Suzetrigine Is Not Expected to Have Clinically Relevant DDIs with Apixaban and Rivaroxaban Based on PBPK Modeling

Suzetrigine (VX-548) is a first-in-class, oral, non-opioid, FDA-approved analgesic for the treatment of moderate to severe acute pain. Based on Phase 1 clinical drug-drug interaction (DDI) studies, suzetrigine is a weak-to-moderate cytochrome P450 3A (CYP3A) inducer and thus has the potential to decrease exposure and impact efficacy of CYP3A substrates, such as apixaban and rivaroxaban, which are commonly used as anticoagulants peri- and post-operatively. Given this, it is important to assess the DDIs of apixaban and rivaroxaban with suzetrigine. Physiologically based pharmacokinetic (PBPK) models are commonly used to assess DDIs mediated through modulation of CYP3A and were used here to quantify the potential effect of co-administration of suzetrigine on apixaban and rivaroxaban PK. The PBPK models were validated using observed data from suzetrigine, apixaban, and rivaroxaban clinical DDI studies. The validated models predict that suzetrigine decreases apixaban AUCinf by 6.1% (90% confidence interval [CI]: 5.7% to 6.4%) and Cmax by 1.8% (90% CI: 1.7% to 1.9%), and rivaroxaban AUCinf by 8.4% (90% CI: 7.2% to 9.6%) and Cmax by 3.5% (90% CI: 3.3% to 3.7%). The predicted small reductions in apixaban and rivaroxaban exposures (AUCinf <10%) are not expected to be clinically relevant since a 20% no-effect boundary is typically used to determine the clinical impact of a DDI. The PBPK model predictions are consistent with the apixaban and rivaroxaban labels, which do not warn against co-administration with weak or moderate CYP3A inducers, such as suzetrigine.