Pediatric Drugs最新文献

Myasthenia gravis (MG) is an antibody-mediated disorder of the neuromuscular junction affecting children and adults. MG is a treatable condition with most patients requiring immunosuppression for disease control and/or remission. Juvenile myasthenia gravis (JMG) is rare in comparison with adult-onset MG but given the same underlying pathophysiology, treatment strategies are similar to those in adults. Until recently, there were only a few randomised controlled trials (RCTs) for MG treatments in adults and none in children, and management strategies were primarily based on expert consensus. In addition, treatment options for refractory MG cases have been severely limited, resulting in poor long-term quality of life in such patients due to the significant disease burden. Recently, there have been several RCTs focussing on novel therapeutic strategies with potentially promising outcomes, suggesting a change in MG management over the coming years and access to more effective and faster-acting drugs for MG patients. This paper will review current and new MG treatments including efgartigimod, eculizumab, rozanolixizumab, ravulizumab, and zilucoplan, with a focus on juvenile myasthenia gravis.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune neurological disorder seen in both pediatric and adult populations. CIDP typically presents with progressive and persistent weakness over at least 4 weeks in addition to sensory symptoms in the extremities. Although CIDP shares common clinical features between children and adults, it sometimes presents as a distinct clinical entity in children that requires close attention and recognition. A major caveat when diagnosing a child with CIDP is the clinical and diagnostic overlap with inherited neuropathies, most commonly Charcot-Marie-Tooth disease (CMT). Demyelinating CMT (dCMT) and CIDP might share similar clinical presentations, and sometimes it might be difficult to differentiate them on the basis of the electrodiagnostic findings or cerebrospinal fluid (CSF) albumino-cytological dissociation. This indeed merits early consideration for genetic testing in patients who do not respond to conventional CIDP therapies. Current treatment options for CIDP include intravenous immunoglobulins (IVIG), corticosteroids (CS), and plasmapheresis (PLEX). The need for novel therapies is essential in instances where patients continue to have symptoms despite the standard therapies or due to adverse effects of long-term use of standard therapies such as CS. This paper reviews the challenges in the diagnosis of CIDP in children and the current as well as novel therapies for CIDP.

Background: Gene and RNA therapies have potential to transform the treatment of rare inherited diseases, but there are concerns about the evidence supporting their use and high costs.

Objective: We analyze the evidence supporting Food and Drug Administration (FDA) approval of gene and RNA therapies for rare inherited diseases and discuss implications for clinical practice and policy.

Methods: We conducted a qualitative analysis of FDA documents outlining the basis of approval for gene and RNA therapies approved for rare inherited diseases between 2016 and 2023. For each drug, we gathered five characteristics of the evidence supporting FDA approval (no phase 3 trial, nonrandomized, no clinical endpoint, lack of demonstrated benefit, and significant protocol deviation) and four characteristics of the FDA approval process (prior rejection or complete response, negative committee vote, discrepancy between label and trial population, and boxed warning). The main outcome was the number of drugs with each characteristic.

Results: Between 2016 and 2023, 19 gene and RNA therapies received FDA approval to treat rare inherited diseases. The most common limitations in the evidence supporting approval of these drugs were nonrandomized studies (8/19, 42%), no clinical endpoint (7/19, 37%), lack of demonstrated benefit or inconsistent results (4/19, 21%), and no phase 3 trial (4/19, 21%). Half (3/6) of accelerated approvals and 57% (5/9) of drugs with breakthrough designation had nonrandomized trials, and gene therapies with one-time dosing were overrepresented (5/7, 71%) among the drugs with nonrandomized trials. Five of six accelerated approvals (83%) and five of nine pediatric drugs (56%), most of which were indicated for Duchenne muscular dystrophy, had no clinical endpoint. Four of nine (44%) pediatric drugs and four of six (67%) accelerated approvals failed to demonstrate benefit compared with none of the nonpediatric drugs and none of the traditional approvals. Five drugs, which all had different indications and represented a mix of RNA and gene therapies, did not have any of these evidence characteristics. Among drugs that received prior rejections or negative committee opinions, all four had nonrandomized trials and lacked a clinical endpoint, and 75% (3/4) lacked demonstrated benefit. Five of nine (56%) pediatric drugs were indicated for broader age groups according to the drug label compared with the trial populations. Of the three drugs with boxed warnings, two had pediatric indications and nonrandomized studies, and one had no phase 3 trial.

