General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children (original) (raw)
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Journal of Pharmacy and Pharmacology
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. It is unfortunate that a communication gap still exists between paediatricians and clinical pharmacologists, who can apply methodologies to validate current prescription practice, in many cases without the need for additional prospective trials. [1]
European regulatory perspective on pediatric physiologically based pharmacokinetic models
International Journal of Pharmacokinetics, 2017
Physiologically based pharmacokinetic (PBPK) models offer a mechanistic understanding of the disposition of the drug in the body. When well informed and conducted, this may lead to more efficient clinical studies in the vulnerable pediatric population. A review of pediatric submissions to European regulatory authorities has shown a limited number of recent examples. The use of PBPK models to inform pediatric drug development is encouraged. It is, however, important to consider the confidence in the predictions. A qualification of the PBPK platform for the intended purpose should be performed, and a learn-and-confirm approach is recommended. Further research in this area is encouraged to inform important parameters, and to increase availability of pediatric data for model qualification.
Toxicological Sciences, 2002
Pharmacokinetics (PK) of xenobiotics can differ widely between children and adults due to physiological differences and the immaturity of enzyme systems and clearance mechanisms. This makes extrapolation of adult dosimetry estimates to children uncertain, especially at early postnatal ages. While there is very little PK data for environmental toxicants in children, there is a wealth of such data for therapeutic drugs. Using published literature, a Children's PK Database has been compiled which compares PK parameters between children and adults for 45 drugs. This has enabled comparison of child and adult PK function across a number of cytochrome P450 (CYP) pathways, as well as certain Phase II conjugation reactions and renal elimination. These comparisons indicate that premature and full-term neonates tend to have 3 to 9 times longer half-life than adults for the drugs included in the database. This difference disappears by 2-6 months of age. Beyond this age, half-life can be shorter than in adults for specific drugs and pathways. The range of neonate/adult half-life ratios exceeds the 3.16-fold factor commonly ascribed to interindividual PK variability. Thus, this uncertainty factor may not be adequate for certain chemicals in the early postnatal period. The current findings present a PK developmental profile that is relevant to environmental toxicants metabolized and cleared by the pathways represented in the current database. The manner in which this PK information can be applied to the risk assessment of children includes several different approaches: qualitative (e.g., enhanced discussion of uncertainties), semiquantitative (age group-specific adjustment factors), and quantitative (estimation of internal dosimetry in children via physiologically based PK modeling).
Physiologically-based pharmacokinetic models for children: Starting to reach maturation?
Pharmacology & Therapeutics, 2020
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Physiologically based pharmacokinetic modeling and simulation in pediatric drug development
CPT: pharmacometrics & systems pharmacology, 2014
Increased regulatory demands for pediatric drug development research have fostered interest in the use of modeling and simulation among industry and academia. Physiologically based pharmacokinetic (PBPK) modeling offers a unique modality to incorporate multiple levels of information to estimate age-specific pharmacokinetics. This tutorial will serve to provide the reader with a basic understanding of the procedural steps to developing a pediatric PBPK model and facilitate a discussion of the advantages and limitations of this modeling technique.
Clinical pharmacokinetics, 2018
Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokineti...
Drug Development for Pediatric Populations: Regulatory Aspects
Pharmaceutics, 2010
Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in particular, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework. This review summarizes the regulatory requirements and strategies for pediatric drug development from an industry perspective. It covers pediatric study planning and conduct, considerations for first dose in children, appropriate sampling strategies, and different methods for data generation and analysis to generate knowledge about the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug in children. The role of Modeling and Simulation (M&S) in pediatrics is highlighted-including the regulatory basis-and examples of the use of M&S are illustrated to support pediatric drug development.
The AAPS Journal, 2014
Although both POPPK and physiologically based pharmacokinetic (PBPK) models can account for age and other covariates within a paediatric population, they generally do not account for real-time growth and maturation of the individuals through the time course of drug exposure; this may be significant in prolonged neonatal studies. The major objective of this study was to introduce age progression into a paediatric PBPK model, to allow for continuous updating of anatomical, physiological and biological processes in each individual subject over time. The Simcyp paediatric PBPK model simulator system parameters were reanalysed to assess the impact of redefining the individual over the study period. A schedule for redefining parameters within the Simcyp paediatric simulator, for each subject, over a prolonged study period, was devised to allow seamless prediction of pharmacokinetics (PK). The model was applied to predict concentration-time data from multiday studies on sildenafil and phenytoin performed in neonates. Among PBPK system parameters, CYP3A4 abundance was one of the fastest changing covariates and a 1-h re-sampling schedule was needed for babies below age 3.5 days in order to seamlessly predict PK (<5% change in abundance) with subject maturation. The re-sampling frequency decreased as age increased, reaching biweekly by 6 months of age. The PK of both sildenafil and phenytoin were predicted better at the end of a prolonged study period using the time varying vs fixed PBPK models. Paediatric PBPK models which account for time-varying system parameters during prolonged studies may provide more mechanistic PK predictions in neonates and infants.