Why are certain age bands used for children in paediatric studies of medicines?

Rational prescribing of medicines requires evidence from clinical trials on efficacy, safety and the dose to be prescribed, based on clinical trials. Regulatory authorities assess these data and information is included in the approved summary of product characteristics. Regulatory guidelines on clinical investigation of medicinal products in the paediatric population generally propose that studies are done in defined age groups but advise that any classification of the paediatric population into age categories is to some extent arbitrary or that the age groups are intended only as a guide. The pharmaceutical companies tend to plan their studies using age groups the regulatory guidelines suggest, to avoid problems when applying for marketing authorisation. These age bands end up in the paediatric label, and consequently into national paediatric formularies. The age bands of the most commonly used age-subsets: neonates, infant/toddlers, children and adolescents, are more historical than based on physiology or normal development of children. Particularly problematic are the age bands for neonates and adolescents. The age of 12 years separating children from adolescents, and the upper limit of the adolescents set by the definition of paediatric age in healthcare, which varies according to the region, are particularly questionable. Modern pharmacometric methods (modelling and simulation) are being increasingly used in paediatric drug development and may allow assessment of growth and/or development as continuous covariables. Maybe time has come to reconsider the rational of the currently used age bands.

Increased acetaminophen related calls to Finnish PIC better reflect acetaminophen sales than serious poisonings.

OBJECTIVE: Acetaminophen (APAP) or paracetamol is a commonly encountered medicine in poisonings. We studied the changes in APAP related calls to the Finnish poison information centre (FPIC), and serious intoxications, involving hepatotoxicity or death in 2001-2014. These data were compared with paracetamol sales in Finland. METHODS: This is a retrospective analysis of the FPIC database calls, national cause of death registry, registries of liver transplantations and molecular adsorbent recycling system (MARS)-treated patients from Helsinki University Hospital together with the National Institute of Health and Welfare registry of patients hospitalized. Data on APAP sales were obtained from the Finnish Medicines Agency. RESULTS: Between 2001 and 2014, the number of calls/year related to human APAP exposures to the FPIC increased from 227 to 1058. No change in the age distribution of enquiries was seen. Most calls involved minors: 58% (range 52-64%) for children under 6 years old, and 9% (range 6-14%) for children of 6-15 years. In Finland, APAP related fatalities have gradually increased from an average of 7/year (range 4-10) in 2000-2005 to an average of 11/year (range 6-17) in 2010-2013, whereas the number of liver transplantations remained low, average 0.6/year (range 0-2). For patients in need of MARS-treatment, a slight decrease was seen. Total APAP sales increased from 5.6 (47% prescription, 53% OTC) to 29.7 (81% prescription, 19% OTC). DDD/1000 inhabitants/day from 2001 to 2014 is recorded. Best linear relationship (R2 = 0.97; p < .001) was observed between total FPIC calls and total sales of APAP in 2001-2014. Fatalities show a weaker relationship with sales (R2 = 0.317; p = .045). CONCLUSIONS: During the study period, we see an increase in FPIC exposure calls accompanied by an increase in APAP sales. Changes in the chosen indicators for serious poisonings show only a weak association. Despite an evident trend between sales and fatalities, the correlation with fatality remains weak due to the small number of fatalities.

Off-label use of antimicrobials in neonates in a tertiary children's hospital.

PURPOSE: Off-label (OL) use of drugs for hospitalized children is very common. OL use occurs especially in the youngest patients, neonates. This study focused on the OL use of antimicrobials in neonates. To our knowledge, only few studies have focused on the prevalence of OL use of antimicrobials in neonates. METHODS: We investigated the OL use of antimicrobials in neonates in a tertiary children's hospital. First, we investigated what were the most consumed OL antimicrobials in defined daily doses according to hospital's registry data from neonatal intensive care unit (NICU) during 2009-2014. Second, we conducted a targeted retrospective study of premature neonates (400-2000 g) with blood culture-positive infections and receiving antimicrobial therapy between 2005 and 2014 (N = 282). The data were obtained from the electronic patient records and from the hospital's electronic infection registry. Statistical analysis was conducted by using a univariate logistic regression model fitted for OL usage. RESULTS: In NICU, 35% (7/20) of antimicrobials used were OL. Eighteen percent (51/282) of premature neonates with blood culture-positive infections received at least one antimicrobial OL. The most commonly used OL antimicrobials in neonates were meropenem 88% (45/51), rifampicin 18% (9/51), and ciprofloxacin 8% (4/51). The odds for OL use were significantly higher the smaller the neonate birth weight was. An increase in birth weight was found to statistically significantly decrease the probability of OL usage (odds ratio = 0.85 for 100 g increase in birth weight, p value <0.001). CONCLUSION: More studies in neonates on especially dosing and pharmacokinetics of antimicrobials are urgently needed.

