Effects of Cytochrome P450 3A4 Induction and Inhibition on the Pharmacokinetics of BI 425809, a Novel Glycine Transporter 1 Inhibitor.
| Autor: | Desch M; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany. michael.desch@boehringer-ingelheim.com., Wunderlich G; Boehringer Ingelheim Canada Ltd, Burlington, ON, Canada., Goettel M; Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany., Goetz S; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany., Liesenfeld KH; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany., Chan TS; Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA., Rosenbrock H; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany., Sennewald R; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany., Link J; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany., Keller S; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany., Wind S; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Baden Württemberg, Germany. |
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| Jazyk: | angličtina |
| Zdroj: | European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2022 Jan; Vol. 47 (1), pp. 91-103. Date of Electronic Publication: 2021 Oct 29. |
| DOI: | 10.1007/s13318-021-00723-y |
| Abstrakt: | Background and Objective: Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin). Methods: In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism. In addition, two open-label, fixed-treatment period, phase I studies in healthy male volunteers are described. Period 1: participants received oral BI 425809 25 mg (single dose) on day 1; period 2: participants received multiple doses, across 10 days, of oral itraconazole or rifampicin combined with a single dose of oral BI 425809 25 mg on day 4/7 of the itraconazole/rifampicin treatment, respectively. Pharmacokinetic and safety endpoints were assessed in the absence/presence of itraconazole/rifampicin and included area under the concentration-time curve (AUC) over the time interval 0-167 h (AUC Results: In vitro results suggested that CYP3A4 accounted for ≥ 90% of the metabolism of BI 425809. BI 425809 exposure (adjusted geometric mean ratio [%]) was higher in the presence of itraconazole (AUC Conclusions: Systemic exposure of BI 425809 was altered in the presence of strong CYP3A4 modulators, corroborating in vitro results that CYP3A4 mediates a major metabolic pathway for BI 425809. Trial Registration Number: NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017). (© 2021. The Author(s).) |
| Databáze: | MEDLINE |
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