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

Abstract

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.

Figure 1

Visualization of the model building und model evaluation steps, including the required data. PK, pharmacokinetic.

Figure 2

Time course of (a) = observerd diarrhea (b) = simulated diarrhea (c) = observed rash/acne (d) = simulated rash/acne severity for model‐building data set and internal evaluation: proportion of patients with no adverse event (green) or concurrent adverse event of grade 1 (yellow), grade 2 (orange), and grade 3 (red). Proportion of patients still on treatment indicated on top x‐axis. AE, adverse event.

Figure 3

Kaplan–Meier‐type visual predictive checks of first diarrhea (a) and first rash/acne grade 2/3 adverse events (b; both censored at time of first dose reduction/discontinuation) and first (c) and second (d) dose reduction and discontinuation (e): observed Kaplan–Meier curve (black solid line) with standard errors (black dashed lines), superimposed with simulated Kaplan–Meier curves (gray lines); shaded area corresponds to 95% confidence interval of the simulations. AE, adverse event.