Modeling Exposure‐Driven Adverse Event Time Courses in Oncology Exemplified by Afatinib
| Autor: | Mats O. Karlsson, Ronald Niebecker, Alexander Staab, Hugo Maas, Matthias Freiwald |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Diarrhea
medicine.medical_specialty Time Factors Afatinib Clinical Decision-Making MEDLINE Antineoplastic Agents Pharmacology and Toxicology Skin Diseases Article Clinical Trials Phase II as Topic Acneiform Eruptions Neoplasms medicine Humans Computer Simulation Pharmacology (medical) Adverse effect Acne business.industry Research Articles Exanthema Farmakologi och toxikologi medicine.disease Rash Dermatology Logistic Models Clinical Trials Phase III as Topic Area Under Curve Modeling and Simulation medicine.symptom business medicine.drug |
| Zdroj: | CPT: Pharmacometrics & Systems Pharmacology |
| ISSN: | 2163-8306 |
| DOI: | 10.1002/psp4.12384 |
| Popis: | Models were developed to characterize the relationship between afatinib exposure and diarrhea and rash/acne adverse event (AE) trajectories, and their predictive ability was assessed. Based on pooled data from seven phase II/III clinical studies including 998 patients, mixed-effects models for ordered categorical data were applied to describe daily AE severity. Clinical trial simulation aided by trial execution models was used for internal and external model evaluation. The final exposure-safety model consisted of longitudinal logistic regression models with first-order Markov elements for both AEs. Drug exposure was included as daily area under the concentration-time curve (AUC), and drug effects on the AEs were correlated. Clinical trial simulation allowed adequate prediction of maximum AE grades and AE severity time courses but overestimated the proportion of AE-dependent dose reductions and discontinuations. Both diarrhea and rash/acne were correlated with afatinib exposure. The developed modeling framework allows a prospective comparison of dosing strategies and study designs with respect to safety. Matthias Freiwald and Mats O. Karlsson contributed equally |
| Databáze: | OpenAIRE |
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