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PK/PD modeling based on NO-ET homeostasis for improving management of sunitinib-induced hypertension in rats
Hao-Chen Liu1, Xiao-Ting Zhou1, Yun-Si Zheng1
1Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
Abstract:
Sunitinib is an oral small molecule multitargeted tyrosine kinase inhibitor, which is currently used to treat severe cancers. Clinical research has shown that patients treated with sunitinib develop hypertension. As soon as sunitinib-induced hypertension appears, it is usual to administer anti-hypertension agent. But this treatment may cause acute blood pressure fluctuation which may lead to additional cardiovascular risk. The aim of this study is to establish a mathematical model for managing sunitinib-induced hypertension and blood pressure fluctuation. A mechanism-based PK/PD model was developed based on animal experiments. Then this model was used to perform simulations, thus to propose an anti-hypertension indication, according to which the anti-hypertension treatment might yield relative low-level AUC and fluctuation of blood pressure. The simulation results suggest that the anti-hypertension agent may yield low-level AUC and fluctuation of blood pressure when relative ET-1 level ranges from -15% to 5% and relative NO level is more than 10% compared to control group. Finally, animal experiments were conducted to verify the simulation results. Macitentan (30 mg/kg) was administered based on the above anti-hypertension indication. Compared with the untreated group, the optimized treatment significantly reduced the AUC of blood pressure; meanwhile the fluctuation of blood pressure in optimized treatment group was 70% less than that in immediate treatment group. This work provides a novel model with potential translational value for managing sunitinib-induced hypertension.
Insights
This study developed a mathematical model to manage sunitinib-induced hypertension. The model helps optimize anti-hypertension treatment, reducing blood pressure fluctuations and cardiovascular risks in cancer patients.
Area of Science:
- Pharmacology
- Mathematical Biology
- Oncology
Background:
- Sunitinib, a tyrosine kinase inhibitor for cancer, commonly causes hypertension.
- Current treatments for sunitinib-induced hypertension risk acute blood pressure fluctuations and cardiovascular events.
Purpose of the Study:
- To develop a mathematical model for managing sunitinib-induced hypertension and associated blood pressure fluctuations.
- To propose an optimized anti-hypertension treatment strategy to minimize cardiovascular risks.
Main Methods:
- A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model was created using animal experiment data.
- Simulations were performed to identify optimal anti-hypertension treatment parameters.
- Macitentan was administered in animal studies to validate simulation findings.
Main Results:
- The model suggests optimal treatment when endothelin-1 (ET-1) levels are -15% to 5% and nitric oxide (NO) levels are >10% compared to controls.
- Optimized treatment with Macitentan significantly reduced blood pressure AUC.
- Blood pressure fluctuation was reduced by 70% compared to immediate treatment in animal models.
Conclusions:
- A novel PK/PD model offers a potential strategy for managing sunitinib-induced hypertension.
- Optimized anti-hypertension management can mitigate blood pressure variability and cardiovascular risks.
- This approach has translational value for clinical application in cancer patient care.
