Pharmacokinetics and ADME Profiling of Tanimilast Following an Intravenous 14C-Microtracer co-administered with an Inhaled Dose in Healthy Male Individuals.

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Michele Bassi, Veronica Puviani, Debora Santoro, Sonia Biondaro, Aida Emirova, Mirco Govoni
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引用次数: 0

Abstract

Tanimilast is an inhaled phosphodiesterase-4 inhibitor currently in phase 3 clinical development for treating chronic obstructive pulmonary disease (COPD) and asthma. This trial aimed to characterize the pharmacokinetics, mass balance, and metabolite profiling of tanimilast. Eight healthy male volunteers received a single dose of non-radiolabeled tanimilast via powder inhaler (NEXThaler® (3200μg)), followed by a concomitant intravenous (IV) infusion of a microtracer ([14C]-tanimilast: 18.5μg and 500nCi). Plasma, whole blood, urine, and feces samples were collected up to 240 hours post-dose to quantify non-radiolabeled tanimilast, [14C]-tanimilast, and total-[14C]. The inhaled absolute bioavailability of tanimilast was found to be approximately 50%. Following IV administration of [14C]-tanimilast, plasma clearance was 22 L/h, the steady-state volume of distribution was 201 L, and the half-life was shorter compared to inhaled administration (14 vs. 39 hours, respectively), suggesting that plasma elimination is limited by the absorption rate from the lungs. 79% (71% in feces; 8% in urine) of the IV dose was recovered in excreta as total-[14C]. [14C]-tanimilast was the major radioactive compound in plasma, while no recovery was observed in urine and only 0.3% was recovered in feces, indicating predominant elimination through metabolic route. Importantly, as far as no metabolites accounting for more than 10% of the circulating drug-related exposure in plasma or the administered dose in excreta were detected, no further qualification is required according to regulatory guidelines. This study design successfully characterized the absorption, distribution, and elimination of tanimilast, providing key pharmacokinetic parameters to support its clinical development and regulatory application. Significance Statement This trial investigates PK and ADME profile of tanimilast, an inhaled PDE4 inhibitor for COPD and asthma. Eight male volunteers received a dose of non-radiolabeled tanimilast via NEXThaler® and a microtracer IV dose. Results show pivotal PK results for the characterization of tanimilast, excretion route and quantification of significant metabolites, facilitating streamlined clinical development and regulatory approval.

健康男性静脉注射 14C 微示踪剂和吸入剂量后他尼司特的药代动力学和 ADME 分析。
他尼司特是一种吸入式磷酸二酯酶-4抑制剂,目前正处于治疗慢性阻塞性肺病(COPD)和哮喘的三期临床开发阶段。该试验旨在描述他尼司特的药代动力学、质量平衡和代谢物特征。八名健康男性志愿者通过粉末吸入器(NEXThaler®(3200微克))接受了单剂量无放射性标记的他尼司特,随后同时静脉注射了微量示踪剂([14C]-他尼司特:18.5微克和500nCi)。在用药后 240 小时内收集血浆、全血、尿液和粪便样本,以量化非放射性标记的他尼司特、[14C]-他尼司特和总[14C]。结果发现,他尼司特的吸入绝对生物利用度约为 50%。静脉注射[14C]-他尼司特后,血浆清除率为22升/小时,稳态分布容积为201升,半衰期比吸入给药短(分别为14小时和39小时),这表明血浆消除受到肺部吸收率的限制。79%的静脉注射剂量(71%在粪便中;8%在尿液中)在排泄物中以总[14C]的形式被回收。血浆中的[14C]-他尼司特是主要的放射性化合物,而尿液中没有回收,粪便中仅回收了0.3%,这表明主要通过代谢途径排出体外。重要的是,只要在血浆中未检测到占循环药物相关暴露量 10%以上的代谢物,或在排泄物中未检测到占给药剂量 10%以上的代谢物,就无需根据监管指南进行进一步鉴定。这项研究设计成功地描述了他尼司特的吸收、分布和消除,为其临床开发和监管应用提供了关键的药代动力学参数。意义声明 本试验研究了吸入式PDE4抑制剂他尼司特的PK和ADME特征,用于治疗慢性阻塞性肺病和哮喘。八名男性志愿者通过 NEXThaler® 和微量示踪剂静脉注射了一定剂量的无放射标记的他尼司特。结果显示,PK 结果对他尼司特的特征描述、排泄途径和重要代谢物的定量至关重要,有助于简化临床开发和监管审批。
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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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