Showing papers in "Pediatric Drugs in 2018"
TL;DR: With few downsides and the potential for disease cures, immunotherapy in the pediatric population has the potential to move to the front-line of therapeutic options.
Abstract: Cancer immunotherapies, widely heralded as transformational for many adult cancer patients, are becoming viable options for selected subsets of pediatric cancer patients. Many therapies are currently being investigated, from immunomodulatory agents to adoptive cell therapy, bispecific T-cell engagers, oncolytic virotherapy, and checkpoint inhibition. One of the most exciting immunotherapies recently FDA approved is the use of CD19 chimeric antigen receptor T cells for pre-B-cell acute lymphoblastic leukemia. With this approval and others, immunotherapy for pediatric cancers is gaining traction. One of the caveats to many of these immunotherapies is the challenge of predictive biomarkers; determining which patients will respond to a given therapy is not yet possible. Much research is being focused on which biomarkers will be predictive and prognostic for these patients. Despite many benefits of immunotherapy, including less long-term side effects, some treatments are fraught with immediate side effects that range from mild to severe, although most are manageable. With few downsides and the potential for disease cures, immunotherapy in the pediatric population has the potential to move to the front-line of therapeutic options.
81 citations
TL;DR: Two additional live, oral rotavirus vaccines were recently licensed and these have improved on some programmatic limitations of earlier vaccines, such as heat stability, cost, and cold-chain footprint, and have the potential to reduce the performance differential and safety concerns associated with live oral rotvirus vaccines.
Abstract: Rotavirus is the leading cause of diarrheal death among children 65% of children had at least one rotavirus diarrhea illness by 5 years of age and rotavirus accounted for > 40% of all-cause diarrhea hospitalizations globally. Two live, oral rotavirus vaccines have been implemented nationally in > 100 countries since 2006 and their use has substantially reduced the burden of severe diarrheal illness in all settings. Vaccine efficacy and effectiveness estimates suggest there is a gradient in vaccine performance between low child-mortality countries (> 90%) and medium and high child-mortality countries (57–75%). Additionally, an increased risk of intussusception (~ 1–6 per 100,000 vaccinated infants) following vaccination has been documented in some countries, but this is outweighed by the large benefits of vaccination. Two additional live, oral rotavirus vaccines were recently licensed and these have improved on some programmatic limitations of earlier vaccines, such as heat stability, cost, and cold-chain footprint. Non-replicating rotavirus vaccines that are parenterally administered are in clinical testing, and these have the potential to reduce the performance differential and safety concerns associated with live oral rotavirus vaccines.
70 citations
TL;DR: Potential vancomycin targets varied based on the population studied but, for general hospitalized pediatric patients, troughs of 6–10 mg/l are likely sufficient to achieve AUC/MIC ≥ 400.
Abstract: In adults, the area under the concentration–time curve (AUC) divided by the minimum inhibitory concentration (MIC) is associated with better clinical and bacteriological response to vancomycin in patients with methicillin-resistant Staphylococcus aureus who achieve target AUC/MIC ≥ 400. This target is often extrapolated to pediatric patients despite the lack of similar evidence. The impracticalities of calculating the AUC in practice means vancomycin trough concentrations are used to predict the AUC/MIC. This review aimed to determine the relationship between vancomycin trough concentrations and AUC/MIC in pediatric patients. We searched the MEDLINE and Embase databases, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials using the medical subject heading (MeSH) terms vancomycin and AUC and pediatric* or paediatric*. Articles were included if they were published in English and reported a relationship between vancomycin trough concentrations and AUC/MIC. Of 122 articles retrieved, 11 met the inclusion criteria. One trial reported a relationship between vancomycin trough concentrations, AUC/MIC, and clinical outcomes but was likely underpowered. Five studies found troughs 6–10 mg/l were sufficient to attain an AUC/MIC > 400 in most general hospitalized pediatric patients. One study in patients undergoing cardiothoracic surgery found a trough of 18.4 mg/l achieved an AUC/MIC > 400. Two oncology studies reported troughs ≥ 15 mg/l likely attained an AUC/MIC ≥ 400. In critical care patients: one study found a trough of 9 mg/l did not attain the AUC/MIC target; another found 7 mg/l corresponded to an AUC/MIC of 400. Potential vancomycin targets varied based on the population studied but, for general hospitalized pediatric patients, troughs of 6–10 mg/l are likely sufficient to achieve AUC/MIC ≥ 400. For MIC ≥ 2 mg/l, higher troughs are likely necessary to achieve an AUC/MIC ≥ 400. More research is needed to determine the relationships between vancomycin trough concentrations, AUC/MIC, and clinical outcomes.
41 citations
TL;DR: Oral pyridostigmine was found to be helpful in children with different GI motility problems and should be considered in such patients when other treatment interventions have not been beneficial.
