Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Boehringer Ingelheim International GmbH, Ingelheim, Germany.
J Psychopharmacol. 2024 Sep;38(9):807-817. doi: 10.1177/02698811241273814. Epub 2024 Sep 12.
Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available.
Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug-drug interactions.
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.
与精神分裂症相关的认知障碍预测功能预后不良，但目前尚无有效的药物治疗方法。
四项 I 期临床试验考察了磷酸二酯酶 2 抑制剂 BI 474121 的安全性、耐受性和药代动力学，以及潜在的药物相互作用。
试验 1 评估了 BI 474121 单剂量递增（SRD）与安慰剂在健康男性中的作用。还考察了药物制剂和食物对药物生物利用度的影响。试验 2 评估了 BI 474121 的 SRD 与安慰剂在健康日本男性中的作用。试验 3 评估了 BI 474121 在健康年轻（合用/不合用咪达唑仑）和老年（不合用咪达唑仑）受试者中的多剂量递增与安慰剂的作用。试验 4 考察了伊曲康唑与 BI 474121 单剂量给药之间的相互作用。
结果/结论：未观察到死亡、严重不良事件（AE）、严重 AE 或特别关注的方案规定的 AE。BI 474121 在禁食条件下吸收迅速，通过片剂制剂达到分析物在血浆中的最大浓度和剂量比例，呈多相下降。多次口服后，BI 474121 稳态在 11 天内达到。多次剂量增加 BI 474121 血浆浓度，但不改变血浆浓度的时间过程。未改变的 BI 474121 尿排泄可忽略不计。未观察到 BI 474121 对 CYP3A4 的临床相关抑制或诱导作用。伊曲康唑合用使 BI 474121 的暴露量高于 BI 474121 单药。
BI 474121 在健康白种人和日本人群中表现出良好的安全性和药代动力学特征，支持进一步的临床开发。
