129: Clinical & Physiologically Based Pharmacokinetic Model Evaluations of Adagrasib as a Perpetrator of Drug-Drug Interactions in Cancer Patients

Statement of Purpose: Adagrasib is a potent, selective and covalent KRAS G12C inhibitor that was recently granted accelerated approval by the US FDA for adult patients with KRAS G12C‑mutated locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy. In vitro, adagrasib is an inhibitor of CYP3A4, CYP2C9, CYP2D6, P-gp and BCRP. A physiologically based pharmacokinetic model (PBPK) was developed to predict the effect of adagrasib in cancer patients at the recommended 600 mg twice daily (BID) on the substrates of these enzymes and transporters to support dosing recommendation in the adagrasib label.

Description of Methods & Materials: A PBPK model was developed in the Simcyp Simulator based on physicochemical and in vitro parameters, and clinical pharmacokinetic (PK) data from two healthy volunteer (HV) studies, including a clinical drug-drug interaction (DDI) study, and a study in patients with KRAS G12C mutated cancer. The clinical DDI study evaluated a single 600 mg dose and 400 mg BID of adagrasib on the PK of a probe-drug cocktail consisting of midazolam, warfarin, dextromethorphan, digoxin and rosuvastatin (CYP3A, CYP2C9, CYP2D6, P-gp and BCRP substrates, respectively). The PBPK model was used to predict adagrasib DDI as a perpetrator against CYP and P-gp substrates in the untested recommended dose of 600 mg BID in patients.

Data & Results: The model was quantitatively evaluated by comparing the predicted to observed ratios for maximal drug concentration (C_max), area under the curve (AUC) and geometric mean ratios (GMRs) for C_max and AUC. The model well-described the single-dose and multiple-dose PK of adagrasib in HVs and patients, with predictions within 1.5-fold of observed values in all cases. PBPK simulations showed that adagrasib 600 mg BID is predicted to increase the AUC of midazolam, warfarin, dextromethorphan and digoxin by 31-, 2.9-, 2.4- and 1.5-fold, respectively. Administration of adagrasib 600 mg single dose did not change rosuvastatin AUC.

Interpretation, Conclusion or Significance: PBPK modeling showed that at the 600 mg BID dosing regimen in cancer patients adagrasib is a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2C9 and CYP2D6. While adagrasib inhibits P-gp, it does not inhibit BCRP. These results support dosing recommendation for substrates of these enzymes and transporters in the adagrasib label.

Disclosures: The study was funded by Mirati Therapeutics.