Abstract: Gastrointestinal (GI) motility disorders are common in children. Treatment is challenging with limited medical and surgical options. Pyridostigmine, an acetyl cholinesterase inhibitor, increases acetylcholine at the neuromuscular junction promoting intestinal contractions. Little is known about the role and dosing of pyridostigmine in pediatric GI motility disorders. We present a case series of children with GI dysmotility managed with oral pyridostigmine. Patients’ diagnoses include chronic intestinal pseudo-obstruction, gastroparesis with delayed small bowel transit, chronic constipation with failure to thrive, and prolonged ileus after pelvic surgery with chronic opioid use. Pyridostigmine was effective and safe in all cases. Pyridostigmine decreased abdominal distention, increased bowel movement frequency, and improved enteral feeding tolerance. Effective dosing ranged between 0.25–2.0 mg/kg/day. One patient experienced cramping abdominal pain while on pyridostigmine, but pain resolved after medication was discontinued. We found oral pyridostigmine to be helpful in children with different GI motility problems. Pyridostigmine should be considered in such patients when other treatment interventions have not been beneficial.
40 citations
TL;DR: PEACE concluded that extrapolation of efficacy data in adults to pediatrics in FOS is supported by strong scientific and clinical evidence, however, safety and pharmacokinetic data cannot be extrapolated from adults to children.
Abstract: Most antiepileptic drugs (AEDs) receive regulatory approval for children years after the drug is available in adults, encouraging off-label use of the drug in children and hindering attempts to obtain quality pediatric data in controlled trials. Extrapolating adult efficacy data to pediatrics can reduce the time between approval in adults and that in children. To extrapolate efficacy from adults to children, several assumptions must be supported, such as (1) a similar disease progression and response to interventions in adults and children, and (2) similar exposure response in adults and children. The Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE) addressed these assumptions in focal-onset seizures (FOS), the most common seizure type in both adults and children. PEACE reviewed the biological and clinical evidence that supported the assumptions that children with FOS have a similar disease progression and response to intervention as adults with FOS. After age 2 years, the pathophysiological underpinnings of FOS and the biological milieu in which seizures are initiated and propagated in children, seizure semiology, electroencephalographic features, etiology and AED response to FOS in children are similar to those in adults with FOS. PEACE concluded that extrapolation of efficacy data in adults to pediatrics in FOS is supported by strong scientific and clinical evidence. However, safety and pharmacokinetic (PK) data cannot be extrapolated from adults to children. Based on extrapolation, eslicarbazepine is now approved for children with FOS, down to age 4 years. Perampanel, lacosamide and brivaracetam are now undergoing PK and safety studies for the purposes of extrapolation down to age 2 or 4 years. When done in conjunction with PK and safety investigations in children, extrapolation of adult data from adults to children can reduce the time delay between approval of effective and safe AEDs in adults and approval in children.
31 citations
TL;DR: Commentary on the last ESPGHAN/NASPGHAN guidelines and on publications made after the consensus conference of 2015 provides commentary on the role of H. pylori infection in failure to thrive, children’s growth, type I diabetes mellitus (T1DM), and celiac disease remains controversial.
Abstract: Helicobacter pylori infection is acquired mainly in childhood and remains an essential cause of peptic ulcer disease and gastric cancer. This article provides commentary on the last ESPGHAN/NASPGHAN guidelines and on publications made after the consensus conference of 2015. The majority of infected children are asymptomatic and pediatric studies do not support a role for H. pylori in functional disorders such as recurrent abdominal pain. The role of H. pylori infection in failure to thrive, children's growth, type I diabetes mellitus (T1DM), and celiac disease remains controversial. The diagnosis of infection should be based on upper-digestive endoscopy with biopsy-based methods. Eradication control after treatment should be based on validated non-invasive tests. Nodular gastritis is the main endoscopic finding of childhood H. pylori infection, but gastroduodenal erosions/ulcers are seen in some children, especially after 10 years of age. When indicated, eradication treatment should be given when good compliance is expected and based on the antimicrobial susceptibility profile.
29 citations
TL;DR: The purpose of this report was to review the state of asthma diagnosis and treatment in China and to examine challenges in achieving earlier diagnosis andreatment and to address a number of issues remain to be addressed.
Abstract: The purpose of this report was to review the state of asthma diagnosis and treatment in China and to examine challenges in achieving earlier diagnosis and treatment. The prevalence of asthma in children in China has increased over past decades, and data published in 2013 indicated a prevalence of 3.0% in children aged 0-14 years. Although this prevalence has increased, the percentage of children with acute asthma attacks decreased from 86% in 2000 to 77% in 2010, and the frequency of hospitalizations for asthma attacks decreased from 54.0 to 47%. These decreases are attributed to aggressive promotion of the Global Initiative for Asthma (GINA) protocol and updated Chinese guidelines for the prevention and treatment of asthma in children. The use of inhaled corticosteroids increased and that of systemic corticosteroids decreased between 2000 and 2010. Despite these advances, a number of issues remain to be addressed. Parents lack basic knowledge of asthma and fear the use of corticosteroids. Physician education regarding the diagnosis of asthma in children aged < 6 years is lacking. Patients require training in the administration of inhaled corticosteroids and control of environmental triggers. The Chinese national guidelines for childhood asthma have been updated, but implementation remains a real challenge.
29 citations
TL;DR: The importance of the bio-psychosocial approach is highlighted, as a majority of children will improve with counselling and reassurance that no serious organic pathologies are suspected, especially when the physician establishes a trustful relationship with both the child and their family.
