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Translational PBPK modeling and model-informed drug development of IDH305, a complex CYP3A4 modulator
Yan Ji1, Wen Lin2, Tycho Heimbach3
1Pharmacokinetic Sciences, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Journal of Pharmaceutical Sciences
|July 31, 2026
Summary
IDH305, an isocitrate dehydrogenase 1 inhibitor, can be taken with light meals and shows modest accumulation with repeat dosing. This finding supports its clinical development in cancer patients.
Area of Science:
- Oncology
- Pharmacokinetics
- Drug Development
Background:
- IDH305 is an orally available, mutant-selective inhibitor of isocitrate dehydrogenase 1 (IDH1) for cancer treatment.
- IDH305 exhibits complex pharmacokinetic properties, including time-dependent inhibition and induction of cytochrome P450 3A4 (CYP3A4).
Purpose of the Study:
- To assess the impact of food on IDH305 pharmacokinetics.
- To predict drug accumulation following repeat dosing.
- To inform the first-in-human (FIH) study of IDH305.
Main Methods:
- Development of two physiologically based pharmacokinetic (PBPK) models for IDH305.
- Utilizing a CYP3A4 humanized mouse model to evaluate drug metabolism.
- Integrating PBPK modeling and preclinical data to predict clinical outcomes.
Main Results:
- PBPK modeling predicted no significant food effect with light meals at the 300 mg dose.
- PBPK modeling and mouse studies predicted modest accumulation (accumulation ratio 1.5-1.9) due to CYP3A4 inhibition and induction.
- Predicted food effect and accumulation were consistent with observed data in the FIH study.
Conclusions:
- An integrative translational approach using PBPK models and preclinical data successfully informed the clinical development of IDH305.
- Model-informed drug development (MIDD) can support molecules with complex metabolic profiles in oncology.
- IDH305 can be administered with light meals, and modest accumulation is expected upon repeat dosing.
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