Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics

Subjects were allocated to seven sequential dose groups; five groups comprised healthy young subjects [BI 425809 QD at 10, 25, 50 or 75 mg, or BI 425809 twice daily (BID) at 75 mg], and two comprised healthy elderly subjects (BI 425809 QD at 25 or 50 mg). Within each dose group, subjects were randomised to receive the active drug or placebo at a ratio of 3:1, such that nine subjects received the active drug and three received placebo. Each subject received a single dose of BI 425809 or placebo on day 1, followed by QD (dose groups 1–6, 10–75 mg) or BID (dose group 8, 75 mg) dosing for 10 days from day 4 onwards. On day 14, all dose groups received one single dose of BI 425809 or placebo. Dose groups were investigated consecutively in ascending order and a documented safety review was undertaken prior to each dose escalation. Healthy elderly subjects were dosed after a respective dose of BI 425809 had been well tolerated in healthy young subjects. Blood samples for pharmacokinetic assessments were taken following the first and last doses, and at regular intervals between days 1 and 14, after which daily samples were collected until day 23. Urine was collected for pharmacokinetic analysis during pre-specified periods following the first and last doses in the QD dose groups only. The effects of different types of food intake on BI 425809 pharmacokinetics were analysed in dose groups 2 and 5 (BI 425809 25 mg in young and elderly subjects, respectively) under light-fed (standardised light breakfast [~ 500 kcal] served 30 min before BI 425809 administration; day 12, dose group 2) [Table 1 of the Electronic Supplementary Material (ESM)], and light-fasted (no food for ≥ 10 h before, until 1 h after BI 425809 administration; day 12, dose group 5) conditions. In both dose groups, additional pharmacokinetic profiles were taken on day 12 and compared with the respective pharmacokinetic profiles on day 14. Fasted conditions (no food for ≥ 10 h before, until 3.5 h after BI 425809 administration) were employed on days 1 and 14, with light-fasted conditions used for the remaining treatment days in all groups except group 8 (Fig. 1). Twice-daily dosing and administration under light-fed conditions were applied to dose group 8 to increase the bioavailability of BI 425809.

Each subject (dose group 7) received two single doses of BI 425809 25 mg separated by a washout period of at least 11 days. The dose of BI 425809 was administered either in the morning or in the evening, per the randomisation scheme. All subjects were in a fasted state for the administration of BI 425809. Blood samples for pharmacokinetic assessment were taken prior to and up to 96 h after administration of the active drug (Fig. 1).

A total of 96 subjects were entered into the study: 84 in part 1, of whom 24 were elderly subjects, and 12 in part 2. Eligible subjects were healthy male or female (of non-childbearing potential) volunteers, 18–50 years of age for young subjects, or 65–80 years of age for elderly subjects, with a body mass index of 18.5–29.9 kg/m².

Subjects were excluded if they exhibited any evidence of a concomitant disease judged as clinically relevant upon physical examination, vital-sign assessment, electrocardiogram (ECG) or laboratory test (haematology, clinical chemistry, infectious serology and urinalysis). Other key exclusion criteria included: gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders; diseases of the central nervous system, other neurological disorders, or psychiatric disorders; history of suicidal behaviour, macular degeneration or relevant orthostatic hypotension, fainting spells or blackouts; chronic or relevant acute infections; history of relevant allergy/hypersensitivity (including allergy to the study medication or its excipients); drug abuse, excessive alcohol intake (> 20 g/day for female individuals and > 30 g/day for male individuals), use of tobacco (more than five cigarettes, one cigar or one pipe per day) or inability to refrain from smoking on study days.