Abstract: Recurrent abdominal pain (RAP) is one of the most common health complaints in both children and adults. Although RAP is considered a functional disorder rather than an organic disease, affected children and their families can still experience anxiety and concerns that can interfere with school, sports, and regular daily activities and lead to frequent attendances at pediatric emergency departments or pediatric gastroenterology clinics. Our review shows experts do not agree on a universally proven management that will work on every child presenting with functional abdominal pain (FAP). Treatment strategies include both non-pharmacological and pharmacological options. Non-pharmacological treatments are usually very well accepted by both children and their parents and are free from medication side effects. Nevertheless, they may be as effective as the pharmacological interventions; therefore, according to many experts and based on the majority of current evidence, a non-pharmacological approach should be the first intervention attempt in children with RAP. In particular, the importance of the bio-psychosocial approach is highlighted, as a majority of children will improve with counselling and reassurance that no serious organic pathologies are suspected, especially when the physician establishes a trustful relationship with both the child and their family. Placebo and pharmacological interventions could be attempted when the bio-psychosocial approach is not applicable or not efficacious. In some difficult cases, finding an effective treatment for FAP can be a challenge, and a number of strategies may need to be tried before symptoms are controlled. In these cases, a multidisciplinary team, comprising a pediatric gastroenterologist, dietician, psychologist, and psychotherapist, is likely to be successful.
27 citations
TL;DR: Alginate significantly decreases the number and extension of both acid and non-acid reflux episodes and associated symptoms in infants, and is associated with improved crying-fussiness, cough and regurgitation episodes.
Abstract: Guidelines are contradictory regarding the use of alginate in infants with persisting gastroesophageal reflux (GER). While The British National Institute for Health and Care (NICE) guidelines consider alginate as a treatment option, the guidelines of the European and North-American Societies for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN, NASPGHAN) do not recommend alginates. We assessed the efficacy of alginate to reduce GER episodes in infants. In a prospective, observational study, we consecutively enrolled all infants referred for pH-multiple intraluminal impedance (pH-MII) recording because of persisting GER symptoms not responsive to behavior and dietetic modifications. A 48-h pH-MII was performed in all infants; a baseline recording was performed during the first 24 h while magnesium or sodium alginate was administered during the second 24 h. The primary endpoint was the difference in the total number of GER episodes per 24 h between the baseline day and the second day during which the alginate was administered. The secondary outcome was the difference in symptoms between each period. We also compared other pH-MII data from before and during alginate administration. We recruited 43 infants (median age 68 days, range 25–306); three pH-MII tracings were excluded because of artifacts. The median number of all MII reflux episodes was significantly reduced during alginate administration (76.0 vs 69.5; p 10% during the alginate period in 31/40 infants (77.5%), without a significant difference between magnesium and sodium alginate. These results suggest that alginate significantly decreases the number and extension of both acid and non-acid reflux episodes and associated symptoms in infants.
24 citations
TL;DR: The mechanism of action, pharmacokinetics, drug–drug interactions, and safety/tolerability profiles of the main AEDs currently used in children and adolescents are reviewed, paying particular regard to issues of relevance when treating this patient population.
Abstract: Selecting the most appropriate antiepileptic drug (AED) or combination of drugs for each patient and identifying the most suitable therapeutic regimen for their needs is increasingly challenging, especially among pediatric populations. In fact, the pharmacokinetics of several drugs vary widely in children with epilepsy because of age-related factors, which can influence the absorption, distribution, metabolism, and elimination of the pharmacological agent. In addition, individual factors, such as seizure type, associated comorbidities, individual pharmacokinetics, and potential drug interactions, may contribute to large fluctuations in serum drug concentrations and, therefore, clinical response. Therapeutic drug concentration monitoring (TDM) is an essential tool to deal with this complexity, enabling the definition of individual therapeutic concentrations and adaptive control of dosing to minimize drug interactions and prevent loss of efficacy or toxicity. Moreover, pharmacokinetic/pharmacodynamic modelling integrated with dashboard systems have recently been tested in antiepileptic therapy, although more clinical trials are required to support their use in clinical practice. We review the mechanism of action, pharmacokinetics, drug-drug interactions, and safety/tolerability profiles of the main AEDs currently used in children and adolescents, paying particular regard to issues of relevance when treating this patient population. Indications for TDM are provided for each AED as useful support to the clinical management of pediatric patients with epilepsy by optimizing pharmacological therapy.
22 citations
TL;DR: The results appear to indicate that adult dosages of metformin could be considered in obese adolescents if pediatric dosages have been therapeutically ineffective.
