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Developmental changes that occur throughout childhood have long been known to impact drug disposition. However, pharmacokinetic studies in the paediatric population have historically been limited due to ethical concerns arising from incorporating children into clinical trials. As such, much of the early work in the field of developmental pharmacology was reliant on difficult-to-interpret in vitro and in vivo animal studies. Over the last 2 decades, our understanding of the mechanistic processes underlying age-related changes in drug disposition has advanced considerably. Progress has largely been driven by technological advances in mass spectrometry-based methods for quantifying proteins implicated in drug disposition, and in silico tools that leverage these data to predict age-related changes in pharmacokinetics. This review summarizes our current understanding of the impact of childhood development on drug disposition, particularly focusing on research of the past 20 years, but also highlighting select examples of earlier foundational research. Equally important to the studies reviewed herein are the areas that we cannot currently describe due to the lack of research evidence; these gaps provide a map of drug disposition pathways for which developmental trends still need to be characterized.

Contains fulltext : 235727.pdf (Publisher’s version ) (Open Access) AIMS: Simulations are an essential tool for investigating scenarios in pharmacokinetics-pharmacodynamics. The models used during simulation often include the effect of highly correlated covariates such as weight, height and sex, and for children also age, which complicates the construction of an in silico population. For this reason, a suitable and representative patient population is crucial for the simulations to produce meaningful results. For simulation in paediatric patients, international growth charts from the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) provide a reference, but these may not always be representative for specific populations, such as malnourished children with HIV or acutely unwell children. METHODS: We present a workflow to construct a virtual paediatric patient population using WHO and CDC growth charts, suggest piecewise linear functions to adjust the median of the growth charts by sex and age, and suggest visual diagnostics to compare with the target population. We applied this workflow in a population of 1206 HIV-positive African children, consisting of 19 742 observations with weight ranging from 3.8 to 79.7 kg, height from 55.5 to 180 cm, and an age between 0.40 and 18 years. RESULTS: Before adjustment, the WHO and CDC charts produced weights and heights higher compared to the observed data. After applying our methodology, we could simulate weight, height, sex and age combinations in good agreement with the observed data. CONCLUSION: The methodology presented here is flexible and may be applied to other scenarios where WHO and CDC growth standards might not be appropriate. In addition we provide R scripts and a large ready-to-use paediatric population.

AIMS To evaluate the pharmacokinetics and safety of once-daily (QD) tadalafil in paediatric patients with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further research. METHODS This was an open-label, multicentre, international, multiple-ascending-dose study. Patients aged ≥2 years were enrolled into 1 of 3 cohorts based on body weight: heavy-weight (≥40 kg), middle-weight (25 to

Aims This study investigates paediatric drug dosage guidelines with the aim of investigating their agreement with body surface area (BSA) scaling principles. Methods A total of 454 drug dosage guidelines listed in the AMH-CDC 2015 were examined. Data extracted included the administration, frequency and dose per age bracket from 0 to 18 years. Drug treatments were categorized as follows: (1) The same dose recommendation in milligrams per kilogram (mg kg-1 ) for all age/weights; (2) Change in the mg kg-1 dosing according to age/weight; (3) Change in dose in mg according to age/weight; (4) Change from mg kg-1 dosing to a dose in mg according to age/weight; (5) The same recommendation for all age/weight groups in mg; or (6) BSA dosing. Example drugs were selected to illustrate dose progression across ages. Results Most drug treatments (63%) have the same mg kg-1 dose for all age/weight groups, 14% are dosed in mg kg-1 across all ages with dose changes according to age/weight, 13% were dosed in mg across all ages with dose changes, 10% switched from mg kg-1 to a set dose in mg, 4.2% have the same dose in mg for all age and weight groups and 2.2% are dosed according to BSA. Conclusions Paediatric dosage guidelines are based on weight-based formulas, available dosing formulations and prior patterns of use. Substantial variation from doses predicted by BSA scaling are common, as are large shifts in recommended doses at age thresholds. Further research is required to determine if better outcomes could be achieved by adopting biologically based scaling of paediatric doses.