Conclusions: Issues related to trial design, outcome, and data integrity in the evidence supporting FDA approval of rare inherited disease gene and RNA therapies raise questions about whether this evidence is adequate to inform prescribing decisions. Gene and RNA therapies with accelerated approval an

The widespread use of drugs for unapproved purposes remains common in children, primarily attributable to practical, ethical, and financial constraints associated with pediatric drug research. Pharmacometrics, the scientific discipline that involves the application of mathematical models to understand and quantify drug effects, holds promise in advancing pediatric pharmacotherapy by expediting drug development, extending applications, and personalizing dosing. In this review, we delineate the principles of pharmacometrics, and explore its clinical applications and prospects. The fundamental aspect of any pharmacometric analysis lies in the selection of appropriate methods for quantifying pharmacokinetics and pharmacodynamics. Population pharmacokinetic modeling is a data-driven method ('top-down' approach) to approximate population-level pharmacokinetic parameters, while identifying factors contributing to inter-individual variability. Model-informed precision dosing is increasingly used to leverage population pharmacokinetic models and patient data, to formulate individualized dosing recommendations. Physiologically based pharmacokinetic models integrate physicochemical drug properties with biological parameters ('bottom-up approach'), and is particularly valuable in situations with limited clinical data, such as early drug development, assessing drug-drug interactions, or adapting dosing for patients with specific comorbidities. The effective implementation of these complex models hinges on strong collaboration between clinicians and pharmacometricians, given the pivotal role of data availability. Promising advancements aimed at improving data availability encompass innovative techniques such as opportunistic sampling, minimally invasive sampling approaches, microdialysis, and in vitro investigations. Additionally, ongoing research efforts to enhance measurement instruments for evaluating pharmacodynamics responses, including biomarkers and clinical scoring systems, are expected to significantly bolster our capacity to understand drug effects in children.

Pediatric obsessive-compulsive disorder (OCD) is a chronic, potentially debilitating psychiatric condition. Although effective treatments exist, at least 10% of youth do not achieve remission despite receiving first-line treatments. This article reviews the extant, albeit limited, evidence supporting treatment approaches for youth with treatment-resistant OCD. A literature search for articles addressing pediatric treatment-resistant OCD was conducted through April 11, 2024. These results were augmented by searching for treatment-resistant OCD in adults; treatment strategies discovered for the adult population were then searched in the context of children and adolescents. In general, intensive treatment programs and antipsychotic augmentation of an antidepressant had the most substantial and consistent evidence base for treatment-resistant youth with OCD, although studies were limited and of relatively poor methodological quality (i.e., open trials, naturalistic studies). Several pharmacological approaches (clomipramine, antipsychotics [e.g., aripiprazole, risperidone], riluzole, ketamine, D-cycloserine, memantine, topiramate, N-acetylcysteine, ondansetron), largely based on supporting data among adults, have received varying levels of investigation and support. There is nascent support for how to treat pediatric treatment-resistant OCD. Future treatment studies need to consider how to manage the significant minority of youth who fail to benefit from first-line treatment approaches.

Background and objective: Mast cells have been implicated in abdominal pain-associated disorders of gut-brain interaction, such as functional dyspepsia. As such, ketotifen, a second-generation antihistamine and mast cell stabilizer, could represent a viable treatment option in these conditions. The primary aim of the current pilot study was to assess clinical response to ketotifen and assess pharmacokinetics in youth with functional dyspepsia.

Methods: We conducted a pilot randomized, double-blind, placebo-controlled, cross-over trial of ketotifen in 11 youth with functional dyspepsia and duodenal mucosal eosinophilia with 4 weeks of active treatment at a dose of 1 mg twice daily. Global clinical response was graded on a 5-point Likert Scale. A single plasma sample was obtained at steady state for pharmacokinetic analysis.

Results: Ketotifen was not superior to placebo with regard to global clinical response. Only 18% of patients demonstrated a complete or near-complete clinical response. The estimated half-life was 3.3 h.

