Physiologically-based pharmacokinetic models for children: Starting to reach maturation? (original) (raw)
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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.
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...
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.
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).
A pharmacokinetic standard for babies and adults
Journal of Pharmaceutical Sciences, 2013
The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults.
Overview of Clinical Pharmacokinetics in Pediatrics: Possible Implications in Therapy
Biomedical & Pharmacology Journal, 2014
Rapid age-related changes in anatomic and physiologic parameters which may profoundly affect pharmacokinetic variables are characteristics of the first post-natal year and continue thereafter in childhood but to a lesser extent. Allometric methods mostly employed in dosage computation in pediatric age group which regrettably consider children as small adults; should be discarded in favour of the physiologically based pharmacokinetic approach considered far more ideal. Delayed gastric emptying resulting from prolongation in time required to achieve maximal plasma concentration (Tmax) occurs commonly in neonates and infants. Developmental changes that occur in body composition and protein binding are very crucial determinants of drug distribution in the pediatric age group. The pharmacokinetics, clinical efficacy and safety profile of administered drugs in children can be profoundly influenced by the developmental expression profile for the enzymes that support phases 1 and 2 metabolism. The lower rate of drug clearance due to impaired renal blood flow in preterm newborns as compared to normal ones necessitates the need for less frequent dosing interval and lower doses for drugs administered during the neonatal period. In conclusion, the outcome of this review emphasizes the need for understanding changes in developmental pharmacology amongst clinicians, particularly age-related variations in pharmacokinetic processes with obvious implications in enhancing clinical response and minimizing adverse effects.
Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology
Journal of clinical pharmacology, 2018
Pediatric clinical pharmacology now encompasses a wide range of activities, including drug pharmacokinetic and pharmacodynamic modeling and simulation, also known as pharmacometrics. Pediatric clinical pharmacologists may be physicians but are more likely to be pharmacists or PhD scientists, and pediatric clinical pharmacology today is largely a research specialty rather than a subspecialty for direct patient care. Pharmacometrics, including "top-down" population modeling and "bottom-up" physiologically based pharmacokinetic modeling, has become an indispensable tool for pharmaceutical industry scientists, government regulators, academic researchers, and even a handful of patient-oriented practitioners. This review summarizes the application of pharmacometrics within each of these domains and predicts future trends of further applications across the spectrum of pediatric clinical pharmacology from drug development to patient care.
Annals of the New York Academy of Sciences, 2005
A workshop was conducted on November 18-19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.
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.