Abstract: In view of the increased use of metformin in obese adolescents, the aim of this study was to determine the pharmacokinetics of metformin in overweight and obese adolescents. In overweight and obese adolescents receiving metformin 500 or 1000 mg twice daily for 37 weeks during a clinical trial, blood samples were collected over 8 h during an oral glucose tolerance test. Population pharmacokinetic modeling was performed using NONMEM. Data for 22 overweight and obese adolescents with a mean total body weight (TBW) of 79.3 kg (range 54.7–104.9), body mass index (BMI) of 29.1 kg/m2 (range 22.9–39.3), and age of 15.9 years (range 11.1–17.5) were analysed. In the model, oral clearance (CL/F) of metformin (1.17 l/min [relative standard error of 6%]) increased significantly with TBW (p < 0.01). More specifically, CL/F increased with both developmental weight (WTfor age and length) and excess body weight (WTexcess), for which an excess weight covariate model was proposed. The CL/F of metformin in obese adolescents (1.17 l/min) is larger than that in non-obese children (0.55 l/min) and similar to that in adults (1.3 l/min) as reported in the literature. This increase may potentially be explained by increased tubular secretion of metformin. These results appear to indicate that adult dosages of metformin could be considered in obese adolescents if pediatric dosages have been therapeutically ineffective. NCT01487993.
TL;DR: Most children and adolescents with RLS and PLMD have low iron storage; therefore, iron therapy should be considered as the first line of treatment in children.
Abstract: Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are under-recognized sleep disorders in children and adolescents. Several recent epidemiological studies have shown that RLS and PLMD are common in the pediatric population, and if left untreated, may lead to cardiovascular and neurocognitive consequences. Therefore, early diagnosis and intervention may help preventing long-term consequences. The management of RLS and PLMD in children involves both non-pharmacologic and pharmacologic approaches. Although there is emerging literature supporting medical therapy in children with RLS and PLMD, the overall experiences with these medications remain limited. Most children and adolescents with RLS and PLMD have low iron storage; therefore, iron therapy should be considered as the first line of treatment in children. Currently, there is no FDA-approved medication for RLS and PLMD in children. There is increasing evidence on the effectiveness of dopaminergic medications in children but the data are quite limited. Other medications such as α2δ-1 ligands, benzodiazepine, and clonidine are frequently used, but have not been adequately investigated in children. Further studies are needed to evaluate the safety and efficacy of pharmacologic therapy for RLS and PLMD in children.
TL;DR: The pragmatic consensus decision to use 50% of the conventional intrathecal dose of methotrexate when it is administered via Ommaya reservoir in front-line ALL therapy is summarised.
Abstract: Prophylactic eradication of central nervous system (CNS) leukaemia is the current standard of care in treating childhood acute lymphoblastic leukaemia (ALL). This is conventionally achieved through regular lumbar punctures with intrathecal injections of methotrexate into the cerebrospinal fluid (CSF). Ommaya reservoirs are subcutaneous implantable devices that provide a secure route of drug delivery into the CSF via an intraventricular catheter. They are an important alternative in cases where intrathecal injection via lumbar puncture is difficult. Among UK Paediatric Principal Treatment Centres for ALL we found considerable variation in methotrexate dosing when using an Ommaya reservoir. We review the current safety and theoretical considerations when using Ommaya reservoirs and evidence for methotrexate dose adjustments via this route. We conclude by summarising the pragmatic consensus decision to use 50% of the conventional intrathecal dose of methotrexate when it is administered via Ommaya reservoir in front-line ALL therapy.
TL;DR: Retrospective analysis of SAEs occurring during treatment with anti-TNF-α agents in patients with juvenile idiopathic arthritis (JIA) or pediatric-onset inflammatory bowel disease (IBD) and at the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” in Trieste, Italy, between June 2001 and February 2016 found anti-tumor necrosis factor alpha therapy was generally well tolerated.
Abstract: Anti-tumor necrosis factor alpha (anti-TNF-α) agents are generally well tolerated, yet they can be associated with serious adverse events (SAEs) in a minority of patients. We examined the incidence of SAEs in a pediatric referral center for chronic rheumatologic and gastroenterological inflammatory disorders. Retrospective analysis of SAEs occurring during treatment with anti-TNF-α agents in patients with juvenile idiopathic arthritis (JIA) (n = 78) or pediatric-onset inflammatory bowel disease (IBD) (n = 105) seen at the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” in Trieste, Italy, between June 2001 and February 2016. Only SAEs grade 3–5 according to the Common Terminology Criteria for Adverse Events version 4.03 and/or requiring definitive therapy discontinuation were reported. Total anti-TNF-α exposure was 390.5 patient-years (PYs). The overall incidence rate of SAEs for etanercept was 4.14/100 PYs. Four patients developed uveitis, two had anxiety disorders, one had a serious zoster infection, and one developed TNF-α antagonist–induced lupus-like syndrome (TAILS). The overall incidence rate of SAEs for infliximab was 22.49/100 PYs. The most common SAEs were anaphylactoid reactions (n = 18), followed by infectious events (n = 9) and TAILS (n = 3). The overall incidence rate of SAEs for adalimumab was 4.71/100 PYs (two infectious SAEs). No malignancies or deaths were observed. A greater incidence rate of infectious SAEs was observed in IBD patients receiving infliximab compared to JIA patients receiving etanercept (8.11 vs 0.52 per 100 PYs). Anti-TNF-α therapy was generally well tolerated. SAEs leading to anti-TNF-α discontinuation were rare and non-fatal. Infliximab was associated with the highest incidence of SAEs. Infectious SAEs were more frequently observed in IBD patients treated with infliximab than in JIA patients receiving etanercept.