The primary endpoint of part 1 and the secondary endpoint of part 2 was the number (N [%]) of subjects with drug-related AEs. Adverse events were defined as any untoward medical occurrence and included any clinically relevant findings from physical examination, laboratory tests, ECG, vital-sign measurement and the exacerbation of any pre-existing condition. Adverse events were classified according to the following criteria: mild, awareness of signs or symptoms that were easily tolerated; moderate, sufficient discomfort to interfere with usual activities; and severe, incapacitating or causing an inability to work or perform usual activities. Further criteria of interest were: neurological examination; safety laboratory tests (clinical chemistry, haematology and urinalysis); 12-lead ECGs; visual tests (Ishihara test, Jaeger Eye Chart and Amsler grid); ophthalmological examination, including fundus photography, (part 1 only); vital signs [blood pressure, pulse rate and respiratory rate (BI 425809 75-mg BID group only)]; oxygen saturation (BI 425809 75-mg BID group only); suicidality monitoring; and assessment of visual analogue scales (VASs) for possible central nervous system effects (subjective feelings) using the scales developed by Bond and Lader [14] and Bowdle et al. [15].

The primary pharmacokinetic endpoints (assessed in part 2) were AUC_0–tz and C_max of the analyte. Secondary endpoints assessed in part 1 included AUC of the analyte from 0 to 24 h (AUC_0–24) and C_max after the first dose; and AUC and C_max at steady state over a uniform dosing interval τ (AUC_τ,ss and C_max,ss) following the last dose. Additional pharmacokinetic parameters assessed during this study are described within the ESM. The pharmacokinetic software used in this study was Phoenix WinNonlin Version 6.3 (Certara L.P. [Pharsight], St. Louis, MO; for the non-compartmental analysis) using the linear-up log-down trapezoidal method. Statistical analysis software, SAS^® Version 9.4 (SAS Institute, Cary, NC, USA), was used to produce graphs and tables.

Based on the commonly used dose group size of 12 subjects, it was planned to include 84 subjects in the multiple-dose component of the study. The size of 12 subjects per dose is often used in multiple rising dose trials of the present type, and is generally considered sufficient for the exploratory evaluation of multiple-dose safety and pharmacokinetics. The pharmacokinetic endpoints AUC_0–24, C_max, AUC_τ,ss and C_max,ss were assessed for dose proportionality (QD treatment groups only; assessed separately for healthy young and healthy elderly subjects). The linearity index was calculated by building the ratio of AUC_τ,ss, over AUC_0–∞ and attainment of steady state was assessed based on trough concentrations of BI 425809. Safety endpoints were examined over time and for any differences from baseline values; baseline was defined as the last measurement before the first study-drug administration.

The second part of this study included 12 subjects in order to reach a certain precision in estimating the ratio of gMean with 95% probability. The effect of evening dosing was determined based on AUC_0–tz and C_max, and the related CI. Safety endpoints were examined over time and for any differences from baseline values. Baseline value was considered to be the last measurement before study-drug administration in the morning and the last measurement before study-drug administration in the evening.

In total, 63.3% of young subjects experienced one or more AEs: 66.7% in the active-treatment arm and 53.3% in the placebo arm. Drug-related AEs were recorded for 60.0% of subjects receiving BI 425809 and 46.7% receiving placebo. A greater number of elderly subjects (79.2%) than young subjects reported one or more AEs during the study; the incidence was higher for subjects receiving the active drug compared with those receiving placebo (88.9 vs. 50.0%, respectively). As with young subjects, drug-related AEs were reported to a greater extent in elderly subjects who received BI 425809 (77.8%) than those who received placebo (50.0%). The overall frequency of subjects with one or more drug-related AE was similar across all treatment groups, indicating that AEs were not dose dependent (Table 1).

All treatment-emergent AEs were of mild or moderate intensity and no serious AEs were reported. Within parts 1 and 2, the most commonly reported AEs for young subjects in both the active and placebo groups were nervous system disorders, and infections and infestations (system organ class), and headache, dizziness, nasopharyngitis and insomnia (preferred term) (Table 1). In elderly subjects, the most commonly reported AEs in the active-treatment and placebo groups were gastrointestinal disorders (system organ class), and fatigue, constipation, hard faeces, dizziness and venepuncture-site haematoma (preferred term) (Table 1). There were no relevant differences between the treatment groups in the profile of reported AEs.

