A quantitative systems pharmacology approach to predict the safe-equivalent dose of doxorubicin in patients with cardiovascular comorbidity

Abstract

Patients with cardiovascular comorbidity are less tolerant to cardiotoxic drugs and should be treated with reduced doses to prevent cardiotoxicity. However, the safe-equivalent dose of antitumor drugs in patients with cardiovascular disease/risk is difficult to predict because they are usually excluded from clinical trials as a result of ethical considerations. In this study, a translational quantitative system pharmacology-pharmacokinetic-pharmacodynamic (QSP-PK-PD) model was developed based on preclinical study to predict the safe-equivalence dose of doxorubicin in patients with or without cardiovascular disease. Virtual clinical trials were conducted to validate the translational QSP-PK-PD model. The model replicated several experimental and clinical observations: the left ventricular ejection fraction (LVEF) was reduced and the left ventricular end-diastolic volume (LVEDV) was elevated in systolic dysfunction rats, the LVEF was preserved and LVEDV reduced in diastolic dysfunction rats, and patients with preexisting cardiovascular disease were more vulnerable to doxorubicin-induced cardiac dysfunction than cardiovascular healthy patients. A parameter sensitivity analysis showed that doxorubicin-induced cardiovascular dysfunction was mainly determined by the sensitivity of cardiomyocytes to cardiotoxic drugs and the baseline value of LVEDV, reflected in LVEF change percentage from the baseline. Blood pressure was the least sensitive factor affecting doxorubicin-induced cardiotoxicity.