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.
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...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 78; no. 11; pp. 1823 - 1832 |
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| Autores principales: | , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Springer Nature
Nov2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=159549288&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 159549288 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Nov2022 vid: 78 iid: 11 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 159549288 159349041 159549288 159549288 10.1007/s00228-022-03393-0 159549288 ppf: 1823 ppct: 9 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: 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. aug: au: Murase, Katsuyuki Lee, Lucy Ma, Jiyuan Barrett, Rosemary Thoolen, Martin affil: PTC Therapeutics, Inc., 100 Corporate Court, 07080, South Plainfield, NJ, USA sug: subj: Enzyme Inhibitors Cytochrome P-450 Enzyme System Tolbutamide Pharmacokinetics Omeprazole Pharmacokinetics Drug Interactions Evaluation Human In Vitro Studies Female Male Adult Confidence Intervals Adult: 19-44 years Female Male ab: 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 (IC50 = 3.7 µM) and CYP2C19 (IC50 = 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 (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. 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. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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