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

Abstract

Background and ObjectiveIncreased 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 concentrationtime 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. 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 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. 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.

The Absolute Bioavailability, Absorption, Distribution, Metabolism, and Excretion of BI 425809 Administered as an Oral Dose or an Oral Dose with an Intravenous Microtracer Dose of [14C]-BI 425809 in Healthy Males

“…Another reason for reduced absolute bioavailability following a single oral dose of BI 425809 25 mg in a tablet form may be elimination via the enzyme CYP3A4 upon first-pass metabolism [ 11 ]. The major metabolic pathway for BI 425809 is mediated by CYP3A4, which is the most highly expressed CYP isoform in the liver and intestines, and is important in determining the exposure of oral medications [ 16 , 17 ]. In the present study, AUC 0–∞,norm was lower after oral dosing versus IV infusion, as was gMean C max , norm , which was around 80% lower following oral administration of BI 425809 versus IV dosing.…”

“…These observations could likely be first-pass metabolism via gastrointestinal and hepatic CYP3A4, which would only affect the oral dosing route. In a previous study, the pharmacokinetic interaction of multiple oral doses of the CYP3A4 inhibitor itraconazole and BI 425809 was assessed [ 18 ]. It was observed that there was a small increase in C max (gMean ratio 116.1% (90% CI 108.0–124.7)) following co-administration of BI 425809 and itraconazole, which most likely reflected the blocking of CYP3A4 in the first-pass metabolism.…”

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

“…The study investigated the effects of 2 mg, 5 mg, 10 mg, or 25 mg BI 425809 administered daily for 12 weeks, as an add-on strategy to antipsychotic monotherapy and cotreatment with a second antipsychotic [ 358 ]. BI 425809 was well tolerated in healthy volunteers as well as in patients [ 358 , 385 ]. A randomized trial combining BI 425809 with computerized cognitive training has been recently planned in order to consolidate the results obtained on cognitive functions [ 384 ].…”

Carbon 14 synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites

“…Twenty metabolites of BI 425809 were identified in male human plasma, urine, and feces. [19][20][21] The structures of 11 of these metabolites were unequivocally determined. Among them are the major metabolites BI 761036 (6) and BI 758790 (9) shown in Scheme 1.…”