progesterone. However, the natural compound could not be utilized in clinical practice because of the high incidence of breakthrough bleeding and its low oral availability. This led to the introduction of orally active progestins. The estrogen was added to ensure proper cycle control.

Areas covered: Concern about side effects of combined oral contraceptive pills (COC) and specifically the increased occurrence of thromboembolism was raised at the very early stages of clinical use. These were attributed to the estrogenic component, ethinyl estradiol (EE). The first pill scare followed the publication in 1977 of evidence of thromboembolism-related mortality in COC users. This and subsequent alarming publications acted as the engine for a successful attempt to substantially decrease the daily content of EE in a COC. Over time, adverse events were also reported for the newer progestins compared to levonorgestrel.

Expert opinion: Attempts have been made to utilize natural estrogens in COC based on the assumption that this will reduce adverse effects. The wide range of progestins available for use in COC renders comparisons between preparations more challenging. Each progestin has its own androgenic, antiandrogenic, antiestrogenic, and mineralocorticoid activity and, consequently, a unique risk and benefit profile.

Background: The combination of oxcarbazepine (OXC) with perampanel (PER) considerably reduces the blood concentration of PER in children, decreasing the antiepileptic effect of PER. This study aimed to predict PER exposure and provide recommendations for dose adjustment in pediatric patients.

Research design and methods: Physiologically based pharmacokinetic (PBPK) models of PER and OXC for adults and pediatrics were developed and verified, followed by drug - drug interaction (DDI) modeling and validation of the models against available pharmacokinetic data.

Results: The simulated results of the PBPK models exhibited a fold-error value between 0.5 and 2, indicating good predictive abilities; the DDI model results supported the observational results. Based on the prediction results, the recommended dosages of PER for 4-10- and 10-14-year-old children are 2-6 and 4-8 mg q.n., respectively. Additionally, the recommended doses of PER in PER with OXC combination therapy for children aged 4-10 and 10-14 years are 6-12 and 10-12 mg q.n., respectively.

Conclusion: The PBPK and DDI models of PER were successfully established, which serve as references for the rational use of this medication in children.

Introduction: Marketing in the late 1950s of Combined Oral Contraceptives (COC) represented the achievement of centuries of research in reproductive endocrinology that included the isolation of the main steroids produced, within the concept of 'internal secretion,' by the ovaries and corpus luteum.

Areas covered: Key observations made at the end of the 19th century proved that the presence of corpus luteum induces temporary infertility in animals and that ovaries secrete hormonally active substances. During the 1930s, the four main hormones (progesterone, estrone, estradiol, and estriol) were identified and their structure determined. The recognition that natural compounds are not effective when given orally, stimulated the search for synthetic steroids. Ethinyl-estradiol, synthesized in 1937, remains even today the most widely used estrogenic component of COC, although other compounds (micronized estradiol, estradiol valerate, estetrol) have been incorporated in COC. A variety of synthetic progestins have become available since the early 1950s having different progestogenic potency, pharmacokinetic and pharmacodynamic properties.

Expert opinion: Started with observations made three centuries ago, development of COC has gone beyond the dream of the early investigators: literally dozens of formulations are available today capable of satisfying the needs of the majority of women of fertile age and the work continues.

Background: Recognizing early treatment indicators that forecast the long-term effectiveness of maintenance therapy in psoriasis (PsO) could support the optimization of personalized treatments. We aimed to evaluate whether an early response can predict long-term outcomes in patients receiving risankizumab or guselkumab, and to explore the factors associated with responses.

Research design and methods: This retrospective study included PsO patients who received risankizumab or guselkumab continuously at least 1 year. The study measured disease severity using the Psoriasis Area Severity Index (PASI) and determined the percentage of patients treated with risankizumab or guselkumab who showed PASI50 at the 3^rd month (early response), and assessed whether early response was associated with maintaining long-term response (PASI75 response at the 1^st year).

Results: A total of 102 patients, including 60 who received risankizumab and 42 who received guselkumab, were enrolled. Early response at the 3^rd month strongly predicted treatment outcomes at 12 months. Among early responders, the likelihood of achieving a long-term response was found to be 94.9%.

Conclusions: In patients with PsO treated with risankizumab or guselkumab, early response was a significant factor in maintaining stable long-term response. Therefore, early response is a clinically relevant factor to consider when optimizing individual therapeutic strategies.

Introduction: Biosimilars have the potential to offer cost savings with comparable efficacy and safety to innovator products and, thus, increase access to treatment for more patients. However, there were significant challenges in the acceptance of oncology biosimilars in our organization in the beginning which we addressed by implementing practical strategies described in the paper.

Areas covered: While much of the published literature places an emphasis on the pharmacoeconomic impact of biosimilars, this paper is a novel addition to the literature because it provides practical experience and detailed processes for the formulary adoption and implementation of oncology biosimilars along with a focus on their pharmacoeconomic impact, education of oncology healthcare professionals, pharmacovigilance, and integration into the electronic health record. A narrative literature review was conducted to identify the existing evidence on biosimilar adoption and implementation in the oncology setting.

Expert opinion: Healthcare organizations must establish a consistent method for assessing and adopting oncology biosimilars to increase efficiency and coordination among the many team members responsible for their introduction into clinical practice. Conducting medication use evaluations and real-world evidence studies of biosimilars can help in building trust among healthcare professionals and patients in biosimilars.

Introduction: Deprescribing is crucial for improving patient safety since polypharmacy in older adults raises the likelihood of negative health outcomes. Artificial intelligence (AI) role in deprescribing has been rarely addressed.

Areas covered: This review looks at how AI techniques are now affecting evidence-based deprescribing for older patients. Studies addressing AI applications, including chatbots, mobile apps, clinical decision support systems (CDSS), and machine learning (ML) algorithms, were found through a thorough literature search. Using a broad range of AI, deprescribing, and older adult-related keywords, relevant studies published up until November 2024 were found through thorough searches of electronic databases. This review finds that these technologies help physicians forecast adverse drug events, identify potentially inappropriate drugs, and enhance medication management.

Expert opinion: AI-powered solutions have potential to improve patient outcomes and deprescribing procedures. However, issues including data quality, clinical acceptability, technology integration, and ethical considerations make practical adoption difficult. Extensive validation studies are required to confirm the safety and efficacy of these instruments. To make sure they enhance rather than complicate the deprescribing process, careful integration and ongoing assessment are necessary. Although AI can facilitate tailored deprescribing practice, it is essential to maintain human clinical touch and the patient-clinician interaction.