A Randomized, Placebo Controlled, Double-blind, Double-dummy, Three-way Crossover Trial to Investigate the Effect of Two Doses of BI 474121 on Ketamine Induced Cognitive Deficits in Healthy Male Subjects

To investigate the effect of BI 474121 compared to placebo on ketamine-induced cognitive deficits to predict efficacy in patients with cognitive disorders.

开始日期2022-11-07

申办/合作机构

Boehringer Ingelheim GmbH

NCT04964453 / Completed临床1期

Safety, Tolerability, and Pharmacokinetics of Single Rising Oral Doses of BI 474121 in Healthy Japanese Male Subjects (Doubleblind, Randomised, Placebo-controlled, Parallel Group Design)

Safety, tolerability, and pharmacokinetics of BI 474121 will be assessed in healthy Japanese male using single rising oral doses in order to provide the basis for an ongoing clinical development of BI 474121 for the treatment of cognitive impairment in patients with Alzheimer's Disease and schizophrenia.

开始日期2021-07-21

申办/合作机构

Boehringer Ingelheim GmbH

NCT04716894 / Completed临床1期

Effect of Itraconazole on the Pharmacokinetics of a Single Oral Dose of BI 474121 in Healthy Male Subjects (an Open-label, Two-period Fixed Sequence Design Study)

The main objective of this trial is to investigate the effect on the exposure of BI 474121 in plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, T) as compared to when given alone as oral single dose (Reference, R).

开始日期2021-02-01

申办/合作机构

Boehringer Ingelheim GmbH

100 项与 BI-474121 相关的临床结果

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100 项与 BI-474121 相关的转化医学

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100 项与 BI-474121 相关的专利（医药）

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项与 BI-474121 相关的文献（医药）

2024-09-01·Journal of Psychopharmacology

Safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121: An overview of phase I randomized trials in healthy volunteers

Article

作者: Goeldner, Rainer-Georg ; Yamamura, Norio ; Schaible, Jennifer ; Scholz, Andreas

Background: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available. Aims: Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug–drug interactions. Methods: Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males. The influence of drug formulation and food on drug bioavailability was also examined. Trial 2 evaluated SRD of BI 474121 versus placebo in healthy Japanese males. Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Trial 4 investigated interactions between itraconazole and single-dose BI 474121 in healthy males. Results/Outcomes: No deaths, serious adverse events (AEs), severe AEs or protocol-specified AEs of special interest were observed. BI 474121 absorbed rapidly during fasting, achieved maximum concentration of analyte in plasma and dose proportionality via tablet formulation, and decreased in a multiphasic manner. BI 474121 steady state occurred within 11 days of multiple oral administration. Multiple doses increased BI 474121 plasma concentrations, but did not alter the time course of plasma concentrations. Urinary excretion of unchanged BI 474121 was negligible. No clinically relevant inhibition or induction of CYP3A4 by BI 474121 was observed. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone. Conclusions/Interpretation: BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development.

British Journal of Clinical Pharmacology

Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies

Article

作者: Rosenbrock, Holger ; Zambori, Janos ; Schaible, Jennifer ; Goeldner, Rainer‐Georg ; van Kraaij, Sebastiaan ; Groeneveld, Geert Jan ; Kremer, Philip ; Schultheis, Christian

AbstractAimsPhosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia.MethodsThe effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121.ResultsIn rats, BI 474121 was associated with a dose‐dependent increase (71% at the highest dose tested [3.0 mg kg−1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum‐measured concentration CSF‐to‐plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose‐adjusted geometric mean: 8.96% overall). BI 474121 2.5–40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure‐related change from baseline ratio, BI 474121: 1.44–2.20 vs. placebo: 1.26). The most common treatment‐emergent adverse event (AE) was mild‐to‐moderate post‐lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed.ConclusionsBI 474121 crosses the blood–brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121.ClinicalTrials.gov number (NCT04672954).

100 项与 BI-474121 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
重度抑郁症	临床2期	波兰	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	德国	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	匈牙利	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	斯洛伐克	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	美国	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	西班牙	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	法国	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	澳大利亚	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	日本	Boehringer Ingelheim GmbH	2020-11-20
重度抑郁症	临床2期	俄罗斯	Boehringer Ingelheim GmbH	2020-11-20

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04672954 (Pubmed)	临床1期	cGMP	-	BI 474121 2.5 mg	願鹹製觸窪廠觸襯鹽糧(廠製廠簾製繭繭範夢餘) = No AEs of special interest were observed 繭憲選廠顧餘鹽齋壓鬱 (餘鹽構糧鬱鹹獵糧願選 ) 更多	积极	2024-06-16
				BI 474121 10 mg
NCT04672954 (CTgov)	临床1期	-	24	Placebo (Placebo)	選蓋膚積選鹽築願鹹範(鹽壓鏇襯艱膚願醖鏇範) = 獵築獵膚醖鏇窪選壓膚糧廠積網壓築構簾膚窪 (鏇築遞簾願艱蓋鹽觸簾, 窪獵壓鹹襯願簾鬱憲網 ~ 網夢鹽醖願壓糧鬱餘夢) 更多	-	2024-03-08
				2.5 milligram (mg) BI 474121 (2.5 Milligram (mg) BI 474121)	選蓋膚積選鹽築願鹹範(鹽壓鏇襯艱膚願醖鏇範) = 艱築衊衊膚糧積醖觸齋糧廠積網壓築構簾膚窪 (鏇築遞簾願艱蓋鹽觸簾, 簾鬱鬱製製鹽範糧艱壓 ~ 築簾繭鹹夢蓋積鏇餘餘) 更多
NCT04964453 (CTgov)	临床1期	阿尔茨海默症 \| 认知功能障碍 \| 精神分裂症	32	Placebo (Placebo)	衊積鏇鏇築齋衊鹽衊鹹(觸夢範膚觸鏇範壓鹹衊) = 醖膚鹽鑰築夢醖壓鬱構膚壓遞鬱鹹窪憲壓窪積 (鏇選齋窪簾餘蓋醖淵積, 顧鏇憲獵襯鹹築鏇製鏇 ~ 鹽膚鑰鬱廠顧齋襯構繭) 更多	-	2024-03-07
				BI 474121 (2.5 mg BI 474121)	衊積鏇鏇築齋衊鹽衊鹹(觸夢範膚觸鏇範壓鹹衊) = 衊獵糧艱鏇醖鏇鏇醖壓膚壓遞鬱鹹窪憲壓窪積 (鏇選齋窪簾餘蓋醖淵積, 構淵齋顧廠顧選鹹顧鹹 ~ 築淵窪鹹膚醖構願蓋齋) 更多