Clinical and Physiologically Based Pharmacokinetic Model Evaluations of Adagrasib Drug–Drug Interactions

Physiologically-based pharmacokinetic (PBPK) modeling is a helpful tool for exploring scenarios that would be difficult or unfeasible to investigate through traditional clinical trials. In this webinar, we’ll highlight how a PBPK model for adagrasib, a covalent inhibitor of the G12C-mutated KRAS protein used to treat non-small cell lung cancer in adults, predicted potential drug-drug interactions (DDIs), provided dosing recommendations, and influenced the adagrasib program and labeling.

Adagrasib is both a substrate and a potent mechanism-based inhibitor (MBI) of cytochrome P450 (CYP) 3A4. As it is subject to auto-inhibition, it’s DDI liability is complex. A PBPK model for adgrasib was developed using Simcyp™ to capture the available clinical pharmacokinetic (PK) and DDI data in healthy volunteers and patients. The model was then used to predict untested DDI scenarios for the therapeutic dose at steady-state in patients.

The model demonstrated that following adagrasib dosing to steady-state, CYP3A4 is almost completely inactivated. Therefore, despite a moderate clinical DDI with itraconazole after a single dose adagrasib, the model predicted very little change in adagrasib exposure with itraconazole when adagrasib was dosed to steady-state. Based on the modeling results, the current labeling removes restrictions for co-administration of CYP3A4 inhibitors once adagrasib has reached steady-state.

The model was also used successfully to predict perpetrator DDI risks and the effects of hepatic impairment on drug exposure.