Clin Drug Investig (2018) 38:737–750 https://doi.org/10.1007/s40261-018-0660-2 OR IGINAL RESEARCH ARTIC L E 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 1 1 2 2 2 • • • • • Viktoria Moschetti Christina Schlecker Sven Wind Sophia Goetz Holger Schmitt 3 2 4 2 • • • Armin Schultz Karl-Heinz Liesenfeld Glen Wunderlich Michael Desch Published online: 30 May 2018 The Author(s) 2018 Abstract pharmacokinetic proﬁles in 12 subjects who received a Background and Objective Schizophrenia and Alzheimer’s single dose of BI 425809 25 mg in the morning and disease are characterised by abnormalities in glutamatergic evening. pathways related to N-methyl-D-aspartate receptor hypo- Results Pharmacokinetic proﬁles were similarly shaped for function. Glycine is an N-methyl-D-aspartate receptor co- all dose groups. Median time to maximum plasma con- agonist; inhibition of glycine transporter 1 may improve centration was 3.0–4.5 h with steady state being reached N-methyl-D-aspartate receptor function. This phase I, ran- between days 6 and 10. Pharmacokinetic parameters domised, two-part study evaluated the safety, tolerability demonstrated dose linearity at the predicted therapeutic and pharmacokinetic proﬁle of BI 425809, a novel glycine exposure range of BI 425809 B 25 mg once daily, but transporter 1 inhibitor, in healthy male and female increased less than dose proportionally for C 50 mg once volunteers. daily. All reported adverse events were of mild-to-moderate Methods Part 1 evaluated BI 425809 10, 25, 50 or 75 mg intensity, 51/84 (61%; part 1) subjects had one or more once daily or 75 mg twice daily in young subjects, and treatment-related adverse event, no serious adverse events 25 mg or 50 mg once daily in elderly subjects. Each dose occurred and no dose dependency was observed. group comprised 12 subjects who received BI 425809 Conclusions Pharmacokinetic properties support both (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; morning and evening dosing. BI 425809 was generally well days 4–14: multiple dosing). Part 2 compared tolerated at all tested doses. Clinicaltrials.gov identiﬁer NCT02337283. Viktoria Moschetti and Christina Schlecker contributed equally to this work. Key Points Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40261-018-0660-2) contains supple- BI 425809 was well tolerated within the tested dose mentary material, which is available to authorized users. range for all subjects (healthy young and elderly), with reported adverse events being of mild-to- & Michael Desch moderate intensity. email@example.com 1 Within the predicted therapeutic exposure range of Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany BI 425809 B 25 mg once daily, pharmacokinetic 2 results demonstrated dose linearity and supported Boehringer Ingelheim International GmbH, Birkendorfer Str. both morning and evening dosing regimens. 65, 88397 Biberach an der Riss, Germany CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany Boehringer Ingelheim (Canada) Ltd., Burlington, ON, Canada 738 V. Moschetti et al. The current study extends this investigation to include less 1 Introduction extreme meal conditions (standard-fat/standard-calorie Cognitive impairment is a signiﬁcant feature of neurode- meal of * 500 kcal) that are more representative of daily life. A recent drug–drug interaction study conﬁrmed in- generative conditions, such as Alzheimer’s disease (AD), and psychiatric conditions, including schizophrenia [1–4]. vitro data indicating that cytochrome P450 (CYP) 3A4 is a major component of the BI 425809 metabolic pathway . These conditions are underpinned by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate The primary objective of this study was to evaluate the safety and tolerability of multiple rising doses of (NMDA) receptor hypofunction in cortical and hip- pocampal brain areas. Such abnormalities have been BI 425809, compared with placebo, in healthy young and elderly subjects. Furthermore, BI 425809 pharmacokinetic associated with the cognitive impairment experienced by parameters were determined to explore dose proportional- these patients [5, 6]. Glycine is an NMDA receptor co- ity, attainment of steady state and the effect of a stan- agonist; inhibition of glycine transporter 1 (GlyT1), which dardised light breakfast on BI 425809 steady-state regulates synaptic glycine levels, may therefore improve NMDA receptor function by raising glycine levels in the exposure. Finally, this study additionally investigated dif- ferences in the pharmacokinetics, safety and tolerability of synaptic cleft . Animal data indicate that improved NMDA receptor signalling leads to an increase in long- BI 425809 when administered in the morning vs. evening, to evaluate whether an evening dosing regimen, which may term potentiation and synaptic plasticity , which improves cognitive function and memory . attenuate sedative or visual adverse events (AEs), would be beneﬁcial for subjects in phase II trials. BI 425809, a potent and selective GlyT1 inhibitor, is a new chemical entity hypothesised to improve cognitive function and memory in patients with schizophrenia and 2 Subjects and Methods AD. A phase I, ﬁrst-in-human, single rising dose study found single doses of BI 425809 up to 100 mg, adminis- 2.1 Ethical Conduct tered as an oral solution, to be generally well tolerated in young healthy male volunteers . All study procedures, protocols and documents met with A pharmacokinetic analysis of BI 425809 supported a once-daily (QD) dosing regimen for future multiple-dose institutional approval following review by the study cen- tre’s independent ethics committee. The study was con- studies . Plasma concentration–time proﬁles were similarly shaped at all dose levels (0.5–150 mg) and were ducted in accordance with the clinical study protocol, the International Conference for Harmonisation of Technical characterised by rapid absorption (median time to maxi- mum plasma concentration of * 45 min) followed by a Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines  and local legislation, in biphasic distribution phase. Dose proportionality was accordance with the principles of the Declaration of Hel- observed in all exposure parameters [area under the con- centration–time curve over the time interval from 0 to the sinki . All subjects provided signed and dated written informed consent prior to study procedures. last quantiﬁable data point (AUC ), area under the con- 0–tz centration–time