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. 2022 Jan;47(1):91-103. doi: 10.1007/s13318-021-00723-y. Epub 2021 Oct 29.

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).

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Adult
  • Area Under Curve
  • Cell Line
  • Cytochrome P-450 CYP3A Inhibitors / blood
  • Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics*
  • Drug Synergism
  • Glycine Plasma Membrane Transport Proteins / metabolism
  • Healthy Volunteers
  • Humans
  • Itraconazole / administration & dosage
  • Itraconazole / blood
  • Itraconazole / pharmacokinetics*
  • Male
  • Middle Aged
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / blood
  • Nootropic Agents / pharmacokinetics*
  • Organic Chemicals / administration & dosage
  • Organic Chemicals / blood
  • Organic Chemicals / pharmacokinetics*
  • Rifampin / administration & dosage
  • Rifampin / blood
  • Rifampin / pharmacokinetics*
  • Schizophrenia / drug therapy*
  • Young Adult

Substances

  • BI 425809
  • Cytochrome P-450 CYP3A Inhibitors
  • Glycine Plasma Membrane Transport Proteins
  • Nootropic Agents
  • Organic Chemicals
  • Itraconazole
  • Rifampin

Associated data

  • ClinicalTrials.gov/NCT02342717
  • ClinicalTrials.gov/NCT03082183