Modeling Exposure-Driven Adverse Event Time Courses in Oncology Exemplified by Afatinib

CPT Pharmacometrics Syst Pharmacol. 2019 Apr;8(4):230-239. doi: 10.1002/psp4.12384. Epub 2019 Feb 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acneiform Eruptions / chemically induced
  • Afatinib / adverse effects*
  • Afatinib / therapeutic use
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Clinical Decision-Making
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Computer Simulation
  • Diarrhea / chemically induced*
  • Exanthema / chemically induced
  • Humans
  • Logistic Models
  • Neoplasms / drug therapy*
  • Skin Diseases / chemically induced*
  • Time Factors


  • Antineoplastic Agents
  • Afatinib