Expert Review of Clinical Pharmacology最新文献

Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis poses a significant clinical challenge, especially given its strong association with obesity and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated impressive results in managing obesity and T2DM, prompting interest in their potential therapeutic role for MASH with fibrosis. The ESSENCE trial recently investigated the effectiveness of once-weekly semaglutide in patients with biopsy-proven MASH and moderate-to-advanced fibrosis. Interim analysis at 72 weeks demonstrated that semaglutide substantially improved liver histology, effectively resolving steatohepatitis and showing improvement in liver fibrosis, compared to placebo. Consistent with these findings, the U.S. Food and Drug Administration has granted accelerated approval to semaglutide (Wegovy) for adults with noncirrhotic MASH and stage 2 or 3 fibrosis. Those hepatic benefits were accompanied with notable improvements in body weight, insulin sensitivity and inflammatory markers. While these preliminary results are encouraging, their clinical relevance will depend on whether they translate into reduced long-term liver complications and amelioration of overall cardio-renal risk. Thus, semaglutide represents a highly promising therapeutic strategy for patients with MASH and fibrosis, addressing critical unmet needs by simultaneously targeting liver pathology and cardiometabolic health.

Introduction: Pregnancy in women with systemic lupus erythematosus presents significant clinical challenges due to heightened risks of complications for both mother and fetus. Therapeutic management must be carefully tailored to safeguard maternal health while ensuring optimal fetal development.

Areas covered: This review explores pharmacological treatments used during pregnancy in women with lupus, focusing on medication safety profiles, risk-benefit analyses of available therapeutic options, and specific challenges posed by comorbidities such as antiphospholipid syndrome and vaccination considerations.

Expert opinion: Although significant advances have been made in managing lupus during pregnancy, many treatments, particularly biologic therapies, still lack sufficient evidence for unrestricted use. This underscores the necessity for vigilant monitoring and individualized treatment protocols. Preconception consultation remains crucial for optimizing therapeutic strategies, ensuring appropriate medication adjustments prior to conception. A coordinated multidisciplinary approach is essential to navigate these complexities and achieve favorable outcomes for both mother and child.

Introduction: Vasomotor symptoms (VMS) and decreased libido are common menopausal symptoms. Patients with breast cancer receiving endocrine therapy experience new or worsening menopausal symptoms. Pharmacologic therapy for VMS has been centered on selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, gabapentin, and clonidine. These therapeutic options fall short in obtaining adequate symptom relief, illustrating a therapeutic gap in efficacious treatment modalities. There are no historical systemic treatment options for low libido.

Areas covered: This review summarizes the current pharmacologic therapy for VMS, focusing on the practical considerations for use of the novel VMS (fezolinetant, elinzanetant) and libido agents (flibanserin, bremelanotide). Literature search was completed with PUBMED, Cochrane Library, and Web of Science. Fezolinetant is a novel neurokinin 3 receptor antagonist that has demonstrated clinical benefit in patients without a history of breast cancer. For libido management, flibanserin and bremelanotide act as serotonin/dopaminergic modulators and melanocortin receptor agonists, respectively.

Expert opinion: These novel agents are eagerly awaited therapeutic options; however, clinical trials excluded breast cancer patients. This review provides clinicians with relevant considerations to assess when recommending these therapies for patients with breast cancer, while awaiting ongoing research to give additional insights for best tailoring therapy for this patient population.

Introduction: Naxitamab (previously named hu3F8) is a humanized monoclonal antibody (mAb) targeting disialoganglioside GD2, a ganglioside homogeneously and abundantly expressed on neuroblastoma and other neuroectodermal tumors. Anti-GD2 mAbs are an integral part of the standard therapeutic paradigm for high-risk neuroblastoma. Naxitamab, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), is approved by regulatory authorities for patients with relapsed or refractory neuroblastoma in the bone and/or bone marrow.

Areas covered: This review provides a comprehensive overview of the preclinical development, clinical efficacy, and safety profile of naxitamab. It summarizes and discusses the key clinical trials, real-world experiences, and adverse events management.

Expert opinion: Naxitamab has shown a favorable toxicity profile and meaningful therapeutic efficacy in relapsed or refractory diseases and as consolidation therapy in high-risk neuroblastoma. Ongoing clinical studies and expanded global use continue to evaluate its safety and efficacy, to optimize its integration with standard care, and to fully exploit its therapeutic potential. Advances in protein engineering can further extend the utility of anti-GD2 mAbs, enabling the creation of radioimmunoconjugates, novel bispecific antibodies, and pre-targeting strategies, offering potent tumor selectivity while mitigating off-target toxicity.