Conclusions: While ketotifen was not superior to placebo, this study highlights several important challenges for developing drug trials for youth with chronic abdominal pain. Recommendations are made for designing a larger treatment trial for ketotifen in this patient group.

Clinical trial registration: This study was registered at ClinicalTrials.gov: NCT02484248.

Bacterial infection is one of the major causes of neonatal morbidity and mortality worldwide. Finding rapid and reliable methods for early recognition and diagnosis of bacterial infections and early individualization of antibacterial drug administration are essential to eradicate these infections and prevent serious complications. However, this is often difficult to perform due to non-specific clinical presentations, low accuracy of current diagnostic methods, and limited knowledge of neonatal pharmacokinetics. Although neonatal medicine has been relatively late to embrace the benefits of machine learning (ML), there have been some initial applications of ML for the early prediction of neonatal sepsis and individualization of antibiotics. This article provides a brief introduction to ML and discusses the current state of the art in diagnosing and treating neonatal bacterial infections, gaps, potential uses of ML, and future directions to address the limitations of current studies. Neonatal bacterial infections involve a combination of physiologic development, disease expression, and treatment response outcomes. To address this complex relationship, future models could consider appropriate ML algorithms to capture time series features while integrating influences from the host, microbes, and drugs to optimize antimicrobial drug use in neonates. All models require prospective clinical trials to validate their clinical utility before clinical use.

Inotuzumab ozogamicin (BESPONSA™) is a CD22-targeted monoclonal antibody drug conjugate (ADC) developed by Pfizer for the treatment of CD22-postive B-cell precursor acute lymphoblastic leukaemia (ALL). Inotuzumab ozogamicin comprises a humanized IgG4 anti-CD22 monoclonal antibody covalently linked to the potent DNA-binding cytotoxic agent N-acetyl-gamma-calicheamicin dimethylhydrazide (CalichDMH) via a linker. Inotuzumab ozogamicin binds to CD22-expressing tumour cells, facilitating the delivery of conjugated CalichDMH, which after intracellular activation induces double strand DNA breaks, ultimately leading to cell cycle arrest and apoptotic cell death. Inotuzumab ozogamicin is approved in the USA, Europe and several countries worldwide for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in adults. On 6 March 2024, inotuzumab ozogamicin received its first pediatric approval in the USA for this indication in patients aged ≥ 1 years. Inotuzumab ozogamicin has since been approved in Japan in March 2024 for the same indication in pediatric patients. This article summarizes the milestones in the development of inotuzumab ozogamicin leading to this first approval for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in pediatric patients.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a potentially serious and life-threatening complication of SLE. The presentation and severity of neuropsychiatric involvement in SLE may show considerable variability. The disease can affect the neural tissue directly or may be associated with vascular involvement, mainly associated with anti-phospholipid (aPL) antibodies. A direct causal link with SLE may sometimes be challenging since there are many confounding factors and the symptoms may be non-specific. Despite its remarkable sensitivity in detecting hemorrhagic and ischemic stroke, transverse myelitis and ischemic infarction, magnetic resonance imaging (MRI) lacks the spatial resolution required to identify microvascular involvement. When standard MRI fails to detect a suspicious lesion, it is advisable to use advanced imaging modalities such as positron emission tomography (PET), single photon emission computed tomography (SPECT) or quantitative MRI, if available. Even with these advanced modalities, the specificity of neuroimaging in NPSLE remains inadequate (60-82% for MRI). Neuropsychiatric syndromes, such as cerebrovascular events, seizures and cognitive impairments appear to be associated with serum aPL antibodies. Some studies have shown that anti-ribosomal P antibodies have a low sensitivity for NPSLE and a limited contribution to the differentiation of different clinical entities. Treatment has two main goals: symptomatic relief and treatment of the disease itself. Commonly used immunosuppressants for NPSLE include cyclophosphamide (CYC), azathioprine (AZA), and mycophenolate mofetil (MMF). According to EULAR's current recommendation, strong immunosuppressants such as CYC and rituximab (RTX) should be preferred. Biologics have also been used in NPSLE. Fingolimod, eculizumab, and JAK inhibitors are potential drugs in the pipeline. Developing targeted therapies will be possible by a better understanding of the pathological mechanisms.