| Title: |
Model-Based Prediction of Irinotecan-Induced Grade 4 Neutropenia in Cancer Patients:Influence of Incorporating Germline Genetic Factors in the Model |
| Authors: |
Karas, Spinel; Mathijssen, Ron H.J.; van Schaik, Ron H.N.; Forrest, Alan; Wiltshire, Tim; Bies, Robert R.; Innocenti, Federico |
| Source: |
Karas, S, Mathijssen, R H J, van Schaik, R H N, Forrest, A, Wiltshire, T, Bies, R R & Innocenti, F 2024, 'Model-Based Prediction of Irinotecan-Induced Grade 4 Neutropenia in Cancer Patients : Influence of Incorporating Germline Genetic Factors in the Model', Clinical Pharmacology and Therapeutics, vol. 115, no. 5, pp. 1162-1174. https://doi.org/10.1002/cpt.3190 |
| Publication Year: |
2024 |
| Subject Terms: |
/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being |
| Description: |
Neutropenia is the major dose-limiting toxicity of irinotecan-based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic/pharmacodynamic model can improve prediction of irinotecan-induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic/pharmacodynamic model was used to predict neutrophil response over time in 197 patients receiving irinotecan. Covariate analysis was performed for demographic/clinical factors and 4,781 genetic variants in 84 drug response- and toxicity-related genes to identify covariates associated with neutrophil response. We evaluated the predictive value of the model for grade 4 neutropenia reflecting different clinical scenarios of available data on identified demographic/clinical covariates, baseline and post-treatment absolute neutrophil counts (ANCs), individual pharmacokinetics, and germline genetic variation. Adding 8 genetic identified covariates (rs10929302 (UGT1A1), rs1042482 (DPYD), rs2859101 (HLA-DQB3), rs61754806 (NR3C1), rs9266271 (HLA-B), rs7294 (VKORC1), rs1051713 (ALOX5), and ABCB1 rare variant burden) to a model using only baseline ANCs improved prediction of irinotecan-induced grade 4 neutropenia from area under the receiver operating characteristic curve (AUC-ROC) of 50–64% (95% confidence interval (CI), 54–74%). Individual pharmacokinetics further improved the prediction to 74% (95% CI, 64–84%). When weekly ANC was available, the identified covariates and individual pharmacokinetics yielded no additional contribution to the prediction. The model including only ANCs at baseline and at week 1 achieved an AUC-ROC of 78% (95% CI, 69–88%). Germline DNA genetic variants may contribute to the prediction of irinotecan-induced grade 4 neutropenia when incorporated into a population pharmacokinetic/pharmacodynamic model. This approach is generalizable to drugs that induce neutropenia and ultimately allows for personalized intervention to ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
0009-9236; 1532-6535 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/38344867; info:eu-repo/semantics/altIdentifier/pissn/0009-9236; info:eu-repo/semantics/altIdentifier/eissn/1532-6535 |
| DOI: |
10.1002/cpt.3190 |
| Availability: |
https://pure.eur.nl/en/publications/9abeaf6d-87f8-4031-ae03-e0f6e0728e3e; https://doi.org/10.1002/cpt.3190; https://pure.eur.nl/ws/files/189482867/Clin_Pharma_and_Therapeutics_-_2024_-_Karas_-_Model_Based_Prediction_of_Irinotecan_Induced_Grade_4_Neutropenia_in_Cancer.pdf; https://www.scopus.com/pages/publications/85185102065 |
| Rights: |
info:eu-repo/semantics/openAccess ; https://www.eur.nl/en/library/media/2024-12-researchoutputsundertaverne-backgroundandtermsofusev2 |
| Accession Number: |
edsbas.A075D434 |
| Database: |
BASE |