Effects of Cytochrome P450 3A4 Induction and Inhibition on the Pharmacokinetics of BI 425809, a Novel Glycine Transporter 1 Inhibitor.
Eur J Drug Metab Pharmacokinet
; 47(1): 91-103, 2022 Jan.
Article
in En
| MEDLINE
| ID: mdl-34716565
ABSTRACT
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 (AUC0â167; itraconazole), 0-168 h (AUC0â168; rifampicin), or 0-infinity (AUC0-∞; rifampicin and itraconazole), maximum measured concentration (Cmax) of BI 425809, and adverse events.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 (AUC0â167 265.3; AUC0-∞ 597.0; Cmax 116.1) and lower in the presence of rifampicin (AUC0â168 10.3; AUC0-∞ 9.8; Cmax 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated.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).
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Organic Chemicals
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Rifampin
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Schizophrenia
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Itraconazole
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Nootropic Agents
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Cytochrome P-450 CYP3A Inhibitors
Type of study:
Prognostic_studies
Limits:
Adolescent
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Adult
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Humans
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Male
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Middle aged
Language:
En
Journal:
Eur J Drug Metab Pharmacokinet
Year:
2022
Document type:
Article
Affiliation country:
Alemania