KEY TAKEAWAYS
- The study aimed to investigate how isavuconazole interacts with sunitinib in advanced RCC treatment.
- The results showed that isavuconazole significantly alters sunitinib metabolism, aiding in its therapeutic management.
Sunitinib, a multi-targeted tyrosine kinase inhibitor, has become a standard treatment option for individuals with advanced renal cell carcinoma (RCC).
Jinyu Hu and the team aimed to explore the mechanisms underlying the interaction between sunitinib and isavuconazole.
The study utilized ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to analyze and quantify sunitinib and its primary metabolite, N-desethyl sunitinib. They evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models.
For the in vivo study, 2 groups of Sprague-Dawley rats were randomly assigned to receive sunitinib with or without isavuconazole co-administration. Additionally, they investigated how isavuconazole affects the metabolic stability of sunitinib and N-desethyl sunitinib in RLM in vitro.
The results demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. In HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM.
In vivo studies indicated that isavuconazole significantly enhanced the pharmacokinetic (PK) characteristics of sunitinib, with AUC(0→t), AUC(0→∞), and Tmax increasing to approximately 211.38%, 203.92%, and 288.89%, respectively, compared to the control group (5 mg/kg sunitinib alone).
The PK characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib.
The study concluded that isavuconazole significantly impacts the metabolism of sunitinib, offering crucial insights for optimizing its therapeutic use.
No funding was provided.
Source: https://pubmed.ncbi.nlm.nih.gov/39261851/
Hu J, Xia H, Chen X, et al. (2024). “Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism.” BMC Cancer. 2024;24(1):1131. Published 2024 Sep 11. doi:10.1186/s12885-024-12904-4
