Regulatory Modeling and Simulation Moves Into the Next Gear in Europe

Graaf, Piet H. van der

doi:10.1038/psp.2013.8

Cited by 3 publications

(2 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fortunately, the benefits of applying quantitative pharmacological methods in clinical practice are now more widely appreciated [ 20 ], in addition to their key roles in research and drug development [ 21 – 25 ]. To reflect this, there is also a growing number of experts in M&S within regulatory agencies [ 26 – 28 ].…”

Section: Pediatric Drug Development: Background and Legislationmentioning

confidence: 99%

Pharmacokinetic–Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance

et al. 2018

View full text Add to dashboard Cite

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies. Key PointsPharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children, and the so-called 'population' approach is suitable for rich or sparse data in terms of the number of samples per subjectThe utility of pediatric PK models can be increased by using a standardized approach to scaling: a suggested method for scaling clearance (CL) is a combination of allometric weight scaling with a sigmoid function to account for organ maturation. This should be used a priori, as a 'base' approach, allowing the effects of age and size to be delineated from other patient-specific factors, such as disease state and organ (dys)function When determining the pediatric dose, instead of directly scaling the dose from adults to children, the pediatric PK parameter estimates should be obtained from a PK model with a standardized scaling approach in order to avoid the use of arbitrary cut-off values (of age/weight) according to a specific (nonstandardized) CL-scaling formula Significant progress has recently been made on pediatric PK modeling; a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects PKPD model-based dose individualization is becoming increasingly popular as the age of personalized medicine dawns

show abstract

Section: Pediatric Drug Development: Background and Legislationmentioning

confidence: 99%

Pharmacokinetic–Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The increasing pace of investments across academia and industry in the areas of modeling and simulation has the potential to streamline and speed‐up drug research and development programs (Van der Graaf, ) (Fig. ).…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling and simulation in animal health. Part I: Moving beyond pharmacokinetics

Riviere

Gabrielsson

Fink

et al. 2015

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

The application of mathematical modeling to problems in animal health has a rich history in the form of pharmacokinetic modeling applied to problems in veterinary medicine. Advances in modeling and simulation beyond pharmacokinetics have the potential to streamline and speed-up drug research and development programs. To foster these goals, a series of manuscripts will be published with the following goals: (i) expand the application of modeling and simulation to issues in veterinary pharmacology; (ii) bridge the gap between the level of modeling and simulation practiced in human and veterinary pharmacology; (iii) explore how modeling and simulation concepts can be used to improve our understanding of common issues not readily addressed in human pharmacology (e.g. breed differences, tissue residue depletion, vast weight ranges among adults within a single species, interspecies differences, small animal species research where data collection is limited to sparse sampling, availability of different sampling matrices); and (iv) describe how quantitative pharmacology approaches could help understanding key pharmacokinetic and pharmacodynamic characteristics of a drug candidate, with the goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans, enabling critical decision making, and eventually bringing safe and effective medicines to patients. This study introduces these concepts and introduces new approaches to modeling and simulation as well as clearly articulate basic assumptions and good practices. The driving force behind these activities is to create predictive models that are based on solid physiological and pharmacological principles as well as adhering to the limitations that are fundamental to applying mathematical and statistical models to biological systems.

show abstract

Peccary, a metaprogramming open-source R platform to improve pharmacometrics efficiency

2022

View full text Add to dashboard Cite

Background: A pharmacometrics (PMx) workflow usually requires several software tools to cover all the steps from data analysis to model evaluation and simulations. However, these tools do not always communicate well together, compromising the efficiency of the whole process. Highly inspired by the markdown/pandoc system, we developed Peccary, an R package and its dedicated Shiny Application with the objective to accelerate the use of previously released R packages through various translation and metaprogramming processes. Methods: Peccary was developed with an agile method, progressively aggregating snippets of R code produced during real-life pharmacometrics works. Its first subpackage, PeccAnalysis, can be used to produce and evaluate various R code for population description (using table1 package), plot exploration (ggplot) and non-compartment analysis (pknca). The second subpackage, PeccaReverse, allows writing a structural model using a minimalist (simplified deSolve) syntax, before metaprogramming model simulations (using either deSolve or RxODE) and design evaluation (through PopED), along with performing various model syntax translations (e.g., into NONMEM, Monolix or nlmixr files). Finally, the third subpackage, PeccaResult, standardizes run outputs of several PMx software (NONMEM, Monolix, Adapt, nlmixr) to perform various diagnostic evaluation tasks. Results: The metaprogramming system used in PeccAnalysis and PeccaReverse has many advantages. First, it simplifies the use of previously mentioned packages (by reducing the required knowledge and the time needed to program the output creation). Second, it creates links between independent tools (for instance using the same inputs for several tasks). Third, the produced R code can be reviewed for eventual manual modification, verification (quality control) or traceable report integration. Conclusion: Overall, Peccary was successful in improving PMx efficiency by providing a Shiny R platform that can produce various outputs during live meetings while keeping the possibility to extract Peccary-independent R source code for further in-depth control.

show abstract

Regulatory Modeling and Simulation Moves Into the Next Gear in Europe

Cited by 3 publications

References 9 publications

Pharmacokinetic–Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance

Pharmacokinetic–Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance

Mathematical modeling and simulation in animal health. Part I: Moving beyond pharmacokinetics

Peccary, a metaprogramming open-source R platform to improve pharmacometrics efficiency

Contact Info

Product

Resources

About