curve over the time interval from 0 2.2 Study Design extrapolated to inﬁnity (AUC ), maximum plasma con- 0–? centration (C )] across the entire dose range. The geo- max This was a phase I study conducted at the Human Phar- metric mean (gMean) terminal half-life was not dose dependent, ranging between 32.5 and 47.0 h . The macology Unit CRS Clinical Research Services in Man- nheim, Germany (Clinicaltrials.gov identiﬁer: bioavailability of BI 425809 administered as a tablet was NCT02337283), consisting of two parts. The ﬁrst part was lower than the bioavailability of BI 425809 administered as randomised, double blinded, and placebo controlled within an oral solution. Adjusted gMean ratios for AUC and 0–tz parallel-dose groups, and aimed to assess the safety, tol- C for BI 425809 administered as a tablet fasted vs. oral max solution fasted were 80.5% [90% conﬁdence interval (CI) erability and pharmacokinetics following multiple doses of BI 425809 10–75 mg, in healthy young and healthy elderly 74.0–87.6) and 50.0% (90% CI 45.1–55.4), respectively. Furthermore, the single rising dose study identiﬁed a subjects compared with placebo. The second part of this study was randomised and open-label, with a two-treat- moderate increase in BI 425809 bioavailability following administration as a tablet under fed conditions (high-fat/ ment, two-sequence, two-period crossover, and aimed to assess the pharmacokinetics, safety and tolerability of high-calorie breakfast of * 1000 kcal) vs. strongly fasted conditions [adjusted gMean ratios: AUC 125.9% (90% single BI 425809 25-mg doses given in the morning or 0–tz evening in healthy young subjects. An overview of the CI 115.7–137.0); C 142.1% [90% CI 128.3–157.4)] . max study design is given in Fig. 1. Pharmacokinetics of Multiple Rising Doses of BI 425809 739 2.2.1 Part 1: Multiple-Dose Component safety review was undertaken prior to each dose escalation. Healthy elderly subjects were dosed after a respective dose Subjects were allocated to seven sequential dose groups; of BI 425809 had been well tolerated in healthy young ﬁve groups comprised healthy young subjects [BI 425809 subjects. Blood samples for pharmacokinetic assessments QD at 10, 25, 50 or 75 mg, or BI 425809 twice daily (BID) were taken following the ﬁrst and last doses, and at regular at 75 mg], and two comprised healthy elderly subjects intervals between days 1 and 14, after which daily samples (BI 425809 QD at 25 or 50 mg). Within each dose group, were collected until day 23. Urine was collected for subjects were randomised to receive the active drug or pharmacokinetic analysis during pre-speciﬁed periods fol- placebo at a ratio of 3:1, such that nine subjects received lowing the ﬁrst and last doses in the QD dose groups only. the active drug and three received placebo. Each subject The effects of different types of food intake on BI 425809 received a single dose of BI 425809 or placebo on day 1, pharmacokinetics were analysed in dose groups 2 and 5 followed by QD (dose groups 1–6, 10–75 mg) or BID (BI 425809 25 mg in young and elderly subjects, respec- (dose group 8, 75 mg) dosing for 10 days from day 4 tively) under light-fed (standardised light breakfast onwards. On day 14, all dose groups received one single [* 500 kcal] served 30 min before BI 425809 adminis- dose of BI 425809 or placebo. Dose groups were investi- tration; day 12, dose group 2) [Table 1 of the Electronic gated consecutively in ascending order and a documented Supplementary Material (ESM)], and light-fasted (no food Fasted Lightly Fasted Fasted 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15–23 Days: BI 425809 10 mg Group 1: HY Dietary exceptions: QD Placebo 10 mg Group 2, Day 12: Subjects fed prior BI 425809 25 mg Group 2: HY to dosing QD Placebo 25 mg Group 8: Fed throughout BI 425809 50 mg Group 3: HY QD PK exceptions: Placebo 50 mg Groups 2 & 5, BI 425809 75 mg Group 4: HY Day 12: Six additional Part 1 QD Placebo 75 mg samples taken Group 7, Day 3/ BI 425809 25 mg Group 5: HE Day 15 following QD Placebo 25 mg evening BI 425809 50 mg administration: One Group 6: HE additional sample taken QD Placebo 50 mg BI 425809 75 mg Group 8: HY BID Placebo 75 mg PK, PK, PK, PK, intensive twice-daily sampling (Days 2–3), intensive once-daily sampling once-daily sampling (Days 4–13) sampling sampling Fasted Fasted 123456789 10 11 12 13 14 15 16 17 Days: BI 425809 BI 425809 11-day washout 25 mg 25 mg Part 2 Group 7: HY period morning morning or evening or evening PK, PK, PK, PK, intensive once-daily intensive once-daily sampling sampling sampling sampling Fig. 1 Study design diagram. BID twice daily, HE healthy elderly, HY healthy young, PK pharmacokinetics, QD once daily 740 V. Moschetti et al. for C 10 h before, until 1 h after BI 425809 administra- cigarettes, one cigar or one pipe per day) or inability to tion; day 12, dose group 5) conditions. In both dose groups, refrain from smoking on study days. additional pharmacokinetic proﬁles were taken on day 12 and compared with the respective pharmacokinetic proﬁles 2.4 Treatments on day 14. Fasted conditions (no food for C 10 h before, until 3.5 h after BI 425809 administration) were employed BI 425809 and placebo tablets were manufactured by on days 1 and 14, with light-fasted conditions used for the Boehringer Ingelheim International GmbH, Germany. remaining treatment days in all groups except group 8 Subjects received either placebo or BI 425809 as 5- or (Fig. 1). Twice-daily dosing and administration under 25-mg tablets according to the dose strength required by light-fed conditions were applied to dose group 8 to the dosing group assigned. To maintain blinding, placebo increase the bioavailability of BI 425809. tablets were matched in size, colour and shape to BI 425809 tablets (white to off-white; round; 5 mg, 2.2.2 Part 2: Morning vs. Evening Dosing * 6 mm in diameter; 25 mg, * 10 mm in diameter). The tablet formulation was considered appropriate based on the Each subject (dose group 7) received two single doses of planned dosing, similarity to the intended market formu- BI 425809 25 mg separated by a washout period of at least lation and the expectation that sufﬁcient exposure would be 11 days. The dose of BI 425809 was administered either in obtained to meet the study aims. the morning or in the evening, per the randomisation scheme. All subjects were in a fasted state for the admin- 2.5 Study Endpoints istration of BI 425809. Blood samples for