TL;DR: There is support for the safety and efficacy of methadone in treating pain in children with cancer, particularly when pain is refractory to conventional treatment, but further evaluation with prospective studies is warranted to develop evidence-based recommendations.
Abstract: Methadone is a synthetic opioid with unique pharmacodynamic and pharmacokinetic properties. It is effective in treating both nociceptive and neuropathic pain, which commonly co-exist in children with cancer. Upon reviewing the literature describing the use of methadone in pediatric oncology patients, publications are limited in number and low in quality of evidence; nevertheless, there is support for the safety and efficacy of methadone in treating pain in children with cancer, particularly when pain is refractory to conventional treatment. Although the risk of life-threatening arrhythmia is commonly cited as an argument against the use of methadone, our review of the literature did not support this finding in children. Further evaluation with prospective studies is warranted to develop evidence-based recommendations for the use of methadone in pediatric oncology.
TL;DR: The literature on resistant Kawasaki disease should be interpreted with reference to current expert consensus guidelines, and few trial data, and studies tend to be small and methodologically heterogeneous, making interpretation difficult and limiting generalisability.
Abstract: "Resistant" Kawasaki disease is defined by the American Heart Association as failure to respond within 36 h following the first dose of intravenous immunoglobulin. The optimal management of resistant Kawasaki disease remains uncertain, the outcomes are potentially serious, and the cost of some treatments is considerable. We review the current evidence to guide treatment of resistant Kawasaki disease. Given the relative rarity, there are few trial data, and studies tend to be small and methodologically heterogeneous, making interpretation difficult and limiting generalisability. The literature on resistant Kawasaki disease should be interpreted with reference to current expert consensus guidelines.
TL;DR: Vilazodone was generally safe and well tolerated, with treatment-emergent AEs similar to those in adult patients, and suicidal behavior in adolescent patients could not be confirmed in this study.
Abstract: Major depressive disorder (MDD) is a serious illness in children and adolescents. Vilazodone is a selective serotonin reuptake inhibitor approved for MDD in adults. This study evaluated the efficacy, safety, and tolerability of vilazodone in adolescent patients, ages 12–17 years, with MDD (NCT01878292). This double-blind, randomized, placebo-controlled, parallel-group, fixed-dose study was conducted at 56 study centers in the United States and was 10 weeks in duration (a 1-week screening period, an 8-week double-blind treatment period, and a 1-week double-blind down-taper period). Outpatients with an MDD diagnosis based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria were included in the study. Clinical inclusion criteria required a Children’s Depression Rating Scale–Revised (CDRS-R) total score of ≥ 40 and Clinical Global Impressions–Severity (CGI-S) score of ≥ 4. Patients were randomized 1:1:1 to 8 weeks of double-blind treatment with placebo (n = 174), vilazodone 15 mg/day (n = 175), or vilazodone 30 mg/day (n = 180). The primary and secondary efficacy parameters were change from baseline to week 8 in CDRS-R total score and CGI-S score, respectively. Safety parameters included adverse events (AEs); clinical laboratory, vital sign, and electrocardiogram parameters; and the Columbia-Suicide Severity Rating Scale. Approximately 86% of patients completed double-blind treatment. There was no statistically significant difference between vilazodone 15 mg/day or 30 mg/day and placebo in change from baseline in CDRS-R score. Change in CGI-S score was not significant after adjustment for multiple comparisons. The most common treatment-emergent AEs were nausea, upper abdominal pain, vomiting, diarrhea, nasopharyngitis, headache, and dizziness. Reports of suicidal ideation (placebo, 33.3%; vilazodone 15 mg/day, 36.0%; vilazodone 30 mg/day, 31.1%) and suicidal behavior (placebo, 1.8%; vilazodone 15 mg/day, 1.1%; vilazodone 30 mg/day, 1.1%) were similar between treatment groups. There were no deaths in the study. The efficacy of vilazodone for the treatment of MDD in adolescent patients could not be confirmed in this study. Vilazodone was generally safe and well tolerated, with treatment-emergent AEs similar to those in adult patients. NCT01878292.
TL;DR: Palivizumab was generally safe and effective for the prevention of LRI caused by RSV in newborns, infants, and children with immunocompromised conditions or Down syndrome up to the age of 24 months.
Abstract: The aim of this study was to assess the safety and effectiveness of palivizumab for the prevention of lower respiratory tract infection (LRI) caused by respiratory syncytial virus (RSV) in children with immunocompromised conditions or Down syndrome. In this multicenter, post-marketing surveillance study (December 2013 to December 2015), children aged ≤24 months with immunocompromised conditions or Down syndrome (without hemodynamically significant congenital heart disease) receiving palivizumab immunoprophylaxis during two RSV seasons were observed until 30 days after the final palivizumab injection. Safety [adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs)] and effectiveness (frequency, incidence, and duration of hospitalization due to RSV infections) were assessed. Of 304 patients receiving palivizumab, 167 (54.9%) had immunocompromised conditions, and 138 (45.4%) had Down syndrome; 260 (85.5%) completed palivizumab immunoprophylaxis. The annual mean (±standard deviation) number of doses was 5.3 (±2.4) per season. Overall, 220 AEs occurred in 99 patients (32.6%), including 89 SAEs in 53 patients (17.4%). Of these, 33 AEs in 25 patients (8.22%) were considered ADRs, and 13 ADRs in 11 patients (3.62%) were considered SADRs. In four patients, five SADRs (nephroblastoma and asthma in the same patient, septic shock, device-related infection, and drug-induced liver injury) were previously unreported; however, none were considered drug-related. During the observation period, five RSV infections occurred and two patients required hospitalization. Palivizumab was generally safe and effective for the prevention of LRI caused by RSV in newborns, infants, and children with immunocompromised conditions or Down syndrome up to the age of 24 months.
