Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic models
Abstract Sensitivity analyses are important components of physiologically based pharmacokinetic (PBPK) model development and are required by regulatory agencies for PBPK submissions. They assess the impact of parametric uncertainty and variability on model estimates, aid model optimization by identi...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13256 |
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| _version_ | 1846121099371216896 |
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| author | Abdulkarim Najjar Abdullah Hamadeh Sophia Krause Andreas Schepky Andrea Edginton |
| author_facet | Abdulkarim Najjar Abdullah Hamadeh Sophia Krause Andreas Schepky Andrea Edginton |
| author_sort | Abdulkarim Najjar |
| collection | DOAJ |
| description | Abstract Sensitivity analyses are important components of physiologically based pharmacokinetic (PBPK) model development and are required by regulatory agencies for PBPK submissions. They assess the impact of parametric uncertainty and variability on model estimates, aid model optimization by identifying parameters requiring calibration, and enable the testing of assumptions within PBPK models. One‐at‐a‐time (OAT) sensitivity analyses quantify the impact on a model output in response to changes in a single parameter while holding others fixed. Global sensitivity analysis (GSA) methods provide more comprehensive assessments by accounting for changes in all uncertain or variable parameters, though at a higher computational cost. This tutorial article presents a software package for conducting both OAT and GSA of PBPK models built in the Open Systems Pharmacology (OSP) Suite. The tool is accessible through either an R script or a graphical user interface, and the outputs consist of sensitivity metrics of pharmacokinetic (PK) parameters, such as Cmax and AUC, evaluated with respect to model input parameters. Results are formatted according to regulatory standards. The OAT analysis methods comprise two‐way local sensitivity analyses and probabilistic uncertainty analyses, whereas the GSA methods include the Morris, Sobol, and EFAST methods. These analyses can be conducted on single PBPK models or pairs of models for the evaluation of the sensitivity of PK parameter ratios in drug–drug interaction studies. The practical application of the package is demonstrated through three illustrative case studies. |
| format | Article |
| id | doaj-art-6f1bf57938af423bb7b8b82f85c954f8 |
| institution | Kabale University |
| issn | 2163-8306 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj-art-6f1bf57938af423bb7b8b82f85c954f82024-12-16T05:57:55ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062024-12-0113122052206710.1002/psp4.13256Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic modelsAbdulkarim Najjar0Abdullah Hamadeh1Sophia Krause2Andreas Schepky3Andrea Edginton4Beiersdorf AG Hamburg GermanySchool of Pharmacy University of Waterloo Kitchener Ontario CanadaBeiersdorf AG Hamburg GermanyBeiersdorf AG Hamburg GermanySchool of Pharmacy University of Waterloo Kitchener Ontario CanadaAbstract Sensitivity analyses are important components of physiologically based pharmacokinetic (PBPK) model development and are required by regulatory agencies for PBPK submissions. They assess the impact of parametric uncertainty and variability on model estimates, aid model optimization by identifying parameters requiring calibration, and enable the testing of assumptions within PBPK models. One‐at‐a‐time (OAT) sensitivity analyses quantify the impact on a model output in response to changes in a single parameter while holding others fixed. Global sensitivity analysis (GSA) methods provide more comprehensive assessments by accounting for changes in all uncertain or variable parameters, though at a higher computational cost. This tutorial article presents a software package for conducting both OAT and GSA of PBPK models built in the Open Systems Pharmacology (OSP) Suite. The tool is accessible through either an R script or a graphical user interface, and the outputs consist of sensitivity metrics of pharmacokinetic (PK) parameters, such as Cmax and AUC, evaluated with respect to model input parameters. Results are formatted according to regulatory standards. The OAT analysis methods comprise two‐way local sensitivity analyses and probabilistic uncertainty analyses, whereas the GSA methods include the Morris, Sobol, and EFAST methods. These analyses can be conducted on single PBPK models or pairs of models for the evaluation of the sensitivity of PK parameter ratios in drug–drug interaction studies. The practical application of the package is demonstrated through three illustrative case studies.https://doi.org/10.1002/psp4.13256 |
| spellingShingle | Abdulkarim Najjar Abdullah Hamadeh Sophia Krause Andreas Schepky Andrea Edginton Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic models CPT: Pharmacometrics & Systems Pharmacology |
| title | Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic models |
| title_full | Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic models |
| title_fullStr | Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic models |
| title_full_unstemmed | Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic models |
| title_short | Global sensitivity analysis of Open Systems Pharmacology Suite physiologically based pharmacokinetic models |
| title_sort | global sensitivity analysis of open systems pharmacology suite physiologically based pharmacokinetic models |
| url | https://doi.org/10.1002/psp4.13256 |
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