pharmacokinetic assessment were taken prior to and up to 96 h after 2.5.1 Safety Assessments administration of the active drug (Fig. 1). The primary endpoint of part 1 and the secondary endpoint 2.3 Subjects of part 2 was the number (N [%]) of subjects with drug- related AEs. Adverse events were deﬁned as any untoward 2.3.1 Inclusion Criteria medical occurrence and included any clinically relevant ﬁndings from physical examination, laboratory tests, ECG, A total of 96 subjects were entered into the study: 84 in vital-sign measurement and the exacerbation of any pre- part 1, of whom 24 were elderly subjects, and 12 in part 2. existing condition. Adverse events were classiﬁed accord- Eligible subjects were healthy male or female (of non- ing to the following criteria: mild, awareness of signs or childbearing potential) volunteers, 18–50 years of age for symptoms that were easily tolerated; moderate, sufﬁcient young subjects, or 65–80 years of age for elderly subjects, discomfort to interfere with usual activities; and severe, with a body mass index of 18.5–29.9 kg/m . incapacitating or causing an inability to work or perform usual activities. Further criteria of interest were: neuro- 2.3.2 Exclusion Criteria logical examination; safety laboratory tests (clinical chemistry, haematology and urinalysis); 12-lead ECGs; Subjects were excluded if they exhibited any evidence of a visual tests (Ishihara test, Jaeger Eye Chart and Amsler concomitant disease judged as clinically relevant upon grid); ophthalmological examination, including fundus physical examination, vital-sign assessment, electrocar- photography, (part 1 only); vital signs [blood pressure, diogram (ECG) or laboratory test (haematology, clinical pulse rate and respiratory rate (BI 425809 75-mg BID chemistry, infectious serology and urinalysis). Other key group only)]; oxygen saturation (BI 425809 75-mg BID exclusion criteria included: gastrointestinal, hepatic, renal, group only); suicidality monitoring; and assessment of respiratory, cardiovascular, metabolic, immunological or visual analogue scales (VASs) for possible central nervous hormonal disorders; diseases of the central nervous system, system effects (subjective feelings) using the scales other neurological disorders, or psychiatric disorders; his- developed by Bond and Lader  and Bowdle et al. . tory of suicidal behaviour, macular degeneration or rele- vant orthostatic hypotension, fainting spells or blackouts; 2.5.2 Pharmacokinetic Analysis chronic or relevant acute infections; history of relevant allergy/hypersensitivity (including allergy to the study The primary pharmacokinetic endpoints (assessed in part medication or its excipients); drug abuse, excessive alcohol 2) were AUC and C of the analyte. Secondary end- 0–tz max intake ([ 20 g/day for female individuals and [ 30 g/day points assessed in part 1 included AUC of the analyte from for male individuals), use of tobacco (more than ﬁve 0 to 24 h (AUC ) and C after the ﬁrst dose; and AUC 0–24 max and C at steady state over a uniform dosing interval s max Pharmacokinetics of Multiple Rising Doses of BI 425809 741 (AUC and C ) following the last dose. Additional present type, and is generally considered sufﬁcient for the s,ss max,ss pharmacokinetic parameters assessed during this study are exploratory evaluation of multiple-dose safety and phar- described within the ESM. The pharmacokinetic software macokinetics. The pharmacokinetic endpoints AUC , 0–24 used in this study was Phoenix WinNonlin Version 6.3 C , AUC and C were assessed for dose propor- max s,ss max,ss (Certara L.P. [Pharsight], St. Louis, MO; for the non- tionality (QD treatment groups only; assessed separately compartmental analysis) using the linear-up log-down for healthy young and healthy elderly subjects). The lin- trapezoidal method. Statistical analysis software, SAS earity index was calculated by building the ratio of Version 9.4 (SAS Institute, Cary, NC, USA), was used to AUC , over AUC and attainment of steady state was s,ss 0–? produce graphs and tables. assessed based on trough concentrations of BI 425809. Safety endpoints were examined over time and for any 18.104.22.168 Bioanalytical Assay BI 425809 plasma and urine differences from baseline values; baseline was deﬁned as concentrations were determined by a validated liquid the last measurement before the ﬁrst study-drug chromatography tandem mass spectrometry assay. The administration. analyses were performed at the Department of Pharma- cokinetics and Drug Metabolism, BI Pharmaceuticals Inc., 2.6.2 Part 2: Morning vs. Evening Dosing Ridgeﬁeld, CT, USA. Linear calibration standard curves (seven concentrations) with 1/9 2 weighting were used to The second part of this study included 12 subjects in order determine BI 425809 concentrations over 1.00–1000 nm. to reach a certain precision in estimating the ratio of gMean Concentrations below the lower limit of quantiﬁcation with 95% probability. The effect of evening dosing was determined based on AUC and C , and the related CI. were not replaced by zero at any timepoint (including the 0–tz max lag phase and pre-dose values). For the non-compartmental Safety endpoints were examined over time and for any analysis, concentration values identiﬁed as below the lower differences from baseline values. Baseline value was con- limit of quantiﬁcation in the lag phase (period between sidered to be the last measurement before study-drug time zero and the ﬁrst time point with a concentration administration in the morning and the last measurement above the quantiﬁcation limit) were set to zero. Back-cal- before study-drug administration in the evening. culation of calibration standards, tabulation of the standard curve ﬁt parameters and measurement of quality-control samples were used to assess assay performance. The 3 Results quality-control plasma samples were prepared in K3- ethylenediaminetetraacetic acid human plasma, and those 3.1 Study Population and Disposition for the urine samples were prepared in 0.05% Tween 20 human urine. Three concentrations were used for both. Ninety-six subjects entered into the study with 93 com- Quality-control samples were then analysed to assess the pleting the planned observation time (Fig. 2). Demographic accuracy and precision of pharmacokinetic measurements. characteristics were similar across all treatment groups (Table 2 of the ESM). Brieﬂy, part 1 of this study included 2.6 Statistical Analyses 57 male