Clin Transl Sci. 2026 May;19(5):e70595. doi: 10.1111/cts.70595.
ABSTRACT
Doxorubicin (DOX) is an effective chemotherapeutic agent; however, its use is limited by dose-dependent cardiotoxicity, which is challenging to detect early with current biomarkers such as NT-proBNP. Growth differentiation factor-15 (GDF15) has emerged as a promising cytokine associated with cardiovascular disease. This study aimed to develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the dynamic relationship between DOX and GDF15 in patients with breast cancer, compare GDF15 responses with NT-proBNP, and evaluate the prognostic utility of GDF15. Using plasma samples from 17 breast cancer patients who received two consecutive DOX cycles, the DOX-GDF15 PK/PD model was estimated in Monolix, using DOX empirical Bayes estimates from our published DOX-NT-proBNP PK/PD model. Simulations were then performed to compare exposure metrics (Cmax, AUC) for GDF15 and NT-proBNP and to evaluate cardiovascular risk stratification based on predefined GDF15 thresholds. Our DOX-GDF15 model adequately described the observed GDF15 profiles, with an indirect stimulation response model incorporating four transit compartments. Baseline GDF15 was positively associated with cumulative DOX dose and BMI. Simulations showed that GDF15 rose rapidly, peaking at ~8 h postinfusion, whereas NT-proBNP peaked at 34 h. Correlations between GDF15 and NT-proBNP Cmax and AUC were consistently positive but weak to moderate. Simulations demonstrated a cumulative DOX dose-dependent increase in GDF15 levels and enabled cardiovascular risk stratification based on predefined GDF15 thresholds, with 8.7% of simulated patients reaching high risk, consistent with reported cardiotoxicity incidence. This PK/PD model generates the hypothesis that GDF15 may serve as an early biomarker of DOX-induced cardiotoxicity and provides a preliminary framework for risk stratification, though further validation in larger trials is warranted.
PMID:42118141 | DOI:10.1111/cts.70595