TL;DR: The epidemiology, pathophysiology, and extrahepatic comorbidities of pediatric NAFLD are discussed, existing therapeutic options for children with NAFLd are reviewed, and novel therapeutic strategies studied in adults that could potentially be studied in children in the future are reviewed.
Abstract: The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased substantially in the past two decades and NAFLD has now become the most common cause of chronic liver disease in children and adolescents. NAFLD is a broad clinicopathologic spectrum ranging from simple steatosis to varying degrees of necroinflammation called nonalcoholic steatohepatitis (NASH), leading to fibrosis and subsequently to cirrhosis. Despite the increasing prevalence and progressive nature of NAFLD even among children, therapy for NAFLD in both adults and children are limited. Weight loss remains the only consistently effective therapy for NAFLD. Pharmacologic options are even more limited in children than in adults with NAFLD. Vitamin E has been shown to be effective in improving histology in children with NASH. Few pharmacologic options such as metformin, probiotics, omega-3 fatty acids, and cysteamine bitartrate have been studied in children, with limited beneficial effects. However, these studies are limited by small sample size and heterogeneity of outcome assessment after treatment. Recent studies show promising results with bariatric surgery with regards to weight loss and improvement in liver histology in adolescents with NAFLD. In this review article, we discuss epidemiology, pathophysiology, and extrahepatic comorbidities of pediatric NAFLD and review existing therapeutic options for children with NAFLD. We also review novel therapeutic strategies studied in adults that could potentially be studied in children in the future.
TL;DR: Evidence affirms that lithium is effective for pediatric bipolar disorder in multiple phases of the illness, and its tolerability has been shown to be comparable with more commonly prescribed medications.
Abstract: Lithium has been an intriguing treatment option in psychiatry for over a century. While seemingly just a simple elemental compound, it has powerful treatment effects for both depression and bipolar disorder. The evidence base for treatment of pediatric bipolar disorder is relatively small, but, in recent years, additional clinical trial data have enabled lithium to re-emerge as a valuable and, in many cases, preferred treatment. Pharmacologically, lithium is complex, with varied effects at both intracellular and extracellular levels. As a treatment for bipolar disorder in pediatrics, lithium is challenging, given its narrow therapeutic window and myriad of potential side effects. However, the efficacy of lithium continues to match that of newer pharmacologic agents, and its tolerability has been shown to be comparable with more commonly prescribed medications. Lithium is still one of few drugs that have been proven to reduce the risk of suicidality, and it may have utility in illnesses beyond affective disorders. Practically, as a primary agent or as an adjunct, lithium continues to claim a rightful place in the treatment armamentarium of child psychiatry. New dosing paradigms have improved tolerability and reduced potential side effects. Recent evidence affirms that lithium is effective for pediatric bipolar disorder in multiple phases of the illness.
TL;DR: Dasatinib therapy in pediatric patients with Ph+ CML-CP was reported to have a similar safety profile to that observed in adults, except there were no occurrences of pleural effusions, pericardial effusion, pulmonary edema, or pulmonary hypertension adverse events.
Abstract: Chronic myeloid leukemia (CML) is a rare hematopoietic stem cell disease that is typically characterized by the abnormal BCR-ABL1 fusion gene on the Philadelphia (Ph) chromosome in neoplastic cells. Dasatinib (Sprycel®) is an orally administered, small molecule tyrosine kinase inhibitor indicated for the treatment of certain hematological malignancies, including Ph-positive CML in the chronic phase (Ph+ CML-CP) in adult and pediatric patients. In open-label phase 1 and phase 2 clinical trials, dasatinib produced early and durable target responses (i.e. molecular, cytogenetic and/or hematologic) in pediatric patients with Ph+ CML-CP that was newly diagnosed or resistant/intolerant to imatinib, with some recipients of the drug also experiencing deep molecular responses. Dasatinib therapy in pediatric patients with Ph+ CML-CP was reported to have a similar safety profile to that observed in adults, except there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, or pulmonary hypertension adverse events. Although long-term outcomes remain to be determined, dasatinib expands the first- and second-line options available for the treatment of Ph+ CML-CP in pediatric patients.
TL;DR: The data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantiprazole AUC0–∞ remained using this dosing approach.
Abstract: Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation. Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6–17 years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM®). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios. A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC0–∞)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children. Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC0–∞ remained using this dosing approach.
TL;DR: The mechanisms of pain associated with acute VOC are reviewed, the current management of VOC is described, and some of the new therapies under evaluation for the management of acute V OC in SCD are described.