Both age groups reported eye disorders; all were classified as mild and subjects recovered within a short period of time. Specific events reported by young subjects included ocular discomfort and increased lacrimation (placebo group), visual blurring and impairment, blepharospasm, ocular discomfort, reduced visual acuity and transient reduced visual acuity (active treatment). Elderly subjects reported ocular discomfort (placebo group), blurred vision, visual impairment and reduced visual acuity (active treatment).

No clinically relevant changes in laboratory parameters, vital signs, 12-lead ECG, neurological examinations, ophthalmological examinations, or oxygen saturation monitoring were observed. No suicidal behaviours were noted. Neither VAS revealed clinically relevant dose-related changes in mood state or perception.

Adverse events were reported by two subjects [nasopharyngitis (n = 1; duration, days 2–7) and headache (n = 1; duration, days 1–2)] following a single morning dose of BI 425809 25 mg. In each case, the AEs were mild or moderate in intensity and considered not to be drug related. No serious AEs were reported. No clinically relevant changes in laboratory parameters, vital signs, 12-lead ECG, neurological examinations, ophthalmological examinations, suicidality monitoring, oxygen saturation monitoring or either VAS were noted.

BI 425809 was absorbed with median time to maximum plasma concentration values of 3.0–4.5 h after single as well as multiple doses (Table 2); plasma concentrations subsequently decreased in a biphasic manner. Steady-state conditions were reached between day 6 and day 10 for all treatment groups (i.e. 2–6 days after the start of multiple dosing). Plasma concentration–time profiles were similarly shaped across all dose groups (Fig. 3a) and both age groups (Fig. 3b). Systemic exposure (C_max, C_max,ss, AUC_0–24 and AUC_τ,ss) demonstrated a trend towards a less-than-dose-proportional increase following both single and multiple doses at 50 mg and above (QD) (Table 2). The BI 425809 gMean terminal half-life after the first dose and the terminal half-life at steady state were similar across treatment groups (QD and BID, 34.2–59.3 h), and the fraction eliminated from urine ranged from 1.77 to 2.71% (after single-dose administration) and from 3.90 to 7.10% (after multiple dosing). The linearity index, assessed separately for each dose group, was generally close to 1 for BI 425809 QD groups but clearly decreased (0.553) in the 75-mg BID group (Table 3 of the ESM).

Subjects receiving BI 425809 25 mg following a standard breakfast (light fed) demonstrated a 23% increase in steady-state C_max compared with fasted conditions [707 vs. 574 nmol/L; gMean ratio (light fed:fasted), 123.2%] along with a 14% increase in steady-state AUC [12,200 vs. 10,700 nmol·h/L; gMean ratio (light fed:fasted), 114.0%] and a delayed time to maximum plasma concentration. As expected, subjects showed similar steady-state exposure under light-fasted (C_max, 662 nmol/L; AUC 11,600 nmol·h/L) and fasted conditions (C_max, 611 nmol/L; AUC, 11,100 nmol·h/L; gMean ratio [light fasted:fasted] C_max, 108.3%; AUC, 104.5%) [Fig. 1 and Table 4 of the ESM]. Additionally, only slight differences in BI 425809 exposure were identified between light-fed and light-fasted conditions at steady state [gMean ratio (light fed:light fasted) C_max, 106.8%; AUC, 105.2%]. At higher doses (75 mg), single administration of BI 425809 with food (subjects in the BI 425809 BID group) at day 1 led to increased absorption of BI 425809 compared with fasted conditions (subjects in the BI 425809 QD group). Indeed, C_max and AUC_0–24 values approximately doubled [884 nmol/L and 12,000 nmol·h/L (fed); 451 nmol/L and 7170 nmol·h/L (fasted), respectively; Table 2].

Overall, gMean pharmacokinetic parameters suggested a trend towards slightly increased BI 425809 exposure following the evening administration, as suggested by a 15% higher gMean C_max (90% CI 98.1–136) and 20% higher AUC_0–tz (90% CI 107–135) compared with morning administration (Table 3). However, when comparing individual AUC_0–tz and C_max values, there appeared to be no systematic trend, with a somewhat higher variability for the morning dosing (Fig. 4).