A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment - the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only ~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally-acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The pharmacokinetics of morphine are well known in pre-term and term neonates, infants, younger and older children, as well as in adults. There are circumstances when a pharmacokinetic study may not be possible in children (especially neonates and infants), and as a result one would like to predict drug clearance in children. Several methods, such as allometric scaling and prediction based on incorporation of physiological parameters, have been suggested. Recently a morphine maturation model has been proposed to predict morphine clearance in the paediatric population. WHAT THIS STUDY ADDS The current study evaluates the predictive performance of the morphine maturation model for the prediction of morphine clearance in pre-term, term, infants and children up to 5 years of age. The results of the study highlight the shortcomings of the model to predict morphine clearance in children in aforementioned age groups. AIMS Recently, a maturation model that incorporates a sigmoidal Emax type model has been proposed for the estimation of morphine clearance in paediatric patients. The primary objective of this report is to evaluate the predictive performance of the morphine maturation model for the prediction of morphine clearance in children of different ages. The secondary objective of this report is to evaluate the predictive performance of exponent 0.75 on bodyweight in the absence of the sigmoidal part of the morphine maturation model. METHODS In order to evaluate the predictive performance of the morphine maturation model, the clearance values of morphine for individual children (preterm neonates to 5-year-old children; n= 147) were obtained from the literature. The predicted clearance of morphine in an individual child, obtained from the maturation model as well as from the fixed exponent 0.75 was compared with the observed clearance in that individual child. RESULTS The morphine maturation model's predictive power in neonates, infants and younger children is poor and the inclusion of the sigmoidal part in the model only helps in reducing the substantial error introduced in the prediction due to the application of exponent 0.75 on bodyweight. Furthermore, the real benefit of the sigmoidal Emax part of the model disappears by 1 year of age. CONCLUSIONS The morphine maturation model has a poor predictive power of morphine clearance in preterm and term neonates, infants and very young children and may not be of any practical value for the prediction of morphine clearance in this age group.

To evaluate the intraregional differences in drug prescribing to children and adolescents.Prescriptions reimbursed by the National Health System, involving 1543 203 children and adolescents18 years old and dispensed during 2005 by the retail pharmacies of 15 local health units (LHU) in the Lombardy Region, were analysed. Logistic regression analysis was performed to evaluate the association between drug prescription and age, gender, prescriber, and setting.A total of 747 790 youths (48%) received at least one drug prescription. The prescription prevalence rate was highest in children 1-5 years old (65%), decreased with increasing age to 38% in adolescents, and was slightly higher in boys than in girls. Antibiotics and anti-asthmatics were the most prescribed therapeutic classes. Amoxicillin + clavulanic acid was the most prescribed drug (18% of children; 20% of packages). Large differences were found in the drug prescription prevalence rate between the different LHUs. The rate ranged between 38.4 and 54.8%, and was not correlated to hospitalization rate in the paediatric population. Being 1-5 years old [odds ratio (OR) 4.51, 95% confidence interval (CI) 4.43, 4.58] and living in the eastern part of the region (OR 2.06, 95% CI 1.99, 2.13) were the factors associated with the highest risk of drug exposure.The results resemble the profiles observed in other Italian contexts, in particular concerning the wide use of antibiotics and anti-asthmatics. However, large differences were found between LHUs, highlighting the need for more detailed investigations on therapeutic needs, drug use, and related variables in different geographic contexts.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Children have reduced access to medicines because of inadequate prescribing information and paucity of suitable formulations. • The USA has implemented a series of measures designed to improve the licensing of medicines for children, which has resulted in an increase in the number of studies and the number of patients studied in investigational trials of medicines in children. • These measures have increased the number of targeted medicines that have had their labelled use extended to children. WHAT THIS STUDY ADDS • Information in the Physicians' Desk Reference did not indicate that there was an improvement in overall access to, and prescribing information about, drugs in the paediatric population in the USA over the time period 1998–2007. AIMS The aims of the present study were to examine the Physicians' Desk Reference (PDR) for changes in the listing of medicines licensed for children in the USA over a 10-year period (1998–2007). METHODS The USA PDR was used to identify products listed in 1998, 2002 and 2007. Information about generic name (active agent), salt, strength, brand name, suitability of formulation, paediatric licensing information and the lowest age of licensing was extracted. Prescription products were collapsed down to chemical entities/fixed-dose combinations. RESULTS Of the prescription entities listed in the PDR, 538 (55.9%), 488 (54.3%) and 394 (51.3%) were licensed for children in 1998, 2002 and 2007, respectively. There was a 39% decrease in the number of entities licensed for the newborn and a 34% decrease for children aged 2–6 years between 1998 and 2007. Formulations suitable for children were listed for 611 (63.4%), 550 (61.2%) and 430 (60.6%), respectively. Prescription entities with both a suitable oral formulation and licensing for children numbered 161 (16.7%), 148 (16.5%) and 100 (14.1%) in 1998, 2002 and 2007, respectively. CONCLUSIONS The listings in the PDR suggest that overall access to prescribing information about drugs in the paediatric population has not shown an increase over the decade. This particularly affected the neonatal age group.