How to optimise drug study design: pharmacokinetics and pharmacodynamics studies introduced to paediatricians.

OBJECTIVES: In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT. METHODS: Based on the experience of experts collaborating in the EU-funded Global Research in Paediatrics consortium, we aimed to inform clinician-scientists working with children on the design of investigator-initiated PKPD studies. KEY FINDINGS: The importance of the identification of an optimal dose for the paediatric population is explained, followed by the differences and similarities of dose-ranging and efficacy studies. The input of clinical pharmacologists with modelling expertise is essential for an efficient dose-finding study. CONCLUSIONS: The emergence of new laboratory techniques and statistical tools allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic. Understanding of the principles and methods discussed in this study is essential to improve the quality of paediatric PKPD investigations, and to prevent the conduct of paediatric RCTs that fail because of inadequate dosing.

Antimicrobial consumption in a tertiary children's hospital in Finland (2003-2013).

BACKGROUND: Numbers of resistant pathogens are constantly increasing, and prudent use of antimicrobials is of paramount importance. In order to see whether any changes in the use of antimicrobials in recent years have occurred, we decided to monitor the consumption of these drugs at a single tertiary paediatric hospital. MATERIALS AND METHODS: This single-centre retrospective study investigated the consumption of antimicrobials in defined daily doses (DDDs according to the Anatomical Therapeutical Chemical /DDD index) in a 130-bed paediatric tertiary hospital. The data on the consumption of antimicrobials were collected from years 2003-2013 by using electronic surveillance records provided by the local pharmacy. The consumption was related to days of hospital care. RESULTS: During 2003-2013, the use of penicillins, cephalosporins and carbapenems increased by 28%, 46% and 110%, respectively. The consumption of both aminoglycosides and vancomycin decreased by 61% and 41%, respectively. Amphotericin B use clearly decreased by 39% while the use of novel azoles and echinocandins increased. CONCLUSIONS: Increased use of carbapenems was the most significant finding of our study. The year-to-year consumption of antibacterials was in general relatively stable and new antibacterials were taken into use conservatively. In contrast to antibacterials, novel antifungals were rapidly adopted into use despite scarce evidence on their safety in children.

Evaluation of Antimicrobial Therapy of Blood Culture Positive Healthcare-Associated Infections in Children.

AIM: Knowledge of the quality of antimicrobial therapy (AMT) used for invasive healthcare-associated infections (HAIs) in paediatrics is scarce. Influence of the final information about the isolated pathogen on the subsequent targeted AMT was investigated in our study. METHODS: Data on 149 children (0-17 years) with blood culture positive HAIs were collected. The causative microbes under investigation were Staphylococcus aureus, Staphylococcus epidermidis, streptococci, Gram negative rods, and mixed infections were likewise included. For adjusting the antimicrobial regimen, an expert panel evaluated the quality of the targeted AMT and the delay of 72 hours after final microbiology results. AMT was regarded as inappropriate if the pathogen was totally resistant to the used antimicrobials (i) or if the chosen therapy was of not optimal efficacy against the pathogen (ii). RESULTS: 17% of the patients received inappropriate AMT. Half of these infections 13/26 (50%) were treated with an antimicrobial to which the isolate was resistant. Three (3/13, 23%) of these patients received antimicrobials which were totally ineffective according to in vitro data. Suboptimal or too broad spectrum AMT was administered to 13/26 (50%) patients. The most common causes of inappropriate use were the use of beta-lactams in oxacillin-resistant Staphylococcus epidermidis infections and vancomycin given in oxacillin-sensitive Staphylococcus aureus infections. CONCLUSION: Approximately 17% of the selected cohort received inappropriate AMT. More attention should be paid to the appropriate use of antimicrobials, and training of prescribers should be urgently provided.

Essential medicines for children.

Millions of children die every year before they reach the age of 5 years, of conditions largely treatable with existing medicines. The WHO Model List of Essential Medicines was launched in 1977 to make the most necessary drugs available to populations whose basic health needs could not be met by the existing supply system. During the first 30 years of the Model List of Essential Medicines, children's needs were not systematically considered. After adoption of the 'Better medicines for children' resolution by the World Health Assembly, things changed. The first WHO Model List of Essential Medicines for Children was drawn up by a Paediatric Expert Subcommittee and adopted in October 2007. The most recent, 4th Model List of Essential Medicines for Children was adopted in 2013. Data from country surveys show that access to essential medicines for children is still generally poor; much more work is needed.

Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients.

CONTEXT: A position paper on the use of whole bowel irrigation (WBI) was first published in 1997 by the American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) and updated in 2004. The aims of this paper are to briefly summarize the content of the 2004 Position Paper and to present any new data and recommendations. METHODS: A systematic review of the literature from January 2003 to February 28, 2013 was conducted using multiple online databases for articles concerning WBI for gastrointestinal decontamination. An evidence table was created for applicable articles. The authors produced the initial draft that was reviewed by AACT and EAPCCT. RESULTS: The literature search produced 60 articles with the possibility of applicable human data. Based mainly on volunteer studies, WBI can be considered for potentially toxic ingestions of sustained-release or enteric-coated drugs particularly for those patients presenting later than 2 h after drug ingestion when activated charcoal is less effective. WBI can be considered for patients who have ingested substantial amounts of iron, lithium, or potassium as the morbidity is high and there is a lack of other potentially effective options for gastrointestinal decontamination. WBI can be considered for removal of ingested packets of illicit drugs in "body packers." However, controlled data documenting improvement in clinical outcome after WBI are lacking. WBI is contraindicated in patients with bowel obstruction, perforation, or ileus, and in patients with hemodynamic instability or compromised unprotected airways. WBI should be used cautiously in debilitated patients and in patients with medical conditions that might be further compromised by its use. The concurrent administration of activated charcoal and WBI might decrease the effectiveness of the charcoal. The clinical relevance of this interaction is uncertain. CONCLUSION: WBI can facilitate removal of select toxicants from the gastrointestinal tract in some patients, but there is no convincing evidence from clinical studies that it improves the outcome of poisoned patients. There is no new evidence that would require a major revision of the conclusions of the 2004 position statement.

First dose in neonates: are juvenile mice, adults and in vitro-in silico data predictive of neonatal pharmacokinetics of fluconazole.

BACKGROUND AND OBJECTIVES: Selection of the first-dose-in-neonates is challenging. The objective of this proof-of-concept study was to evaluate a pharmacokinetic bridging approach to predict a neonatal dosing regimen. METHODS: We selected fluconazole as a paradigm compound. We used data from studies in juvenile mice and adults to develop population pharmacokinetic models using NONMEM. We also develop a physiologically-based pharmacokinetic model from in vitro-in silico data using Simcyp. These three models were then used to predict neonatal pharmacokinetics and dosing regimens for fluconazole. RESULTS: From juvenile mice to neonates, a correction factor of maximum lifespan potential should be used for extrapolation, while a "renal factor" taking into account renal maturation was required for successful bridging based on adult and in vitro-in silico data. Simulations results demonstrated that the predicted drug exposure based on bridging approach was comparable to the observed value in neonates. The prediction errors were -2.2, +10.1 and -4.6 % for juvenile mice, adults and in vitro-in silico data, respectively. CONCLUSION: A model-based bridging approach provided consistent predictions of fluconazole pharmacokinetic parameters in neonates and demonstrated the feasibility of this approach to justify the first-dose-in-neonates, based on all data available from different sources (including physiological informations, preclinical studies and adult data), allowing evidence-based decisions of neonatal dose rather than empiricism.

Limited impact of EU paediatric regulation on Finnish clinical trials highlights need for Nordic collaboration.

UNLABELLED: The Finnish Investigators Network for Paediatric Medicines (FINPEDMED) was established in 2007, to meet the expected increase in paediatric clinical trials following the new EU Paediatric Regulation. Between 2007 and 2012, FINPEDMED received 91 trial requests, 18 trials were started, and in 24 cases, Finnish investigators were not selected by sponsors. CONCLUSION: This experience from Finland highlights the need for Nordic collaboration to increase expertise, recruitment base and attractiveness for sponsors.

Reflection: medicines for children--science alone is not enough.

