Effects of Cytochrome P450 3A4 Induction and Inhibition on the Pharmacokinetics of BI 425809, a Novel Glycine Transporter 1 Inhibitor

Le résumé fourni par la source

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). 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 0‒167 ; itraconazole), 0–168 h (AUC 0‒168 ; rifampicin), or 0–infinity (AUC 0-∞ ; rifampicin and itraconazole), maximum measured concentration ( C max ) of BI 425809, and adverse events. 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 0‒167 : 265.3; AUC 0−∞ : 597.0; C max : 116.1) and lower in the presence of rifampicin (AUC 0‒168 : 10.3; AUC 0−∞ : 9.8; C max : 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated. 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. NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017)

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.