In vitro to clinical translational pharmacokinetic/pharmacodynamic modeling of doxorubicin (DOX) and dexrazoxane (DEX) interactions: Safety assessment and optimization

Figure 1. Schematic of the in vitro cellular-level toxicodynamic model (TD) for the single and combinatorial effects of Doxorubicin (DOX) and Dexrazoxane (DEX) on AC16 human cardiomyocytes. Definitions of parameters for the model are listed in Table 1. The solid lines with arrows denote turnover of the indicated response. The green circle represents cell viability while the blue boxes represent transit compartments to describe the delay in the stimulation of death by DOX. Solid black rectangles represent inhibition and open solid rectangles represent stimulation processes induced by DOX and DEX as single agents and as indicated by dashed black arrows. The cardioprotective effect of DEX on DOX-induced cardiotoxicity is indicated by red dashed arrows, with the red solid rectangle representing an inhibition process.

Figure 2. (A) Simulated degradation kinetics of DOX (top) and DEX (bottom) at indicated concentrations in a cell culture media. The first-order degradation rate (kdeg) for DOX and DEX were estimated as in Supp. Fig. 1 and were assumed to be constant at indicated concentrations. (B, C). Model fittings for the in vitro effects of the single agents, DOX (B, top) and DEX (B, bottom) as well as the combinatorial effects of DOX and DEX (C) at indicated concentrations over time on the cell viability of human cardiomyocytes AC16s (toxicodynamic model). All observed data are represented by solid circles while the smooth lines are model fittings or simulations.

Figure 3. Model structure of clinical pharmacokinetics for doxorubicin (DOX) (3-compartment; Left, Top) and for Dexrazoxane (DEX) (2-compartment; Left, Bottom). Schematic of the in vitro cellular-level toxicodynamic model (TD) for the single and combinatorial effects of Doxorubicin (DOX) and Dexrazoxane (DEX) (Right) on human cardiomyocytes. Time-varying concentrations were utilized to drive the DOX + DEX TD model as represented by the green dashed arrows.

Figure 4. (A,B) Model simulations for doxorubicin (DOX) clinical pharmacokinetics over three dosing cycles (A) and one dosing cycle (B) at indicated dose levels. (C,D) Model simulations for dexrazoxane (DEX) clinical pharmacokinetics over three dosing cycles (C) and one dosing cycle (D) at indicated dose levels. (E) Area under the effect (cell viability) curves for 50 mg/m2 DOX administered once every three weeks for three dosing cycles in the presence of varying DEX:DOX dose ratios as indicated. AUECs are represented as the ratio of AUECDEX+DOX/AUECDOX.. The shaded bar represents the optimal dose ratio that demonstrates maximum cardio protection with DEX.

Figure 5. (A) Doxorubicin (DOX) clinical pharmacokinetic simulations: Blue profile—50 mg/m2 administered every three weeks (Q3W) for three cycles, Red profile—16.67 mg/m2 administered once every week (Q1W) as a dose-fractionated regimen. (B) Area under the effect (cell death) curves for doxorubicin (DOX) administered as a Q3W or Q1W regimen in the presence or absence of dexrazoxane (DEX) over three weeks (one dosing cycle) and (C) over nine weeks (three dosing cycles). Black solid bars represent Q3W regimens and open bars represent Q1W regimens of DOX. The Q3W DOX regimen with 10:1 DEX:DOX ratio at the indicated dose levels demonstrates maximum cardio protection.