PURPOSE: Access to medicines filling children's therapeutic needs is a long-standing global problem. The problem has been recognised and initiatives for correction were adopted in the USA in the late 1990s, and in the European Union in the first decade of this century. Paediatric medicines are particularly problematic in middle- and low-income countries, where most of the children of the world live. METHODS: A paediatric medicines initiative involving the WHO in parallel with the US and EU initiatives was seen as important by the global paediatric and paediatric clinical pharmacology community, but the WHO was resistant to getting involved. RESULTS: Advocacy, networking, cooperation, persistence, hard work and some luck were needed to get the "Better medicines for children" resolution 60.20 adopted by the World Health Assembly in May 2007. CONCLUSION: Science has been a key enabler of the developments leading to and following the adoption of the paediatric initiatives, but as the example of the WHO shows, science alone was not enough to make the change.

A time-to-event model for acute rejections in paediatric renal transplant recipients treated with ciclosporin A.

AIMS: Ciclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUCs) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome. METHODS: Patient records at the Children's Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling, bootstrap-stepwise covariate modelling and cross-validated stepwise covariate modelling. The clinical relevance of the effects was assessed with the time at which 90% of the patients were AR free (t90). RESULTS: Data from 87 patients (0.7-19.8 years old, 54 experiencing an AR) were analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90% interval 1.13-8.40 h mg l⁻¹), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median t90 was 5.8 days (90% confidence interval 5.1-6.8) for long dialysis times (90th percentile) and 7.4 days (6.4-11.7) for short dialysis times (10th percentile). CONCLUSIONS: A survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help to avoid unnecessarily high CsA dosing in children.

[Antidotes--often expensive and not always available]. / Antidootit--usein kalliita eivätkä aina saatavilla.

While there is seldom need for most anti-poisoning agents and antidotes, they should be quickly available, when needed. Local worst-case scenarios, regional staggering of the treatment, and distances must be taken into account at the health care unit level. Hospitals are fairly well equipped with the recommended antidotes. Replenishment of the stocks is complicated by continual disruptions in supply of antidotes. New antidotes in the updated recommendation include calcium folinate (leucovorin) for methanol poisoning and octreotide for the treatment of hypoglycemia caused by intoxications resulting from antidiabetics of the sulfonyl urea group.

The status of paediatric medicines initiatives around the world--What has happened and what has not?

PURPOSE: This review was conducted to examine the current status of paediatric medicines initiatives across the globe. METHODS: The authors made a non-systematic descriptive review of current world situation. RESULTS: Two regions, the United States (US) and the European Union (EU), and the World Health Organization (WHO) have introduced strong paediatric initiatives to improve children's health through improving access to better paediatric medicines. The experience from the US initiative indicates that it is possible to stimulate development and study of paediatric medicines and provide important new information for improvement of paediatric therapy. The early results from the EU initiative are similarly encouraging. In Canada, Japan, Australia and other developed countries, specific paediatric medicines initiatives have been less extensive and weaker, with modest results. Disappointingly, current evidence suggests that results from clinical trials outside the US often do not benefit children in the country in which the trials were largely conducted. Pharmaceutical companies that have derived a financial benefit commensurate with the cost of doing the paediatric trials in one country do not seem to be making the results of these trials available to all countries if there is no financial incentive to the company. The WHO campaign 'make medicines child size' has produced substantive accomplishments in building improved foundations to improve mechanisms that will enhance children's access to critical medicines in resource-limited settings. However, practically all of this work has been performed using an amalgamation of short-term funding from a variety of sources as opposed to a sustained, programmatic commitment. CONCLUSIONS: Although much still needs to be done, it's clear that with concerted efforts and appropriate resources, change is possible but slow. Retaining and fostering public and political interest in paediatric medicines is challenging, but pivotal for success.

Application of the optimal design approach to improve a pretransplant drug dose finding design for ciclosporin.

A time and sampling intensive pretransplant test dose design was to be reduced, but at the same time optimized so that there was no loss in the precision of predicting the individual pharmacokinetic (PK) estimates of posttransplant dosing. The following variables were optimized simultaneously: sampling times, ciclosporin dose, time of second dose, infusion duration, and administration order, using a published ciclosporin population PK model as prior information. The original design was reduced from 22 samples to 6 samples/patient and both doses (intravenous oral) were administered within 8 hours. Compared with the prior information given by the published ciclosporin population PK model, the expected standard deviations (SDs) of the individual parameters for clearance and bioavailability could be reduced by, on average, 40% under the optimized sparse designs. The gain of performing the original rich design compared with the optimal reduced design, considering the standard errors of the parameter estimates, was found to be minimal. This application demonstrates, in a practical clinical scenario, how optimal design techniques may be used to improve diagnostic procedures given available software and methods.

