Evaluation of Drug–Drug Interaction Potential of Enarodustat (JTZ‐951) Using a Cytochrome P450 Probe Cocktail

The drug interaction potential of enarodustat (doses: 25, 50 mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once‐daily administration for 15 days in a phase 1 multiple‐ascending‐dose study in healthy subjects. Probe substrates specific for the enzymes, i.e., caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were administered orally as a cocktail with (day 15) and without (day −3) enarodustat. Drug interaction was based on geometric mean maximum plasma concentration (C max ) and area under the plasma concentration‐time curve from the time of dosing to infinity (AUC inf ) ratios (day 15/day −3) for CYP1A2, 2C9, 2C19, 2D6, 3A4, and urinary excretion of dextromethorphan metabolite dextrorphan for CYP2D6. At the 2 enarodustat doses, for caffeine, the geometric mean ratios (range) for C max and AUC inf were 0.99–1.06 and 1.61–1.63, respectively. The ratios for peak concentrations and total exposures were 0.98–1.07 and 0.71–1.78 for tolbutamide and omeprazole, respectively. For dextrorphan the C max and AUC inf ratios were 0.83–0.90 and 1.02–1.04, respectively. The mean dextrorphan cumulative amount excreted into the urine from the time of dosing to 24 hours values on day −3 and day 15 were 8.25 mg and 8.20 mg at the lower dose, and 9.40 mg and 9.51 mg at the higher dose. The ratios for midazolam C max and AUC inf were 1.42–1.63. Overall, there was a lack of enarodustat dose dependency regarding the geometric mean ratios and 90% confidence intervals and urinary excretion of dextrorphan. There were some cases where the 90% confidence intervals at the 2 enarodustat doses were outside the 0.80–1.25 range, but changes in the geometric mean ratios were all <2‐fold.