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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.
Abstract:
IDH305 was developed as an orally available, mutant-selective, allosteric inhibitor of isocitrate dehydrogenase (IDH)1 for cancer treatment. It is a substrate, time-dependent inhibitor, and inducer of cytochrome P450 (CYP)3A4. As part of model-informed drug development (MIDD) of IDH305, two prospective physiologically based pharmacokinetic (PBPK) models were developed and CYP3A4 humanized mouse model was utilized to inform the first-in-human (FIH) study, where patients with advanced malignancies were to take IDH305 twice daily. The objectives are addressing whether food could be given with IDH305 and whether accumulation or reduction of PK exposure would occur follow repeat dosing. The absorption PBPK model predicted no food effect of light meals at 300 mg dose and informed the FIH study to allow dosing with light meals in cancer patients. The metabolic PBPK model, along with CYP3A4 humanized mouse studies, evaluated the interplay of CYP3A4 inhibition and induction and predicted a net outcome of modest accumulation (accumulation ratio 1.5-1.9). Both the predicted food effect and accumulation ratio were consistent with the observed data in the FIH study. This integrative translational approach informed clinical development of IDH305 and can be used to support MIDD of molecules with complex metabolic properties in oncology drug development.
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