The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling.
We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing.
The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had > or = 1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics.
Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.
"In recent years there has in fact been a rise in the number of paediatric drug safety and efficacy studies, as well as changes in drug labelling for young patients that show unique paediatric doses are often necessary [17, 18]. Furthermore, some diseases that occur in children either do not develop in adults or have a different effect/prevalence in adults, making it necessary to develop drugs specifically for children. "
[Show abstract][Hide abstract] ABSTRACT: The development of personalised medicine is of considerable importance for paediatric patient populations, and represents a move away from the use of treatment dosages based on experience with the same compounds in adults. Currently, however, we know little about developmental pharmacogenomics and, although many biomarkers are available for clinical research use, there have been few applications in the management of paediatric diseases. This paper reviews where we are in the journey towards achieving paediatric personalised medicine and describes a group of diseases requiring such an approach. The personalised medicine approach is particularly relevant for the treatment of rare childhood diseases, and the group of life-threatening neurological disorders known as lysosomal storage diseases represents a potential study population. The genetic bases of these disorders are generally well defined, there is the potential for diagnosis at birth or prenatally, and there are a range of therapeutic options available or under development.
EPMA Journal, The 06/2011; 2(2):231-9. DOI:10.1007/s13167-011-0081-2
"In April 2008, the European Medicines Agency (EMA) organised a “Workshop on Modelling in Paediatric Medicines” . More recently, M&S have been proposed as a framework for the evaluation of drugs by regulators taking into account different clinical scenarios [7, 13]. "
[Show abstract][Hide abstract] ABSTRACT: Although practical and ethical constraints impose special requirements for the evaluation of treatment safety and efficacy in children, the main issue remains the empirical basis for patient stratification and dose selection at the early stage of the development of new chemical and biological entities. The aim of this review is to highlight the advantages and limitations of modelling and simulation (M&S) in supporting decision making during paediatric drug development.
A literature search on Pubmed's database Medical Subject Headings (MeSH) has been performed to retrieve relevant publications on the use of model-based approaches in paediatric drug development and therapeutics.
M&S enable the assessment of the impact of different regimens as well as of different populations on a drug's safety and efficacy profile. It has been widely used in the last two decades to support pre-clinical and early clinical drug development. In fact, M&S have been applied to drug development as decision tools, as study optimization tools and as data analysis tools. In particular, this approach can be used to support dose adjustment in specific subgroups of a population. M&S may therefore allow the individualisation of drug therapy in children, improving the risk-benefit ratio in this population.
The lack of consensus on how to assess the impact of developmental factors on pharmacokinetics, pharmacodynamics, efficacy and safety has so far prevented a broader use of M&S. This problem is compounded by the limited collaboration between stakeholders, which prevents data sharing in this field. In this article, we emphasise the need for a concerted effort to promote the effective use of this technology in paediatric drug development and avoid unnecessary exposure of children to clinical trials.
European Journal of Clinical Pharmacology 05/2011; 67 Suppl 1(S1):75-86. DOI:10.1007/s00228-010-0974-3 · 2.97 Impact Factor
"More often, the trend and extent of the pharmacokinetic difference between pediatrics and adults across different age groups are not predictable. Clearance and volume of distribution of drugs can be higher, but can also potentially be lower in younger children, compared with older children or adults . Therefore, simply adjusting the pediatric dose according to the body weight/BSA may not be an accurate dosing approach. "
[Show abstract][Hide abstract] ABSTRACT: Although pediatric doses for biotherapeutics are often based on patients' body weight (mg/kg) or body surface area (mg/m2), linear body size dose adjustment is highly empirical. Growth and maturity are also important factors that affect the absorption, distribution, metabolism and excretion (ADME) of biologics in pediatrics. The complexity of the factors involved in pediatric pharmacokinetics lends to the reconsideration of body size based dose adjustment. A proper dosing adjustment for pediatrics should also provide less intersubject variability in the pharmacokinetics and/or pharmacodynamics of the product compared with no dose adjustment. Biological proteins and peptides generally share the same pharmacokinetic principle with small molecules, but the underlying mechanism can be very different. Here, pediatric and adult pharmacokinetic parameters are compared and summarized for selected biotherapeutics. The effect of body size on the pediatric pharmacokinetics for these biological products is discussed in the current review.
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