Expert Review of Clinical Pharmacology最新文献

Introduction: Managing epilepsy in patients with end-stage kidney disease presents unique challenges due to altered pharmacokinetics of anti-seizure medications (ASMs) and the effects of dialysis treatments. Dialysis can significantly affect ASM clearance, requiring careful dosing adjustments to maintain therapeutic efficacy while avoiding toxicity. This review aims to provide an up-to-date overview of the current knowledge and to offer practical clinical guidance on the use of ASMs in patients undergoing hemodialysis and peritoneal dialysis.

Areas covered: Relevant literature on ASMs in dialysis patients was searched in MEDLINE and Google Scholar. Additional information was retrieved from the summary of product characteristics for each ASM.

Expert opinion: Evidence on the management of ASMs in patients receiving dialysis is still limited, mainly based on small observational studies and case reports. Currently, no official guidelines are available. Effective treatment strategies require individualized approaches. ASMs with low protein binding and predominant renal elimination generally require post-dialysis dose adjustments. Therapeutic drug monitoring may be indicated in some cases. Data regarding the impact of different dialysis filter types on ASM clearance are sparse. The paucity of data, especially for newer ASMs, underscores the urgent need for further research to establish comprehensive, evidence-based recommendations for this vulnerable patient population.

Introduction: To provide an up-to-date overview of current pharmacological treatments and promising emerging therapies for dry eye disease (DED), a multifactorial and increasingly prevalent ocular surface disorder.

Areas covered: A targeted literature search was conducted using PubMed, Scopus, ClinicalTrials.gov, and additional online sources to identify recent advances in the pharmacological management of DED. The review focuses on therapies approved across major regulatory bodies, as well as investigational agents in late-stage clinical development. Special attention is given to novel drug delivery platforms and innovative therapeutic mechanisms.

Expert opinion: Rapid innovation in both therapeutic targets and drug delivery technologies is transforming the treatment landscape for DED. Advanced formulations, such as nanomicelles, mucus-penetrating particles, and preservative-free emulsions, are improving ocular bioavailability, reducing adverse effects, and enhancing patient adherence. The future of DED pharmacotherapy lies in personalized, multimodal strategies that address the full spectrum of disease mechanisms, including inflammation, tear film instability, neurosensory dysfunction, and epithelial damage. The recent FDA approval of AR-15512, a TRPM8 agonist, exemplifies the trend toward mechanism-specific therapies designed to deliver both symptomatic relief and disease modification. As the therapeutic armamentarium expands globally, continued clinical trials and real-world studies will be essential to ensure durable efficacy and optimize patient outcomes.

Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis. For decades, the only medication treatments that were widely accepted were the use of renin-angiotensin aldosterone inhibitors and corticosteroids. The early 2020s have brought a flurry of new treatments to the once dark IgA treatment landscape. Sparsentan is a novel dual-endothelin angiotensin receptor antagonist that has been approved as an add-on therapy for the treatment of IgAN.

Areas covered: We discuss the treatment landscape and the unmet needs for treating IgA nephropathy. Multiple clinical trials showing the efficacy of sparsentan including DUET, PROTECT, SPARTACUS, and SPARTAN will be described. Additionally, we will preview the future options for IgA patients.

Expert opinion: Sparsentan is a major step forward in improving outcomes for patients with IgAN. This once-a-day agent, in addition to other standards of care, limits proteinuria and progression to ESKD and kidney transplantation. The ability to lower proteinuria without weakening the immune system is a substantial gain for patients. As an agent that impacts the glomeruli directly, sparsentan is able to limit damage in mechanisms that previous RASi and steroids have not. Including sparsentan in the combination treatment for IgAN must be considered for adequate kidney protection.

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.