Building an adaptive dose simulation framework to aid dose and schedule selection
Abstract Establishing a dosing regimen that maximizes clinical benefit and minimizes adverse effects for novel therapeutics is a key objective for drug developers. Finding an optimal dose and schedule can be particularly challenging for compounds with a narrow therapeutic window such as in oncology....
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-11-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13027 |
| _version_ | 1797449907436519424 |
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| author | Richard Hooijmaijers Ridhi Parasrampuria Eleonora Marostica Geraldine Ferron‐Brady Teun M. Post Sandra A. G. Visser |
| author_facet | Richard Hooijmaijers Ridhi Parasrampuria Eleonora Marostica Geraldine Ferron‐Brady Teun M. Post Sandra A. G. Visser |
| author_sort | Richard Hooijmaijers |
| collection | DOAJ |
| description | Abstract Establishing a dosing regimen that maximizes clinical benefit and minimizes adverse effects for novel therapeutics is a key objective for drug developers. Finding an optimal dose and schedule can be particularly challenging for compounds with a narrow therapeutic window such as in oncology. Modeling and simulation tools can be valuable to conduct in silico evaluations of various dosing scenarios with the goal to identify those that could minimize toxicities, avoid unscheduled dose interruptions, or minimize premature discontinuations, which all could limit the potential for therapeutic benefit. In this tutorial, we present a stepwise development of an adaptive dose simulation framework that can be used for dose optimization simulations. The tutorial first describes the general workflow, followed by a technical description with basic to advanced practical examples of its implementation in mrgsolve and is concluded with examples on how to use this in decision‐making around dose and schedule optimization. The adaptive simulation framework is built with pharmacokinetic, pharmacodynamic (i.e., biomarkers, activity markers, target engagement markers, efficacy markers), and safety models that include evaluations of unexplained interindividual and intraindividual variability and covariate impact, which can be replaced and expanded (e.g., combination setting, comparator setting) with user‐defined models. Subsequent adaptive simulations allow investigation of the impact of starting dose, dosing intervals, and event‐driven (exposure or effect) dose modifications on any end point. The resulting simulation‐derived insights can be used in quantitatively proposing dose and regimens that better balance benefit and adverse effects for further evaluation, aiding dose selection discussions, and designing dose modification recommendations, among others. |
| first_indexed | 2024-03-09T14:32:48Z |
| format | Article |
| id | doaj.art-96dc123b4b514d36af8c07bddd333909 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-09T14:32:48Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-96dc123b4b514d36af8c07bddd3339092023-11-27T20:51:16ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-11-0112111602161810.1002/psp4.13027Building an adaptive dose simulation framework to aid dose and schedule selectionRichard Hooijmaijers0Ridhi Parasrampuria1Eleonora Marostica2Geraldine Ferron‐Brady3Teun M. Post4Sandra A. G. Visser5Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P) Leiden The NetherlandsGSK Collegeville Pennsylvania USALeiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P) Leiden The NetherlandsGSK Collegeville Pennsylvania USALeiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P) Leiden The NetherlandsGSK Collegeville Pennsylvania USAAbstract Establishing a dosing regimen that maximizes clinical benefit and minimizes adverse effects for novel therapeutics is a key objective for drug developers. Finding an optimal dose and schedule can be particularly challenging for compounds with a narrow therapeutic window such as in oncology. Modeling and simulation tools can be valuable to conduct in silico evaluations of various dosing scenarios with the goal to identify those that could minimize toxicities, avoid unscheduled dose interruptions, or minimize premature discontinuations, which all could limit the potential for therapeutic benefit. In this tutorial, we present a stepwise development of an adaptive dose simulation framework that can be used for dose optimization simulations. The tutorial first describes the general workflow, followed by a technical description with basic to advanced practical examples of its implementation in mrgsolve and is concluded with examples on how to use this in decision‐making around dose and schedule optimization. The adaptive simulation framework is built with pharmacokinetic, pharmacodynamic (i.e., biomarkers, activity markers, target engagement markers, efficacy markers), and safety models that include evaluations of unexplained interindividual and intraindividual variability and covariate impact, which can be replaced and expanded (e.g., combination setting, comparator setting) with user‐defined models. Subsequent adaptive simulations allow investigation of the impact of starting dose, dosing intervals, and event‐driven (exposure or effect) dose modifications on any end point. The resulting simulation‐derived insights can be used in quantitatively proposing dose and regimens that better balance benefit and adverse effects for further evaluation, aiding dose selection discussions, and designing dose modification recommendations, among others.https://doi.org/10.1002/psp4.13027 |
| spellingShingle | Richard Hooijmaijers Ridhi Parasrampuria Eleonora Marostica Geraldine Ferron‐Brady Teun M. Post Sandra A. G. Visser Building an adaptive dose simulation framework to aid dose and schedule selection CPT: Pharmacometrics & Systems Pharmacology |
| title | Building an adaptive dose simulation framework to aid dose and schedule selection |
| title_full | Building an adaptive dose simulation framework to aid dose and schedule selection |
| title_fullStr | Building an adaptive dose simulation framework to aid dose and schedule selection |
| title_full_unstemmed | Building an adaptive dose simulation framework to aid dose and schedule selection |
| title_short | Building an adaptive dose simulation framework to aid dose and schedule selection |
| title_sort | building an adaptive dose simulation framework to aid dose and schedule selection |
| url | https://doi.org/10.1002/psp4.13027 |
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