Evaluation of vatiquinone drug-drug interaction potential in vitro and in a phase 1 clinical study with tolbutamide, a CYP2C9 substrate, and omeprazole, a CYP2C19 substrate, in healthy subjects.

Abstract

In this study, the drug-drug interaction potential of vatiquinone with cytochrome P450 (CYP) substrates was investigated in both in vitro and clinical studies. The inhibitory potential of vatiquinone on the activity of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 was assessed in vitro. In an open-label, drug-drug interaction study in 18 healthy human subjects, a single oral dose of 500mg tolbutamide and 40mg omeprazole was administered on day 1, followed by a washout of 7days. Multiple oral doses of 400mg vatiquinone (three times a day [TID]) were administered from day 8 to day 13 with coadministration of a single oral dose of 500mg tolbutamide and 40mg omeprazole on day 12. In vitro, vatiquinone inhibited CYP2C9 (IC50 = 3.7µM) and CYP2C19 (IC50 = 5.4µM). In the clinical study, coadministration of vatiquinone did not affect the pharmacokinetic (PK) profile of tolbutamide and omeprazole. The 90% confidence intervals (CIs) of geometric least-square mean ratios for maximum plasma concentration (Cmax), areas under the plasma concentration-time curve (AUC0-t), and AUC0-inf of tolbutamide and omeprazole were entirely contained within the 80 to 125% no effect limit, except a minor excursion observed for Cmax of omeprazole (geometric mean ratio [GMR], 94.09; 90% CI, 78.70-112.50). Vatiquinone was generally well tolerated, and no clinically significant findings were reported. The in vitro and clinical studies demonstrated vatiquinone has a low potential to affect the pharmacokinetics of concomitantly administered medications that are metabolized by CYP enzymes.