Drug Interactions between daprodustat and trimethoprim

MONITOR: Coadministration with inhibitors of CYP450 2C8 may increase the plasma concentrations and the risk of adverse effects associated with daprodustat, which is primarily metabolized by the isoenzyme. When gemfibrozil (600 mg twice daily for 5 days), a potent CYP450 2C8 inhibitor, was administered with a single daprodustat dose of 100 mg on day 4 of gemfibrozil administration, daprodustat peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.9-fold and 18.6-fold, respectively. In addition, daprodustat Cmax and AUC are predicted to increase by at least 3-fold and 4-fold, respectively, following concomitant administration with clopidogrel 75 mg once daily (a moderate CYP450 2C8 inhibitor). When trimethoprim (200 mg twice daily for 5 days), a weak CYP450 2C8 inhibitor, was coadministered with a single daprodustat dose of 25 mg on day 4 of trimethoprim administration, daprodustat Cmax and AUC increased by 1.3-fold and 1.5-fold, respectively.

MANAGEMENT: Caution is recommended when daprodustat is coadministered with CYP450 2C8 inhibitors. Monitoring of hemoglobin levels and adjusting the dose of daprodustat may be considered following initiation or discontinuation of treatment with CYP450 2C8 inhibitors.