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 (Cmax ) and area under the plasma concentration-time curve from the time of dosing to infinity (AUCinf ) 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 Cmax and AUCinf 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 Cmax and AUCinf 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 Cmax and AUCinf 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.

 

Comments:

Based on the information provided, the drug interaction potential of enarodustat on the activity of several cytochrome P450 (CYP) enzymes was evaluated. The evaluation was done in a phase 1 multiple-ascending-dose study involving healthy subjects. Probe substrates specific to each enzyme were administered orally as a cocktail with enarodustat on day 15 and without enarodustat on day -3.

Here are the findings of the study:

1. CYP1A2 (probed using caffeine):
   - Geometric mean ratios (day 15/day -3) for Cmax: 0.99-1.06
   - Geometric mean ratios (day 15/day -3) for AUCinf: 1.61-1.63
   - These ratios indicate that enarodustat at both doses (25 mg and 50 mg) did not have a significant effect on CYP1A2 activity.

2. CYP2C9 (probed using tolbutamide):
   - Geometric mean ratios (day 15/day -3) for peak concentrations: 0.98-1.07
   - Geometric mean ratios (day 15/day -3) for total exposures: 0.71-1.78
   - These ratios suggest that enarodustat at both doses had minimal impact on CYP2C9 activity.

3. CYP2C19 (probed using omeprazole):
   - Geometric mean ratios (day 15/day -3) for peak concentrations: Not provided
   - Geometric mean ratios (day 15/day -3) for total exposures: 0.71-1.78
   - The lack of information on peak concentrations makes it difficult to draw conclusions about the effect of enarodustat on CYP2C19 activity.

4. CYP2D6 (probed using dextromethorphan):
   - Geometric mean ratios (day 15/day -3) for Cmax: 0.83-0.90
   - Geometric mean ratios (day 15/day -3) for AUCinf: 1.02-1.04
   - These ratios indicate that enarodustat had minimal impact on CYP2D6 activity.

5. CYP3A4 (probed using midazolam):
   - Geometric mean ratios (day 15/day -3) for Cmax: 1.42-1.63
   - Geometric mean ratios (day 15/day -3) for AUCinf: Not provided
   - The lack of information on AUCinf makes it difficult to draw conclusions about the effect of enarodustat on CYP3A4 activity.

In general, the results suggest that enarodustat did not have a significant impact on the activity of the evaluated CYP enzymes, except for a slight decrease in CYP2D6 activity (as indicated by the lower Cmax ratio for dextromethorphan). However, the changes observed in the geometric mean ratios were all less than 2-fold, indicating a lack of clinically significant drug interactions.

It's important to note that the information provided is a summary of the findings, and it is always recommended to consult the complete study or consult a healthcare professional for a comprehensive understanding of drug interactions and their potential implications.

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S9656	Enarodustat (JTZ-951)	Enarodustat (JTZ-951) is a potent and orally active HIF prolyl hydroxylase inhibitor with IC50 of 0.22 μM for PHD2 and EC50 of 5.7 μM for EPO release from Hep3B cells. Enarodustat has the potential for the treatment of renal anemia.

Related Targets

HIF