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Published on: October 17, 2025
Ontogeny and sorafenib metabolism
Eric I Zimmerman1, Justin L Roberts, Lie Li
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Summary
Sorafenib metabolism to its active N-oxide metabolite varies by age, sex, and azole antifungal use in children. These factors are crucial for optimizing sorafenib therapy in pediatric patients.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Drug Metabolism
Background:
- Sorafenib is a kinase inhibitor used in treating various cancers.
- Its active metabolite, sorafenib N-oxide, contributes to its therapeutic effect.
- Understanding factors influencing sorafenib metabolism is key for effective treatment, especially in pediatric populations.
Purpose of the Study:
- To investigate the impact of ontogeny (developmental stage) on sorafenib metabolism to sorafenib N-oxide.
- To identify factors contributing to interpatient variability in sorafenib N-oxide formation.
- To assess the potential for drug-drug interactions with azole antifungal agents.
Main Methods:
- Pharmacokinetic studies in 30 children and young adults receiving sorafenib.
- In vitro metabolism assays using human cytochrome P450 (CYP) enzymes.
- Analysis of sorafenib metabolism and CYP3A4 expression in human liver samples from young donors.
- In vitro and in vivo evaluation of drug-drug interactions with azole antifungals.
Main Results:
- No significant age-related differences in sorafenib oral clearance were found.
- Sorafenib N-oxide formation was exclusively mediated by CYP3A4.
- In children ≤10 years, boys exhibited approximately 2-fold higher N-oxide ratios than girls.
- Azole antifungals (posaconazole, voriconazole) potently inhibited N-oxide formation in vitro and in vivo.
Conclusions:
- Interpatient variability in sorafenib metabolism is influenced by age, sex, and co-administration of azole antifungals.
- CYP3A4 plays a critical role in sorafenib N-oxide formation.
- These findings have implications for the clinical management of sorafenib in children and other CYP3A4-metabolized kinase inhibitors.
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