Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitors
Abstract Several PI3K inhibitors are in clinical development for the treatment of various forms of cancers, including pan‐PI3K inhibitors targeting all four PI3K isoforms (α, β, γ, and δ), and isoform‐selective inhibitors. Diarrhea and immune‐mediated colitis are among the adverse events observed wi...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-05-01
|
| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12749 |
| _version_ | 1818239623496728576 |
|---|---|
| author | Kapil Gadkar Christina Friedrich Vincent Hurez Maria‐Luisa Ruiz Leslie Dickmann Mohit Kumar Jolly Leah Schutt Jin Jin Joseph A. Ware Saroja Ramanujan |
| author_facet | Kapil Gadkar Christina Friedrich Vincent Hurez Maria‐Luisa Ruiz Leslie Dickmann Mohit Kumar Jolly Leah Schutt Jin Jin Joseph A. Ware Saroja Ramanujan |
| author_sort | Kapil Gadkar |
| collection | DOAJ |
| description | Abstract Several PI3K inhibitors are in clinical development for the treatment of various forms of cancers, including pan‐PI3K inhibitors targeting all four PI3K isoforms (α, β, γ, and δ), and isoform‐selective inhibitors. Diarrhea and immune‐mediated colitis are among the adverse events observed with PI3K inhibition which limits the maximal tolerated dose. A quantitative systems pharmacology model was developed to investigate PI3K‐inhibitor‐induced colitis. The effects of individual PI3K isoforms on relevant cellular pathways were incorporated into a mechanistic representation of mucosal inflammation. A virtual clinical population captures the observed clinical variability in the onset timing and rates of diarrhea and colitis for seven clinically tested PI3K inhibitors. Model‐based analysis suggests that colitis development is governed by both the inhibition of PI3Kδ, which drives T cell differentiation and proliferation, and PI3Kα, which regulates epithelial barrier integrity. Specifically, when PI3Kα is inhibited below a given threshold, epithelial barrier dysfunction precipitates an exaggerated T effector response due to PI3Kδ‐inhibition, leading to risk of diarrhea and colitis. This synergy explains why the lowest diarrhea and colitis rates are seen with the weakest PI3Kδ inhibition (alpelisib), and higher rates are seen with strong PI3Kδ inhibition if PI3Kα is even mildly inhibited (e.g., idelalisib), whereas strong PI3Kδ inhibition in the absence of PI3Kα inhibition does not result in high colitis rates (umbralisib). Thus, the model‐based analysis suggests that PI3Kα and δ inhibition play unique but synergistic roles in driving colitis. Finally, we explore if and how dose‐regimen might influence colitis rates for molecules that inhibit both PI3Kα and PI3Kδ. |
| first_indexed | 2024-12-12T13:00:29Z |
| format | Article |
| id | doaj.art-4d3f8999655d4cd4aa9f1a6f87ba8b9e |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-12-12T13:00:29Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-4d3f8999655d4cd4aa9f1a6f87ba8b9e2022-12-22T00:23:47ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062022-05-0111561662710.1002/psp4.12749Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitorsKapil Gadkar0Christina Friedrich1Vincent Hurez2Maria‐Luisa Ruiz3Leslie Dickmann4Mohit Kumar Jolly5Leah Schutt6Jin Jin7Joseph A. Ware8Saroja Ramanujan9Genentech South San Francisco California USARosa & Co., LLC San Carlos California USARosa & Co., LLC San Carlos California USARosa & Co., LLC San Carlos California USAGenentech South San Francisco California USAGenentech South San Francisco California USAGenentech South San Francisco California USAGenentech South San Francisco California USAGenentech South San Francisco California USAGenentech South San Francisco California USAAbstract Several PI3K inhibitors are in clinical development for the treatment of various forms of cancers, including pan‐PI3K inhibitors targeting all four PI3K isoforms (α, β, γ, and δ), and isoform‐selective inhibitors. Diarrhea and immune‐mediated colitis are among the adverse events observed with PI3K inhibition which limits the maximal tolerated dose. A quantitative systems pharmacology model was developed to investigate PI3K‐inhibitor‐induced colitis. The effects of individual PI3K isoforms on relevant cellular pathways were incorporated into a mechanistic representation of mucosal inflammation. A virtual clinical population captures the observed clinical variability in the onset timing and rates of diarrhea and colitis for seven clinically tested PI3K inhibitors. Model‐based analysis suggests that colitis development is governed by both the inhibition of PI3Kδ, which drives T cell differentiation and proliferation, and PI3Kα, which regulates epithelial barrier integrity. Specifically, when PI3Kα is inhibited below a given threshold, epithelial barrier dysfunction precipitates an exaggerated T effector response due to PI3Kδ‐inhibition, leading to risk of diarrhea and colitis. This synergy explains why the lowest diarrhea and colitis rates are seen with the weakest PI3Kδ inhibition (alpelisib), and higher rates are seen with strong PI3Kδ inhibition if PI3Kα is even mildly inhibited (e.g., idelalisib), whereas strong PI3Kδ inhibition in the absence of PI3Kα inhibition does not result in high colitis rates (umbralisib). Thus, the model‐based analysis suggests that PI3Kα and δ inhibition play unique but synergistic roles in driving colitis. Finally, we explore if and how dose‐regimen might influence colitis rates for molecules that inhibit both PI3Kα and PI3Kδ.https://doi.org/10.1002/psp4.12749 |
| spellingShingle | Kapil Gadkar Christina Friedrich Vincent Hurez Maria‐Luisa Ruiz Leslie Dickmann Mohit Kumar Jolly Leah Schutt Jin Jin Joseph A. Ware Saroja Ramanujan Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitors CPT: Pharmacometrics & Systems Pharmacology |
| title | Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitors |
| title_full | Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitors |
| title_fullStr | Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitors |
| title_full_unstemmed | Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitors |
| title_short | Quantitative systems pharmacology model‐based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3‐kinase inhibitors |
| title_sort | quantitative systems pharmacology model based investigation of adverse gastrointestinal events associated with prolonged treatment with pi3 kinase inhibitors |
| url | https://doi.org/10.1002/psp4.12749 |
| work_keys_str_mv | AT kapilgadkar quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT christinafriedrich quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT vincenthurez quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT marialuisaruiz quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT lesliedickmann quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT mohitkumarjolly quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT leahschutt quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT jinjin quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT josephaware quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors AT sarojaramanujan quantitativesystemspharmacologymodelbasedinvestigationofadversegastrointestinaleventsassociatedwithprolongedtreatmentwithpi3kinaseinhibitors |