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

• Published in: European journal of clinical pharmacology Vol. 78; no. 11; pp. 1823 - 1831
• Main Authors: Murase, Katsuyuki, Lee, Lucy, Ma, Jiyuan, Barrett, Rosemary, Thoolen, Martin
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2022; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cytochrome P450; Drug dosages; Drug interaction; Drug interactions; Omeprazole; Pharmacokinetics; Pharmacology/Toxicology; Tolbutamide; Drug-drug interactions; Healthy volunteers; Pharmacokinetics; CYP inhibition; Vatiquinone
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-022-03393-0

Purpose In this study, the drug-drug interaction potential of vatiquinone with cytochrome P450 (CYP) substrates was investigated in both in vitro and clinical studies. Methods 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 500 mg tolbutamide and 40 mg omeprazole was administered on day 1, followed by a washout of 7 days. Multiple oral doses of 400 mg vatiquinone (three times a day [TID]) were administered from day 8 to day 13 with coadministration of a single oral dose of 500 mg tolbutamide and 40 mg omeprazole on day 12. Results In vitro, vatiquinone inhibited CYP2C9 (IC 50  = 3.7 µM) and CYP2C19 (IC 50  = 5.4 µM). 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 ( C max ), areas under the plasma concentration–time curve (AUC 0-t ), and AUC 0 -inf of tolbutamide and omeprazole were entirely contained within the 80 to 125% no effect limit, except a minor excursion observed for C max 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. Conclusion 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.