Introduction: Long-acting growth hormone (LAGH) preparations have been developed to reduce the burden of daily injections and improve compliance in children and adults with growth hormone deficiency (GHD). Somapacitan is the only LAGH approved for both pediatric and adult GHD that has been in the market for nearly 2 years for these indications. It has now up to 4 years of follow up data from pediatric clinical trials.

Areas covered: In this article, we will review the rationale for developing somapacitan and other LAGH, the pharmacologic characteristics, pharmacokinetics, and pharmacodynamics of somapacitan. We will summarize the clinical trial results of safety, efficacy, and adherence of somapacitan in comparison to daily growth hormone (GH) in both adults and children. We will also provide practical recommendations on the initiation and monitoring of somapacitan, and discuss potential future uses of this LAGH.

Expert opinion: Continued somapacitan therapy in clinical trials in children with GHD has shown ongoing catch-up growth while having a similar safety profile to daily growth hormone. However, it will be important to capture real world data demonstrating ongoing safety, efficacy, and adherence in children and adults receiving somapacitan and other LAGH therapies.

Introduction: Breast cancer is the most common cancer in women. As global populations age, the number of older adults with breast cancer is expected to increase significantly. Recently, progress has been made across all subtypes of breast cancer with the development of new targeted therapeutics and the success of novel combinations. However, treating older adults remains challenging due to the limited representation of this population in clinical trials, resulting in a lack of robust data on treatment efficacy and tolerability.

Areas covered: We reviewed FDA-approved therapies for breast cancer since 2020. We analyzed pivotal clinical trials leading to registration, as well as subanalyses of older populations and real-world studies for each approved therapy, with a focus on their impact in older adults.

Expert opinion: Breast cancer is a quickly changing field with many new therapeutics and novel combinations on the horizon. With each new approval, it is critical to assess expected side effects and approach each patient with an individualized plan. Many clinical trials enroll a small number of older adults, making it difficult to extrapolate data to geriatric populations. Future trials should incorporate broader eligibility criteria and include geriatric-specific endpoints to better inform treatment decisions for older adults with breast cancer.

Introduction: Benzodiazepine derivatives and Z-drugs have traditionally been the cornerstone of pharmacological insomnia treatment. However, concerns regarding increased risks of falls, next-morning residual effects, dose tolerance, dependence, and withdrawal symptoms have prompted growing interest in alternative therapies.

Areas covered: This review critically assesses the effectiveness and challenges of lemborexant, a dual orexin receptor antagonist (DORA), in treating insomnia. It draws on current pharmacokinetic and clinical pharmacodynamic evidence, including data from phase 3 trials and meta-analyses.

Expert opinion: Lemborexant, with relative selectivity for the orexin receptor type 2, offers robust efficacy for both sleep initiation and maintenance. Its pharmacokinetic profile yields a quick onset and steep decline in plasma levels, helping minimize next-morning residual effects despite a long terminal half-life. Network meta-analyses demonstrate improvements in subjective and objective sleep measures, with lemborexant often ranking highest among hypnotics. Somnolence is the most common adverse event, while withdrawal symptoms, dependence, falls, cognitive impairment, and driving deficits are uncommon or comparable to placebo. Nightmares and sleep paralysis occur infrequently. Evidence supports its safe use in older adults and patients with obstructive sleep apnea or chronic obstructive pulmonary disease. Further research should address its role in psychiatric and medical comorbidities, and substance use disorders.

Introduction: Older people with dementia and mental health disorders frequently have co-occurring acute and chronic conditions resulting in polypharmacy. However, these populations are under-represented in clinical trials, and drug efficacy and tolerability are poorly understood. Electronic health records data represent valuable resources to investigate medication safety.

Areas covered: This report outlines the complexity of pharmacotherapy in late life and the key factors that need to be taken into consideration. In relation to the impoverished evidence base to support prescribing, it considers the important potential role of electronic health records data resources in addressing this, particularly within the UK National Health Service (NHS). The different types of current NHS databases in specialist and primary care are discussed alongside research outputs using these resources related to pharmacotherapy in people with dementia and/or late life mental disorders.

Expert opinion: NHS databases have particular value because of comprehensive catchment-based care provided by mental health and dementia diagnostic services and detailed long-term prescribing data captured in primary care. However, care for these disorders is usually delivered across multiple sectors with differing strengths and limitations in information availability and more work is needed in improving linked data infrastructures.