and 27 female subjects (young and elderly); all except two were Caucasian. Part 2 of the study consisted of Descriptive statistics were calculated for all safety and ten male and two female healthy young subjects (all Cau- pharmacokinetic endpoints. Safety was assessed in the casian). Mean (standard deviation) age was 40.5 (8.3) years treated set, which included all randomised subjects who for young subjects and 71.0 (4.1) years for elderly subjects. received one or more doses of the study drug. Pharma- During part 1, two subjects discontinued, one young sub- cokinetic parameters were assessed in subjects from the ject after the sixth dose of placebo and one elderly subject treated set who provided one or more evaluable secondary after the ﬁrst dose of BI 425809 50 mg. During part 2, all pharmacokinetic endpoint values (pharmacokinetic set). A except one subject (a healthy young subject discontinued more detailed description of the statistical analyses can be following administration of the single morning dose) found in the ESM. completed the planned observation time per protocol. 2.6.1 Part 1: Multiple-Dose Component 3.2 Safety and Tolerability Based on the commonly used dose group size of 12 sub- A summary of all AEs by system organ class and preferred jects, it was planned to include 84 subjects in the multiple- term (C 5% incidence in either part 1 or part 2) is provided dose component of the study. The size of 12 subjects per in Table 1. dose is often used in multiple rising dose trials of the 742 V. Moschetti et al. Assessed for eligibility Enrolment (N = 192) Excluded (N = 96) Recruited (N = 96) Part 1 Part 2 Allocation (N = 84) (N = 12) Randomised Randomised (N = 84) (N = 12) Allocated to Allocated to Allocated to Allocated to BI 425809 placebo morning dose first evening dose first (n = 63) (n = 21) (n = 6) (n = 6) Follow-up Discontinued BI 425809 (n = 1) Discontinued BI 425809 (n = 1) Discontinued placebo (n = 1) � Increased blood creatinine phosphokinase � Nausea and vomiting (BI 425809 and placebo) � Gastrointestinal pain and diarrhoea (placebo) Analysis Safety: Analysed (n = 12) Treated set (TS) analysed (n = 82) Excluded from analysis (n = 2) Reason: Discontinuation from trial PKS analysed (HY, n = 45; HE, n = 17) Plasma PK, excluded from analysis (n = 4) Reasons: � Discontinuation from trial � AE of vomiting � AE of diarrhoea � Failed to reach steady state Urine PK, excluded from analysis (n = 4) Reasons: � Incorrect collection Fig. 2 CONSORT diagram. AE adverse event, HE healthy elderly, provided one or more PK endpoints judged as evaluable, Treated set HY healthy young, PK pharmacokinetics, PKS all subjects from the all subjects who received at least one dose of study drug/placebo Treated set who received BI 425809, participated in part 1, and Pharmacokinetics of Multiple Rising Doses of BI 425809 743 Table 1 Summary of adverse events by system organ class and preferred term [C 5% total incidence (part 1 or part 2 where applicable)] for young subjects and elderly subjects AE by SOC, n (%) Young subjects Elderly subjects Preferred term, Part 1 Part 2 Parts 1 and 2 n (%) Placebo BI Total BI BI Total Placebo BI Total n =15 N =60 n =57 N =72 n =6 n =24 10 mg 25 mg 50 mg 75 mg 75 mg Total 25 mg 25 mg 50 mg Total QD QD QD QD BID BI QD QD QD BI n =9 n =9 n =9 n =9 n =9 n =45 n =12 n =9 n =9 n =18 Total with AEs 8 5 7 6 6 6 30 38 2 32 40 3 8 8 16 19 (53.3) (55.6) (77.8) (66.7) (66.7) (66.7) (66.7) (63.3) (16.7) (56.1) (55.6) (50.0) (88.9) (88.9) (88.9) (79.2) Subjects with investigator- 7 4 6 6 5 6 27 34 0 27 34 3 6 8 14 17 deﬁned drug-related AEs (46.7) (44.4) (66.7) (66.7) (55.6) (66.7) (60.0) (56.7) (–) (47.4) (47.2) (50.0) (66.7) (88.9) (77.8) (70.8) Subjects with AEs leading 1 0 0 0 0 0 0 1 0 0 1 0 0 1 1 1 to study discontinuation (6.7) (–) (–) (–) (–) (–) (–) (1.7) (–) (–) (1.4) (–) (–) (11.1) (5.6) (4.2) Infections and infestations 4 1 2 1 1 0 5 9 1 6 10 1 3 3 6 7 (26.7) (11.1) (22.2) (11.1) (11.1) (–) (11.1) (15.0) (8.3) (10.5) (13.9) (16.7) (33.3) (33.3) (33.3) (29.2) Nasopharyngitis 2 0 2 0 1 0 3 5 1 ––0 1 1 2 2 (13.3) (–) (22.2) (–) (11.1) (–) (6.7) (8.3) (8.3) (–) (11.1) (11.1) (11.1) (8.3) Folliculitis – ––––––– –––0 2 1 3 3 (–) (22.2) (11.1) (16.7) (12.5) Psychiatric disorders 1 0 1 0 0 3 4 5 0 4 5 0 2 2 4 4 (6.7) (–) (11.1) (–) (–) (33.3) (8.9) (8.3) (–) (7.0) (6.9) (–) (22.2) (22.2) (22.2) (16.7) Insomnia 1 0 0 0 0 3 3 4 0 ––– ––– – (6.7) (–) (–) (–) (–) (33.3) (6.7) (6.7) (–) Nervous system disorder 3 4 3 3 5 2 17 20 1 18 21 1 2 3 5 6 (20.0) (44.4) (33.3) (33.3) (55.6) (22.2) (37.8) (33.3) (8.3) (31.6) (29.2) (16.7) (22.2) (33.3) (27.8) (25.0) Dizziness 1 1 0 1 3 2 7 8 0 ––1 1 2 3 4 (6.7) (11.1) (–) (11.1) (33.3) (22.2) (15.6) (13.3) (–) (16.7) (11.1) (22.2) (16.7) (16.7) Headache 3 3 3 3 4 0 13 16 1 ––0 1 1 2 2 (20.0) (33.3) (33.3) (33.3) (44.4) (–) (28.9) (26.7) (8.3) (–) (11.1) (11.1) (11.1) (8.3) Eye disorders 2 0 2 3 0 2 7 9 0 7 9 1 1 1 2 3 (13.3) (–) (22.2) (33.3) (–) (22.2) (15.6) (15.0) (–) (12.3) (12.5) (16.7) (11.1) (11.1) (11.1) (12.5) Ocular discomfort 1 0 0 0 0 2 2 3 0 ––– ––– – (6.7) (–) (–) (–) (–) (22.2) (4.4) (5.0) (–) Vision blurred 0 0 2 1 0 0 3 3 0 ––– ––– – (–) (–) (22.2) (11.1) (–) (–) (6.7) (5.0) (–) Gastrointestinal disorders 1 0 3 0 2 0 5 6 0 5 6 2 6 5 11 13 (6.7) (–) (33.3) (–) (22.2) (–) (11.1) (10.0) (–) (8.8) (8.3) (33.3) (66.7) (55.6) (61.1) (54.2) Constipation – ––––––– –––0 0 4 4 4 (–) (–) (44.4) (22.2) (16.7) Hard faeces – ––––––– –––2 2 0 2 4 (33.3) (22.2) (–) (11.1) (16.7) 744 V. Moschetti et al. Table 1 continued AE by SOC, n (%) Young subjects Elderly subjects Preferred term, Part 1 Part 2 Parts 1 and 2 n (%) Placebo BI Total BI BI Total Placebo BI Total n =15 N =60 n =57 N =72 n =6 n =24 10 mg 25 mg 50 mg 75 mg 75 mg Total 25 mg 25 mg 50 mg Total QD QD QD QD BID BI QD QD QD BI n =9 n =9 n =9 n =9 n =9 n =45 n =12 n =9 n =9 n =18 Nausea – ––––––– –––0 1 1 2 2 (–) (11.1) (11.1) (11.1) (8.3) Vomiting – ––––––– –––0 1 1 2 2 (–) (11.1) (11.1) (11.1) (8.3) Musculoskeletal and 0 1 0 1 1 0 3 3 0 3 3 0 1 2 3 3 connective tissue (–) (11.1) (–) (11.1) (11.1) (–) (6.7) (5.0) (–) (5.3) (4.2) (–) (11.1) (22.2) (16.7) (12.5) disorders Back pain – ––––––– –––0 1 1 2 2 (–) (11.1) (11.1) (11.1) (8.3) General disorders and 2 0 0 2 1 1 4 6 04 6 1 2 4 6 7 administration site (13.3) (–) (–) (22.2) (11.1) (11.1) (8.9) (10.0) (7.0) (8.3) (16.7) (22.2) (44.4) (33.3) (29.2) conditions Fatigue 2 0 0 0 1 0 1 3 0 ––1 0 –– – (13.3) (–) (–) (–) (11.1) (–) (2.2) (5.0) (–) (6.7) (–) Venepuncture site – ––––––– –––0 1 4 4 5 haematoma (–) (11.1) (44.4) (22.2) (20.8) Injury, poisoning and – ––––––– –––1 2 0 2 3 procedural complications (16.7) (22.2) (–) (11.1) (12.5) AE adverse event, BI BI 425809, BID twice daily, QD once daily, SOC system organ class Subjects in part 2 received two single doses of BI 425809 or placebo separated by a C 11-d washout period, while subjects in part 1 received daily doses of BI 425809 or placebo over 12 d Pharmacokinetics of Multiple Rising Doses of BI 425809 745 3.2.1 Part 1: Multiple-Dose Component or moderate in intensity and considered not to be drug related. No serious AEs were reported. No clinically rele- In total, 63.3% of young subjects experienced one or more vant changes in laboratory parameters, vital signs, 12-lead AEs: 66.7% in the active-treatment arm and 53.3% in the ECG, neurological examinations, ophthalmological exam- placebo arm. Drug-related AEs were recorded for 60.0% of inations, suicidality monitoring, oxygen saturation moni- subjects receiving BI 425809 and 46.7% receiving placebo. toring or either VAS were noted. A greater number of elderly subjects (79.2%) than young subjects reported one or more AEs during the study; the 3.3 Pharmacokinetic Results incidence was higher for subjects receiving the active drug compared with those receiving placebo (88.9 vs. 50.0%, A full list of secondary pharmacokinetic parameters (part respectively). As with young subjects, drug-related AEs 1) is detailed in Table 3 of the ESM. were reported to a greater extent in elderly subjects who received BI 425809 (77.8%) than those who received pla- 3.3.1 Part 1: Multiple-Dose Component cebo (50.0%). The overall frequency of subjects with one or more drug-related AE was similar across all treatment BI 425809 was absorbed with median time to maximum groups, indicating that AEs were not dose dependent plasma concentration values of 3.0–4.5 h after single as (Table 1). well as multiple doses (Table 2); plasma concentrations All treatment-emergent AEs were of mild or moderate subsequently decreased in a biphasic manner. Steady-state intensity and no serious AEs were reported. Within parts 1 conditions were reached between day 6 and day 10 for all and 2, the most commonly reported AEs for young subjects treatment groups (i.e. 2–6 days after the start of multiple in both the active and placebo groups were nervous system dosing). Plasma concentration–time proﬁles were similarly disorders, and infections and infestations (system organ shaped across all dose groups (Fig. 3a) and both age groups class), and headache, dizziness, nasopharyngitis and (Fig. 3b). Systemic exposure (C , C , AUC and max max,ss 0–24 insomnia (preferred term) (Table 1). In elderly subjects, AUC ) demonstrated a trend towards a less-than-dose- s,ss the most commonly reported AEs in the active-treatment proportional increase following both single and multiple and placebo groups were gastrointestinal disorders (system doses at 50 mg and above (QD) (Table 2). The BI 425809 organ class), and fatigue, constipation, hard faeces, dizzi- gMean terminal half-life after the ﬁrst dose and the ter- ness and venepuncture-site haematoma (preferred term) minal half-life at steady state were similar across treatment (Table 1). There were no relevant differences between the groups (QD and BID, 34.2–59.3 h), and the fraction treatment groups in the proﬁle of reported AEs. eliminated from urine ranged from 1.77 to 2.71% (after Both age groups reported eye disorders; all were clas- single-dose administration) and from 3.90 to 7.10% (after siﬁed as mild and subjects recovered within a short period multiple dosing). The linearity index, assessed separately of time. Speciﬁc events reported by young subjects inclu- for each dose group, was generally close to 1 for BI 425809 ded ocular discomfort and increased lacrimation (placebo QD groups but clearly decreased (0.553) in the 75-mg BID group), visual blurring and impairment, blepharospasm, group (Table 3 of the ESM). ocular discomfort, reduced visual acuity and transient Subjects receiving BI 425809 25 mg following a stan- reduced visual acuity (active treatment). Elderly subjects dard breakfast (light fed) demonstrated a 23% increase in reported ocular discomfort (placebo group), blurred vision, steady-state C compared with fasted conditions [707 vs. max visual impairment and reduced visual acuity (active 574 nmol/L; gMean ratio (light fed:fasted), 123.2%] along treatment). with a 14% increase in steady-state AUC [12,200 vs. No clinically relevant changes in laboratory parameters, 10,700 nmolh/L; gMean ratio (light fed:fasted), 114.0%] vital signs, 12-lead ECG, neurological examinations, oph- and a delayed time to maximum plasma concentration. As thalmological examinations, or oxygen saturation moni- expected, subjects showed similar steady-state exposure toring were observed. No suicidal behaviours were noted. under light-fasted (C , 662 nmol/L; AUC max Neither VAS revealed clinically relevant dose-related 11,600 nmolh/L) and fasted conditions (C , 611 nmol/ max changes in mood state or perception. L; AUC, 11,100 nmolh/L; gMean ratio [light fasted:- fasted] C , 108.3%; AUC, 104.5%) [Fig. 1 and Table 4 max 3.2.2 Part 2: Morning vs. Evening Dosing of the ESM]. Additionally, only slight differences in BI 425809 exposure were identiﬁed between light-fed and Adverse events were reported by two subjects [na- light-fasted conditions at steady state [gMean ratio (light sopharyngitis (n = 1; duration, days 2–7) and headache fed:light fasted) C , 106.8%; AUC, 105.2%]. At higher max (n = 1; duration, days 1–2)] following a single morning doses (75 mg), single administration of BI 425809 with dose of BI 425809 25 mg. In each case, the AEs were mild food (subjects in the BI 425809 BID group) at day 1 led to 746 V. Moschetti et al. Table 2 Pharmacokinetic parameters after single and multiple doses of BI 425809 during part 1 Pharmacokinetic BI 425809 parameter Young subjects Elderly subjects 10 mg QD 25 mg QD 50 mg QD 75 mg QD 75 mg BID 25 mg QD 50 mg QD n =9 n =9 n =9 n =9 n =9 n =8 n =8 Single-dose administration AUC , nmolh/L 1410 (20.1) 3720 (18.2) 6020 (24.4) 7170 (17.9) 12,000 (13.7) 3460 (18.5) 5620 (17.9) 0–24 AUC , 141 (20.1) 149 (18.2) 120 (24.4) 95.6 (17.9) 160 (13.7) 139 (18.5) 112 (17.9) 0–24,norm nmolh/L/mg C , nmol/L 109 (19.0) 278 (19.7) 397 (28.7) 451 (17.9) 884 (8.72) 235 (18.7) 371 (25.9) max C , nmol/L/mg 10.9 (19.0) 11.1 (19.7) 7.95 (28.7) 6.01 (17.9) 11.8 (8.72) 9.4 (18.7) 7.43 (25.9) max,norm t , h 4 (3.5, 5) 4.5 (2, 5) 4.5 (3.5, 12) 4 (2, 5) 4.02 (3, 5) 3.5 (2, 5) 4.5 (2, 8) max Multiple-dose administration AUC , nmolh/L 3870 (22.2) 10,600 (31.7) 14,200 (29.4) 16,500 (29.6) 18,800 (20.2) 11,000 (11.6) 13,900 (30.8) s,ss AUC , 387 (22.2) 425 (31.7) 285 (29.4) 220 (29.6) 251 (20.2) 439 (11.6) 278 (30.8) s,ss,norm nmolh/L/mg C , nmol/L 221 (19.5) 582 (27.6) 800 (26.3) 1020 (23.1) 1930 (17.2) 618 (10.9) 802 (25.0) max,ss C , nmol/L/ 22.1 (19.5) 23.3 (27.6) 16.0 (26.3) 13.6 (23.1) 25.8 (17.2) 24.7 (10.9) 16.0 (25.0) max,ss,norm mg b,c t , h 4.5 (2, 5) 3.75 (2, 6) 3.5 (2, 6) 4.5 (2, 6) 3.5 (2, 4.5) 3 (2, 4.52) 4.5 (3.5, 6) max,ss AUC area under the concentration–time curve from 0 to 24 h, AUC area under the concentration–time curve at steady state over a uniform 0–24 s,ss dosing interval, BID twice daily, C maximum plasma concentration, C , maximum plasma concentration at steady state over a uniform max max,ss dosing interval, CV coefﬁcient of variation, norm dose normalised, QD once daily, t , time to C t time from last dosing to C at max max, max,ss max steady state over a uniform dosing interval Geometric mean (%CV), unless otherwise stated For dose group BI 425809 75 mg BID, AUC , AUC , C , C , and t are given whereby 22 relates to 22 h s,22 s,22,norm max,22 max,22,norm max,22 For t and t the median and range (minimum, maximum) are given max max,ss a b 10000 1000 100 100 1 10 0 1224364860 72 312 336 360 384 408 432 456 480 504 528 0 1224364860 72 312 336 360 384 408 432 456 480 504 528 Time [hours] Time [hours] 10 mg QD, young (n = 9/9) 25 mg QD, young (n = 9/8) 25 mg QD, young (n = 9/8) 25 mg QD, elderly (n = 9/9) 50 mg QD, young (n = 9/9) 75 mg QD, young (n = 9/9) 25 mg QD, elderly (n = 9/9) 50 mg QD, elderly (n = 9/8) 75 mg BID, young (n = 9/9) Fig. 3 Geometric mean drug plasma concentration–time proﬁles of BI 425809 after single and multiple oral administration of BI 425809 tablets: a once daily (QD) or twice daily (BID) in young and elderly subjects and b QD in young vs. elderly subjects (semi-log scale) BI 425809 plasma concentration [nmol/L] BI 425809 plasma concentration [nmol/L] Pharmacokinetics of Multiple Rising Doses of BI 425809 747 increased absorption of BI 425809 compared with fasted trials with GlyT1 inhibitors . As such, the visual effects conditions (subjects in the BI 425809 QD group). Indeed, of active BI 425809 administration were extensively C and AUC values approximately doubled monitored throughout this study. Additionally, ophthal- max 0–24 [884 nmol/L and 12,000 nmolh/L (fed); 451 nmol/L and mological examination, including fundus photography, was 7170 nmolh/L (fasted), respectively; Table 2]. performed. Visual AEs were reported by nine subjects across the treatment groups; all were mild, quickly rever- 3.3.2 Part 2: Morning vs. Evening Dosing sible and did not appear to be dose dependent. Visual analogue scales to monitor possible central nervous system Overall, gMean pharmacokinetic parameters suggested a effects (subjective feelings) by evaluating external and trend towards slightly increased BI 425809 exposure fol- internal perception, alertness, mood and calmness were lowing the evening administration, as suggested by a 15% employed during the multiple-dose component of this higher gMean C (90% CI 98.1–136) and 20% higher study and did not reveal any clinically relevant differences max AUC (90% CI 107–135) compared with morning between the treatment groups. Overall, the frequency of 0–tz administration (Table 3). However, when comparing indi- subjects with one or more drug-related AE was similar vidual AUC and C values, there appeared to be no across all treatment groups indicating a lack of dose 0–tz max systematic trend, with a somewhat higher variability for the dependency. Contrary to this, however, administration of morning dosing (Fig. 4). BI 425809 as a solution during the previous single rising dose study demonstrated that higher doses were associated with an increased incidence of AEs, the most common 4 Discussion being central nervous system and visual effects. This dif- ference may be explained by a greater speed of absorption This study demonstrated that BI 425809 administered orally following administration of BI 425809 as a solution, as multiple rising doses of 10, 25, 50 and 75 mg QD, or compared with the tablet formulation . 75 mg BID in healthy young subjects, or as multiple doses of There were no clinically relevant differences in the 25 or 50 mg QD in elderly subjects, over 11 days, was pharmacokinetics, safety and tolerability between healthy generally well tolerated. All treatment-related AEs were young and healthy elderly subjects during this study. Given considered of mild or moderate intensity and were in general that one of the key indications for this therapy will largely alignment with recent reports on GlyT1 inhibitors [16–18]. consist of elderly patients with AD, the good tolerability of Selective GlyT1 inhibition results in increased synaptic BI 425809 observed within the elderly subjects included glycine levels, which may be favourable for the treatment here is of particular importance. of cognitive impairment associated with schizophrenia and Plasma concentration–time proﬁles of BI 425809 were AD [5–7]. Increases in glycine levels, however, have been shaped similarly across all dose groups, and dose propor- associated with visual disturbances and electroretinogram tionality was observed in exposure parameters (C , max alterations [19, 20]. Inhibition of the GlyT1 transporter in AUC , C and AUC ) for BI 425809 10 and 0–24 max,ss s,ss the rat retina leads to electroretinogram alterations, which 25 mg. At doses of C 50 mg, the increase in exposure was may explain the visual disturbances reported in clinical clearly less than dose proportional. By contrast, dose-linear Table 3 Bioavailability of BI 425809 administered as a 25-mg single morning or evening dose (part 2) Pharmacokinetic BI 425809 25 mg QD parameter N =12 Adjusted gMean evening Adjusted gMean morning Adjusted gMean ratio Intraindividual gCV, dose dose evening/morning % (90% CI [%]) AUC , nmolh/L 8410 7000 120 (107–135) 14.6 0–tz C , nmol/L 278 241 115 (98.1–136) 21.2 max AUC nmolh/L 10,400 8770 118 (104–134) 16.1 0–?, t , h 4.50 (2.00, 8.00) 4.00 (1.00, 4.50) – – max AUC area under the concentration–time curve over the time