Abstract: Acute vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Multiple complex pathophysiological processes can result in pain during a VOC. Despite significant improvements in the understanding and management of SCD, little progress has been made in the management of pain in SCD, although new treatments are being explored. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment of VOC pain, but new classes of drugs are being tested to prevent and treat acute pain. Advancements in the understanding of the pathophysiology of SCD and pain and the pharmacogenomics of opioids have yet to be effectively utilized in the management of VOC. Opioid tolerance and opioid-induced hyperalgesia are significant problems associated with the long-term use of opioids, and better strategies for chronic pain therapy are needed. This report reviews the mechanisms of pain associated with acute VOC, describes the current management of VOC, and describes some of the new therapies under evaluation for the management of acute VOC in SCD.
TL;DR: New treatment principles using FVIII mimetics or monoclonal antibodies that rebalance the pro- and anti-coagulation system by interfering with production of anti-thrombin or tissue factor pathway inhibitor have the benefits of long-lasting activity, subcutaneous administration, and being useful in patients both with and without neutralizing antibodies.
Abstract: Regular prophylactic treatment with factor VIII (FVIII) and factor IX (FIX) concentrates in hemophilia A and B, respectively, is introduced in early infancy and has resulted in dramatic improvement of the conditions. Recombinant FVIII and FIX concentrates have been available for > 25 years and have been modified and refined through the years; however, unfortunately frequent intravenous administrations are still necessary. The half-lives of these products have now been extended (EHL) by fusion with albumin, the Fc-portion of IgG, or by being PEGylated. This has been very successful for EHL-FIX, with 3–5 times longer half-life, and to a lesser degree for EHL-FVIII with a half-life extension of only 1.5 times the conventional products. New treatment principles using FVIII mimetics or monoclonal antibodies that rebalance the pro- and anti-coagulation system by interfering with production of anti-thrombin or tissue factor pathway inhibitor have the benefits of long-lasting activity, subcutaneous administration, and being useful in patients both with and without neutralizing antibodies. As the ultimate treatment, recent progress has also been made with gene therapy of both hemophilia A and B.
TL;DR: The findings indicate areas for further research focusing on inappropriate prescribing to children and safety issues in children’s medicine use and monitoring changing patterns of use over time is important for the evaluation of effective therapies in children and any potential harmful consequences of prescribing.
Abstract: Research examining trends in the outpatient prescription medicine use of New Zealand children is limited. Our objective was to provide an overview of prescription medicine use in New Zealand children and assess changing patterns in use from 2010 to 2015. We conducted a retrospective cohort study including all New Zealand primary care-registered children aged < 18 years using data from the national pharmaceutical claims database. We calculated the prevalence of use within four age groups in each year by anatomical therapeutic class, therapeutic group and drug. Rate ratios were calculated to compare the prevalence of use in 2010 and 2015. In total, 1,496,026 children with a mean of 2.7 years of potential drug exposure were included. The overall prevalence of drug use was 70% in 2010 and 73% in 2015. In 2015, medicine use was highest in children aged < 2 years (90%) and lowest in children aged 12–17 years (65%). Antibacterials, analgesics, topical corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and antihistamines were the most widely used medicines. The prevalence of use of systemic and topical antibiotics decreased by 2 and 10%, respectively, between 2010 and 2015, but there was increased use of analgesics (10%), NSAIDs (39%), antihistamines (15%) and antinausea and vertigo agents (306%). Our findings indicate areas for further research focusing on inappropriate prescribing to children and safety issues in children’s medicine use. Monitoring changing patterns of use over time is important for the evaluation of effective therapies in children and any potential harmful consequences of prescribing.
TL;DR: Simulation results indicated that amikacin 20 mg/kg once daily provided a higher probability of target attainment with lower toxicity than dosing three times daily, and combination therapy is recommended for pathogens with an MIC of ≥ 8 mg/l.
Abstract: Our objective was to determine the population pharmacokinetic parameters of amikacin in pediatric patients to contribute to the future development of a revised optimum dose and population-specific dosing regimens. We performed a retrospective chart review in non-critical pediatric patients (aged 1–12 years) who received amikacin for suspected or proven Gram-negative infection at a university hospital. The population pharmacokinetic models were developed using Monolix 4.4. Pharmacokinetic/pharmacodynamic (PK/PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. The analysis included 134 amikacin plasma concentrations from 67 patients with a mean ± standard deviation age of 4.1 ± 3.9 years and bodyweight of 15 ± 8.4 kg. The patients received an amikacin total daily dose (TDD) of 23 ± 7.3 mg/kg, which resulted in peak and trough concentrations of 20.65 ± 7.6 and 2.4 ± 1.7 mg/l, respectively. The estimated pharmacokinetic parameters for amikacin were 1.2 l/h and 6.5 l for total body clearance (CL) and the volume of distribution (V), respectively. Dosing simulations showed that the standard dosing regimen (15 mg/kg/day) of amikacin achieved the PK/PD target of peak serum concentration (Cpeak)/minimum inhibitory concentration (MIC) ≥ 8 for an MIC of 2 mg/l; higher doses were required to achieve higher MIC values. The simulation results indicated that amikacin 20 mg/kg once daily provided a higher probability of target attainment with lower toxicity than dosing three times daily. In addition, combination therapy is recommended for pathogens with an MIC of ≥ 8 mg/l.
TL;DR: A paucity of data has revealed regarding the use of histamine-2 receptor antagonists and proton pump inhibitors in infants despite the absence of well-controlled clinical studies, the prescription rate of these medications has increased internationally.
Abstract: Gastroesophageal reflux (GER) is the retrograde movement of gastric (and sometimes duodenal) contents into the esophagus. While the majority of GER is physiologic, for patients, it can be associated with symptoms. While some symptoms are merely bothersome (crying), others can be life threatening (cough, gagging, choking). The main driver of GER in infants is the frequent feedings that produce increased intra-abdominal pressure, which is known to trigger transient relaxations of the lower esophageal sphincter. The recent 2018 clinical practice guidelines reported by the North American and European Societies for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN/ESPGHAN) have recommended non-pharmacologic management initially with subsequent consideration of brief trials with acid suppressants. The main target for these acid suppressants is the gastric parietal cells. Our review of the literature has revealed a paucity of data regarding the use of histamine-2 receptor antagonists and proton pump inhibitors in infants. Despite the absence of well-controlled clinical studies, the prescription rate of these medications has increased internationally. Risks to patients of all ages have become increasingly recognized, with new associations being reported all too often. Here we report our review of all pharmacologic modalities as well as some non-surgical options.
TL;DR: A case-based approach is used to examine appropriate access of children of minor parents in an international vaccine trial and concludes with a set of recommendations to facilitate appropriate access and equity related to the participation ofChildren ofMinor parents in clinical research.
Abstract: Children of minor parents are under-represented in clinical trials. This is largely because of the ethical, legal, and regulatory complexities in the enrolment, consent, and appropriate access of children of minor parents to clinical research. Using a case-based approach, we examine appropriate access of children of minor parents in an international vaccine trial. We first consider the scientific justification for inclusion of children of minor parents in a vaccine trial. Laws and regulations governing consent generally do not address the issue of minor parents. In their absence, local community and cultural contexts may influence consent processes. Rights of the minor parent include dignity in their role as a parent and respect for their decision-making capacity in that role. Rights of the child include the right to have decisions made in their best interest and the right to the highest attainable standard of health. Children of minor parents may have vulnerabilities related to the age of their parent, such as increased rates of poverty, that have implications for consent. Neuroscience research suggests that, by age 12–14 years, minors have adult-level capacity to make research decisions in situations with low emotion and low distraction. We conclude with a set of recommendations based on these findings to facilitate appropriate access and equity related to the participation of children of minor parents in clinical research.
TL;DR: Current experience with immune checkpoint inhibitors, phosphatidyl-inositol-3-kinase inhibitors, and Bruton’s tyrosine kinase inhibitors appear to be very promising new treatment options in adult lymphoma patients.
Abstract: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) comprise approximately 15% of all childhood malignancies. Cure rates for both lymphoma entities have evolved tremendously during the last couple of decades, raising the 5-year survival rates to almost 100% for HL and to 85% for NHL. The mainstay therapy for both malignancies is still chemotherapy-with different regimens recommended for different types of disease. In HL, combined modality treatment, i.e., chemotherapy followed by radiotherapy, has long been the standard regimen. In order to reduce long-term side effects, such as second malignancies, most major pediatric HL consortia have studied response-based radiotherapy reduction strategies over the last 3 decades. For recurrent disease, high-dose chemotherapy followed by an autologous or an allogeneic hematopoietic stem-cell transplant is an option. No targeted agents have yet gained regulatory approval for use in pediatric patients with lymphoma. For adult lymphoma patients, the CD20 antibody rituximab and the CD30 antibody-drug conjugate brentuximab vedotin are targeted agents used regularly in first- and second-line treatment regimens. More recently, immune checkpoint inhibitors, phosphatidyl-inositol-3-kinase inhibitors, and Bruton's tyrosine kinase inhibitors appear to be very promising new treatment options in adult lymphoma. Here, we discuss the current experience with these types of agents in pediatric lymphoma patients.
TL;DR: This review summarizes the properties of the medicinal products currently available for the treatment of C1-INH-HAE, the indications for their use in pediatric patients, and the findings of the clinical trials conducted in this patient population.
Abstract: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a form of bradykinin-mediated angioedema. It is a rare disorder with an onset during childhood in most instances. Therefore, familiarity with the options for the management of pediatric cases is indispensable. The recurrent angioedematous episodes do not respond to conventional treatments and may evolve into a life-threatening condition. In view of the recommendations adopted by international consensus in 2016, patient management and follow-up should be guided by an individualized strategy. During the last decade, various medicinal products with novel modes of action and different posology have been developed for the treatment of C1-INH-HAE. These drugs either inhibit the release of bradykinin (plasma-derived C1-inhibitors, recombinant C1-inhibitors, kallikrein inhibitors) or prevent the released bradykinin from binding to its receptor (bradykinin B2 receptor antagonists). This review summarizes the properties of the medicinal products currently available for the treatment of C1-INH-HAE, the indications for their use in pediatric patients, and the findings of the clinical trials conducted in this patient population. It is concluded by a brief outline of future therapeutic options.