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

Michael Desch, Glen Wunderlich, Markus Goettel, Sophia Goetz, Karl-Heinz Liesenfeld, Tom S Chan, Holger Rosenbrock, Regina Sennewald, Jasmin Link, Sascha Keller, Sven Wind, Michael Desch, Glen Wunderlich, Markus Goettel, Sophia Goetz, Karl-Heinz Liesenfeld, Tom S Chan, Holger Rosenbrock, Regina Sennewald, Jasmin Link, Sascha Keller, Sven Wind

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 (AUC0‒167; itraconazole), 0-168 h (AUC0‒168; 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 (AUC0‒167: 265.3; AUC0-∞: 597.0; Cmax: 116.1) and lower in the presence of rifampicin (AUC0‒168: 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).

Conflict of interest statement

MD, MG, SG, KHL, HR, RS, JL, SK, and SW are employees of Boehringer Ingelheim International GmbH, GW is an employee of Boehringer Ingelheim (Canada), and TSC is an employee of Boehringer Ingelheim Pharmaceuticals Inc. Authors did not receive any direct compensation relating to the development of this manuscript.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design. BID twice daily, DDI drug-drug interaction, QD once daily, S screening
Fig. 2
Fig. 2
Comparison of individual and gMean AUC0–167/168 and Cmax of BI 425809 after a single oral administration of BI 425809 25 mg alone and after concomitant administration with a itraconazole or b rifampicin. AUC area under the concentration-time curve, AUC0‒167/168 area under the concentration-time curve of BI 425809 in the plasma over the time interval from 0 to 167/168 h, Cmax maximum measured concentration of BI 425809 in plasma, gMean geometric mean
Fig. 3
Fig. 3
gMean drug concentration-time profiles of BI 425809 in plasma after single oral administration of BI 425809 25 mg with or without itraconazole (a) or rifampicin (b) (semi-log scale). gMean geometric mean

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