interval from 0 to the last quantiﬁable data point, AUC area under the 0–tz 0–? concentration–time curve over the time interval from 0 extrapolated to inﬁnity, C maximum plasma concentration, gCV geometric coefﬁcient max of variation, gMean geometric mean, t time to C max max For t , the median and range (minimum, maximum) are given max 748 V. Moschetti et al. a b 12000 Individual data 500 Individual data gMean (n = 12/11) gMean (n = 12/11) 3000 100 25 mg QD, morning 25 mg QD, evening 25 mg QD, morning 25 mg QD, evening Fig. 4 Intra-individual comparison of a area under the concentra- values of BI 425809 after single oral administration of 25 mg in the tion–time curve over the time interval from 0 to the last quantiﬁable morning or in the evening in healthy young subjects. gMean data point (AUC ) and b maximum plasma concentration (C ) geometric mean, QD once daily 0–tz max pharmacokinetics following single administration of vitro and clinical studies have indicated that BI 425809 is BI 425809 as an oral solution from 0.5 to 150 mg has been primarily metabolised by CYP3A4, and has the potential to demonstrated , suggesting that the less-than-dose-pro- induce CYP3A4 activity [11, 21]. Given that this phe- portional increase in plasma exposure in the current study nomenon was only apparent for the 75-mg BID dose group, can be attributed to the tablet formulation, likely owing to it can be concluded that autoinduction of CYP3A4 at impaired dissolution of the drug from its tablet form rather dosing regimens leading to lower exposure is of minor than effects on absorption or disposition of the drug. importance. Indeed, BI 425809 demonstrates low intrinsic solubility. In summary, these data suggest that decreased Given that only a slight increase in plasma exposure was bioavailability observed at higher tablet dosing regimens is seen following administration of BI 425809 75 mg com- caused by two factors; low intrinsic solubility and autoin- pared with 50 mg (tablet formulation), it was anticipated duction. Neither, however, appear to be relevant to the that higher QD doses would not achieve further signiﬁcant anticipated therapeutic dose range. increases in plasma exposure. Consequently, a 75-mg BID An additional factor found to impact upon BI 425809 dosing regimen under fed conditions was introduced to plasma exposure level is food. A recent investigation maximise plasma exposure, and thereby the exposure demonstrated a 42% increase in C , and a 26% increase max multiplies, in comparison with the maximum anticipated in AUC, following a single dose of BI 425809 25 mg therapeutic dose of 25 mg QD. This approach successfully administered as a tablet with a high-fat/high-calorie meal counteracted the impaired bioavailability of BI 425809, vs. under fasted conditions . This is in line with the low increasing plasma exposure by * 70%, based on AUC intrinsic solubility of BI 425809 as it has recently been 0–24 and C after the ﬁrst dose, compared with the 75-mg QD demonstrated that increased bile secretion, known to max regimen, an effect that may be attributed to administration accompany high-fat meal consumption, plays an important of the tablets with food. Nevertheless, such results must be role in drug accessibility, possibly owing to improved treated with caution given that the comparison was solubility . In the present study, additional exploratory between subject groups rather than intra-individually. data were generated to characterise the administration of Interestingly, AUC increased by just 14%, while BI 425809 with food. s,ss C increased by 90% following administration of Administration of BI 425809 25 mg in young subjects, max,ss BI 425809 75 mg BID vs. 75 mg QD, indicating that after in the presence of a standardised light breakfast, led to only multiple dosing an additional mechanism is impacting a 14 and 23% increase in steady-state AUC and C , max plasma exposure. This is further illustrated by a linearity respectively, compared with fasted conditions. As men- index below 1 for the 75-mg BID dose group, compared tioned above, the food effect seems to be increased with a value close to 1 for the QD treatment groups. (* 70%) at higher doses, e.g. when comparing single-dose Autoinduction of BI 425809 metabolism may be the data of the 75-mg dosing regimens. Considering this dose underlying mechanism behind such observations, as in- dependency, it may be reasonable to speculate that at doses BI 425809 AUC [mol h/L] 0–tz BI 425809 C [nmol/L] max Pharmacokinetics of Multiple Rising Doses of BI 425809 749 was provided by Louisa Pettinger, PhD, and Sam Halliwell, PhD, of below 25 mg such a food effect may be reduced or even Fishawack Communications, and was funded by Boehringer Ingel- completely eradicated. heim International GmbH. It must be noted that the food-effect investigations employed during this study are clearly exploratory in nat- Conﬂict of interest The authors met the criteria for authorship as recommended by the International Committee of Medical Journal ure; however, they might be closer to the conditions Editors. All authors (except Armin Schultz, who is an employee of apparent in clinical practice. Because evaluations were CRS Clinical Research Services, Mannheim) are employees of partly conducted after multiple dosings with differing food Boehringer Ingelheim, but received no direct compensation related to conditions, the preceding doses and conditions might have the development of this manuscript. Armin Schultz has no disclosures to declare. impacted the food effect readout. Furthermore, the above- mentioned factors such as dose dependency of tablet Ethics approval All procedures performed in studies involving bioavailability and autoinduction at higher doses require a human participants were in accordance with the ethical standards of differential consideration of the inﬂuence of food on the institutional and/or national research committee and with the 1964 BI 425809 exposure. Helsinki Declaration and its later amendments or comparable ethical standards. Exposure to a BI 425809 25-mg tablet was approxi- mately 15–20% higher [15% higher gMean C (90% CI max Consent to participate Informed consent was obtained from all 98.1–136) and 20% higher AUC (90% CI 107–135)] 0–tz individual participants included in the study. when administered in the evening compared with the Open Access This article is distributed under the terms of the morning. Considering an exposure