Evaluation of Growth Differentiation Factor 15 as an Early Biomarker of Anthracycline‐Induced Cardiotoxicity Using an Integrated PK / PD Model

Figures

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  FIGURE 1. Schematic representation of the pharmacokinetic–pharmacodynamic (PK/PD) models describing doxorubicin, its metabolite doxorubicinol, Nt‐proBNP, and GDF15. Figures (A) and (B) summarize the previously published PK/PD model of dox, doxol, and Nt‐proBNP [13]. (A) The pharmacokinetic component includes a three‐compartment model for doxorubicin (central compartment, V c, and two peripheral compartments, Vp2 and Vp3) with metabolism to doxorubicinol (V doxol). The pharmacodynamic component links predicted doxorubicin concentrations with indirect response models to (B) NT‐proBNP (5‐transit compartments) and (C) GDF15 (4‐transit compartments). [+]: Stimulatory effect; DOX, doxorubicin; doxol, doxorubicinol; k out, degradation rate constant; k tr, transit rate constant; Transit, transit compartment; GDF15, growth differentiation factor 15; R 0, baseline concentration; NT‐proBNP: N‐terminal probrain natriuretic peptide. Created using BioRender.com.

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  FIGURE 2. Relationship between baseline (precycle) GDF15 concentrations and chemotherapy cycle. Baseline (precycle) GDF15 concentrations stratified by chemotherapy cycle (Cycles 1–4), corresponding to increasing cumulative doxorubicin exposure (60, 120, 180, and 240 mg/m2, respectively). Each dot represents an individual patient observation, and bars represent median with interquartile range. Graph created using GraphPad Prism (Version 10.2.3).

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  FIGURE 3. Growth differentiation factor 15 (GDF15) concentrations following doxorubicin infusion. Individual patient responses (blue lines) and group mean (black lines) are shown for two cumulative dose groups (60–120 mg/m2 and 180–240 mg/m2). (A) Early response phase (0–5 h) and (B) full observation period (0–48 h).

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  FIGURE 4. Prediction‐corrected visual predictive checks (pcVPCs) for GDF15 following doxorubicin infusion. (A) Overall pcVPC for all observations. (B) pcVPCs stratified by cumulative dose (left: 60–120 mg/m2; right: 180–240 mg/m2). Points are observed concentrations; blue solid lines are observed 5th/50th/95th percentiles; shaded bands represent the 90% prediction intervals from the model simulations: pink for the median, and blue for the lower (5th) and upper (95th) percentiles.

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  FIGURE 5. Relationships between simulated GDF15 and NT‐proBNP responses. (A) Baseline NT‐proBNP vs. baseline GDF15. (B) Peak NT‐proBNP vs. peak GDF15. (C) NT‐proBNP AUC vs. GDF15 AUC. (D) percent change from baseline in NT‐proBNP vs. GDF15. (E) Percent AUC change in NT‐proBNP vs. percent AUC change in GDF15; outliers are highlighted in red and were excluded from the regression fit. Each point represents one individual; blue lines represent linear regression using the ordinary least square method.

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  FIGURE 6. Relationship between accumulated doxorubicin dose and GDF15 concentrations. (A) Simulated GDF15 concentrations from 1000 virtual patients at Day 14 post‐infusion, representing the last day before the subsequent chemotherapy cycle, are plotted against accumulated doxorubicin dose (60, 120, 180, and 240 mg/m2). Each point represents an individual patient, with a fitted linear regression line shown in red. Horizontal dashed lines indicate predefined GDF15 thresholds for cardiovascular risk categories [11, 28]: low risk (< 1200 pg/mL), moderate risk (1200–1800 pg/mL), and high risk (> 1800 pg/mL). (B) Percentage distribution of simulated patients across GDF15 risk categories, stratified by accumulated dose, derived from the simulation in (A). The stacked bars show both the proportion of patients within each risk category and the contribution of different accumulated dose groups to the overall distribution within each risk category.