Virulence genes of Aeromonas isolates, bacterial endotoxins and cyanobacterial toxins from recreational water samples associated with human health symptoms.

Exposure to cyanobacterial water blooms has been associated with various kinds of adverse health effects. In addition to cyanobacteria and their toxins, the bacteria associated with cyanobacteria could also be the etiological agents. We isolated Aeromonas strains (n = 176) from water samples (n = 38) taken from sites where cyanobacteria were suspected to have caused human health symptoms, of which fever and gastrointestinal symptoms were the most common. The isolates were screened by PCR for six virulence gene types (12 genes). The majority (90%) of the strains contained at least one of the virulence genes. Most common amplification products were those of genes (act/aerA/hlyA) that encode cytotoxic enterotoxin and haemolytic products. The genes encoding cytotonic enterotoxins (ast and alt), phospholipase (lip/pla/lipH3/alp-1), elastase (ahyB) and flagellin subunits (flaA/flaB) were also present in 5-37% of the Aeromonas strains. Analysed toxins (cyanobacterial hepatotoxins and neurotoxins, and bacterial endotoxins) were not detectable or were present in only low concentrations in the majority of the samples. The results indicated that the toxins were unlikely to be the main cause of the reported adverse health effects, whereas more attention should be paid to bacteria associated with cyanobacteria as a source of health effects.

Global aspects of drug development.

About nine million children die every year before they reach the age of 5 years, of conditions largely amendable with existing medicines. Lack of medicines is not the single most important health problem of children, but work to provide children with better access to appropriate medicines is essential for achievement of the child health goals set. Taking into consideration the global aspect in the development of paediatric medicines the benefits of the regional paediatric initiatives can be spread worldwide. This chapter provides insights in the challenges and opportunities of developing paediatric medicines for health needs of children in the developing world. The Essential Medicines List for children first made available in 2008 serves as an example of the many tools available from WHO to improve children's access to the medicines they need.

[Poisonous plants]. / Myrkylliset kasvit.

Approximately ten species of dangerously poisonous plants are found in Finland. Severe plant poisonings are very rare. Edible plants eaten raw or wrongly processed may cause severe symptoms. As first aid, activated charcoal should be given to the person who has eaten a plant causing a risk of significant poisoning. In case of exposure to topically irritating plant fluids, the exposed person's eyes must be irrigated and mouth or skin washed with copious amounts of water. In combination with solar UV radiation, light-sensitizing plants cause local burns. The diagnosis of plant poisoning is usually based on incidental information; the plant should be identified in order to make the correct treatment decisions.

Evolution of paediatric off-label use after new significant medicines become available for adults: a study on triptans in Finnish children 1994-2007.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Off-label use in children is widespread. New medicines lack marketing authorization for paediatric use, even when they represent significant therapeutic advantages and are intended for treatment of conditions common in children. • Until now no information exists on how off-label use in children develops over time after a significant new medicine is approved for adults and what happens when it is later labelled for one paediatric age group. WHAT THIS STUDY ADDS: • Off-label use of a new significant medicine begins in adolescents and extends to younger children with delay. First marketing authorization to adolescents, providing a more child-friendly formulation, results in increase of off-label use in younger children, and has limited effect on total off-label use. AIM: To investigate the evolution of paediatric off-label use after a therapeutically new group of medicines for a common condition becomes available for adults but is labelled for children with a delay of several years. METHODS: Triptans were used as a model, because migraine is common in children, and is the only indication for triptans. Data on all triptan prescriptions 1994-2007 were extracted from the nationwide Finnish Prescription Register. Prescriptions for children were compared over time. RESULTS: Paediatric patients with triptan prescriptions increased from 204 in 1994 to 2618 in 2007. Sumatriptan accounted for 64% of all paediatric triptan prescriptions. When sumatriptan in a nasal formulation was labelled for children ≥ 12 years in 2003, off-label prescribing to younger children (6-11 years) doubled in 2003-2004. Sumatriptan on-label prescriptions increased to 728 adolescents (45% of sumatriptan in the age group) in 2007, but its off-label use continued also to increase to 1119 (61% of paediatric sumatriptan prescriptions) in 2007. In that year 72% of paediatric triptan use was off-label, 28% on-label. CONCLUSIONS: When a new significant medicine becomes available in adults, off-label use in children starts slowly but continues to extend to younger children reaching a market size which is little influenced by late appearance of a labelled product. Paediatric treatment remains dominated by off-label use despite labelling of a product in an age appropriate formulation to the most relevant age group.