multiple of 3.2-fold Creative Commons Attribution-NonCommercial 4.0 International when comparing AUC and C between the 25-mg 0–24 max License (http://creativecommons.org/licenses/by-nc/4.0/), which per- dose group and the well tolerated 75-mg BID dose group, a mits any noncommercial use, distribution, and reproduction in any potential exposure increase by 20% for the evening dosing medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons is considered not clinically relevant at least with regard to license, and indicate if changes were made. safety. It might be speculated that there is a slight circadian rhythm for the absorption, distribution, metabolism and excretion mechanisms of BI 425809, alternatively this may be owing to procedural differences for the evening vs. References morning dosing. Overall, based on current data, the expo- sure increase of 15–20% (if a true effect) is not considered 1. Evans JD, Bond GR, Meyer PS, et al. Cognitive and clinical clinically relevant, suggesting that either morning or eve- predictors of success in vocational rehabilitation in schizophre- nia. Schizophr Res. 2004;70(2–3):331–42. ning doses could be considered for future studies. 2. Kurtz MM, Wexler BE, Fujimoto M, et al. Symptoms versus neurocognition as predictors of change in life skills in schizophrenia after outpatient rehabilitation. Schizophr Res. 5 Conclusions 2008;102(1–3):303–11. 3. Velligan DI, Mahurin RK, Diamond PL, et al. The functional signiﬁcance of symptomatology and cognitive function in In this phase I, multiple rising-dose study, BI 425809 was schizophrenia. Schizophr Res. 1997;25(1):21–31. well tolerated within the tested dose range in healthy young 4. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deﬁcits and elderly subjects. Within the predicted therapeutic and functional outcome in schizophrenia: are we measuring the ‘‘right stuff’’? Schizophr Bull. 2000;26(1):119–36. exposure range of BI 425809 B 25 mg QD, pharmacoki- 5. Goff DC, Coyle JT. The emerging role of glutamate in the netic parameters demonstrated no obvious deviation from pathophysiology and treatment of schizophrenia. Am J Psychia- dose linearity. try. 2001;158(9):1367–77. 6. Danysz W, Parsons CG. Alzheimer’s disease, beta-amyloid, Acknowledgements The authors thank Jakub Pekarek and Marion glutamate, NMDA receptors and memantine: searching for the Schmid for their technical support of the pharmacokinetic analyses, connections. Br J Pharmacol. 2012;167(2):324–52. and Jasmin Link for her review of the manuscript. 7. Hashimoto K. Glycine transport inhibitors for the treatment of schizophrenia. Open Med Chem J. 2010;4:10–9. Compliance with Ethical Standards 8. Cooke SF, Bliss TV. Long-term potentiation and cognitive drug discovery. Curr Opin Investig Drugs. 2005;6(1):25–34. Funding The work presented here, including the conduct of the 9. Collingridge GL, Volianskis A, Bannister N, et al. The NMDA study, data analysis and interpretation, was funded by Boehringer receptor as a target for cognitive enhancement. Neuropharma- Ingelheim. The sponsor was given the opportunity to review the cology. 2013;64:13–26. manuscript for medical and scientiﬁc accuracy as well as intellectual 10. Moschetti V, Desch M, Goetz S, et al. Safety, tolerability and property considerations. Editorial support in the form of initial pharmacokinetics or oral BI 425809, a glycine transporter 1 preparation of the outline based on input from all authors, and col- inhibitor, in healthy male volunteers: a partially randomised, lation and incorporation of author feedback to develop subsequent single-blind, placebo-controlled, ﬁrst-in-human study. Eur J Drug Metab Pharmacokinet. 2018;43(2):239–49. drafts, assembling tables and ﬁgures, copy editing and referencing 750 V. Moschetti et al. 11. Desch M, Goettel M, Goetz S, et al. Effects of the potent cyto- adjunctive treatment with bitopertin, a glycine reuptake inhibitor, chrome p450 3A4 inhibitor, itraconazole, on the pharmacoki- in Japanese patients with schizophrenia. BMC Psychiatry. netics of BI 425809, a new glycine transporter 1 (GlyT1) 2016;16(1):1. inhibitor. Clin Pharmacol Ther. 2017;101(S1):S52. 18. Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of 12. International Council For Harmonisation Of Technical Require- bitopertin, a glycine reuptake inhibitor, on negative symptoms of ments For Pharmaceuticals For Human Use (ICH). ICH har- schizophrenia: a randomized, double-blind, proof-of-concept monised guideline. Integrated addendum to ICH E6 (R1): study. JAMA Psychiatry. 2014;71(6):637–46. guideline for good clinical practice E6 (R2). Current Step 4 19. Liem-Moolenaar M, Peeters P, Kamerling IMC, et al. Early stage version; 9 Nov 2016. development of the glycine-1 re-uptake inhibitor SCH 900435: 13. World Medical Association. World Medical Association Decla- central nervous system effects compared with placebo in healthy ration of Helsinki: ethical principles for medical research men. Br J Clin Pharmacol. 2013;75(6):1455–67. involving human subjects. JAMA. 2013;310(20):2191–4. 20. Liu CN, Pettersen B, Seitis G, et al. GlyT1 inhibitor reduces 14. Bond A, Lader M. The use of analogue scales in rating subjective oscillatory potentials of the electroretinogram in rats. Cutan Ocul feelings. Br J Med Psychol. 1974;47(3):211–8. Toxicol. 2014;33(3):206–11. 15. Bowdle TA, Radant AD, Cowley DS, et al. Psychedelic effects of 21. Desch M, Schmitt H, Hohl K, et al. Pharmacokinetic interaction ketamine in healthy volunteers: relationship to steady-state of BI 425809, a new glycine transporter 1 (GlyT1) inhibitor, with plasma concentrations. Anesthesiology. 1998;88(1):82–8. cytochrome p450 (CYP) isoenzymes and p-glycoprotein (P-gp) 16. D’Souza DC, Singh N, Elander J, et al. Glycine transporter probe drug. Clin Pharmacol Ther. 2017;101(S1):S52. inhibitor attenuates the psychotomimetic effects of ketamine in 22. Lyng E, Havenaar R, Shastri P, et al. Increased bioavailability of healthy males: preliminary evidence. Neuropsychopharmacology. celecoxib under fed versus fasted conditions is determined by 2012;37(4):1036–46. postprandial bile secretion as demonstrated in a dynamic gas- 17. Hirayasu Y, Sato S-I, Takahashi H, et al. A double-blind ran- trointestinal model. Drug Dev Ind Pharm. 2016;42(8):1334–9. domized study assessing safety and efﬁcacy following one-year
Clinical Drug Investigation – Springer Journals
Published: May 30, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera