No relevant pharmacokinetic interaction between the KRAS G12C inhibitor sotorasib and the direct oral anticoagulant rivaroxaban in healthy subjects

Abstract Cancer patients have an increased risk of thromboembolic events. Consequently, anticoagulants such as rivaroxaban are often prescribed. With the increasing use of targeted therapies, there is a growing concern about potential drug–drug interactions, as these therapies can affect metabolic enzymes and transporters (i.e., cytochrome P450 3A and P‐glycoprotein). When used in combination with rivaroxaban, these interactions may elevate a patient's risk of thromboembolic events or bleeding. Our primary objective was to investigate the effect of sotorasib on the pharmacokinetics of rivaroxaban and determine the safety of this combination in healthy volunteers. In an open label, single‐sequence, pharmacokinetic drug–drug interaction study in healthy subjects, the influence of a once‐daily 960 mg dose sotorasib for a period of 14 days was evaluated on the pharmacokinetics of a single 20 mg dose rivaroxaban. This clinical study followed the FDA guidance on drug interaction studies. A clinically relevant pharmacokinetic interaction was considered absent if the 90% confidence intervals (CIs) of the geometric mean ratios for C max and AUC 0–∞ were within the no‐effect boundaries of 0.70–1.43. A total of 20 healthy subjects completed the study. The geometric mean ratios 1.00 (90% CI 0.90–1.12) for C max and 0.79 (90% CI 0.73–0.86) for AUC 0–∞ fell inside the predefined criteria, indicating no clinically relevant pharmacokinetic interaction. In addition, rivaroxaban and sotorasib were well tolerated by the healthy subjects. These results suggest that rivaroxaban can be safely co‐administered without the need for switching to another treatment or dose adjustments in patients treated with sotorasib.