Saleh Soundos, Mundry Tobias, Nagelschmitz Johannes, Buetehorn Ulf, Holzschuh Stephan, Nikkho Sylvia M
Bayer AG, Pharmaceuticals R&D, Pharma Research Center, Wuppertal, Germany.
Bayer AG, Pharmaceuticals R&D, Clinical Development, Berlin, Germany.
Clin Pharmacokinet. 2025 May 22. doi: 10.1007/s40262-025-01503-6.
Mosliciguat is the first soluble guanylate cyclase activator designed for dry powder inhalation. It is currently under development for the treatment of pulmonary hypertension; the inhaled route of administration delivers the drug to the pulmonary vasculature with the aim of improving pulmonary hemodynamics. We conducted three phase I trials in healthy male volunteers to characterize the pharmacokinetic profile of mosliciguat, focusing on lung deposition after inhalation with a low-resistance device in a lactose carrier-based dry powder formulation.
Study 1 was a randomized, open-label, four-way crossover study (Part 2) comparing the pharmacokinetics of mosliciguat by inhalation (1000 μg), inhalation (1000 μg) with charcoal block, in oral solution (1000 μg), and intravenously (100 μg). (The oral and intravenous doses were selected in Part 1 of the study.) Study 2 was an 8-day, randomized, single-blind, placebo-controlled, multiple-dose escalation study of once-daily inhaled mosliciguat (480, 1000, and 2000 μg). Study 3 was a 2-week, multiple-dose, randomized, placebo-controlled, single-blind study of once-daily inhaled mosliciguat 1000 μg.
In Study 1 (Part 2) the absolute bioavailability of inhaled mosliciguat was 18.8% without charcoal block and 16.3% with charcoal block. The absolute bioavailability of oral mosliciguat was 23.1%. Pharmacokinetic parameters showed low-to-moderate inter-subject variability. Time to maximum plasma concentration (t) was 2.0 h after inhalation and 1.0 h after oral administration; half-life was 15.1 and 4.4 h, respectively. Based on accumulation ratios in Study 2, the area under the concentration-time curve (AUC) and maximum plasma concentration (C) increased by 45-51% and 15-21%, respectively, across doses at day 8. In Study 2 the half-life of inhaled mosliciguat with multiple dosing was 57.4 and 42.3 h at doses of 1000 and 2000 µg, respectively. Data showed moderate variability in AUC and C (geometric coefficients of variation, 26.6% and 24.7%, respectively, in study 3 on day 1). Trough levels showed accumulation ratios of 1.7-2.1 in Study 2 (day 8) and 2.5 in Study 3 (day 14). In all three studies, mosliciguat was well tolerated, without major systemic effects on heart rate or blood pressure.
Inhaled mosliciguat had a longer t and half-life than oral mosliciguat. Accumulation data suggest formation of a mosliciguat depot in the lungs and continuous transfer to the systemic circulation, with an indication of an increase in accumulation ratio with longer duration of treatment.
莫西利胍是首个设计用于干粉吸入的可溶性鸟苷酸环化酶激活剂。目前正在开发用于治疗肺动脉高压；吸入给药途径将药物输送至肺血管系统，旨在改善肺血流动力学。我们在健康男性志愿者中进行了三项I期试验，以表征莫西利胍的药代动力学特征，重点关注在基于乳糖载体的干粉制剂中使用低阻力装置吸入后的肺部沉积情况。
研究1是一项随机、开放标签、四交叉研究（第2部分），比较吸入（1000μg）、吸入（1000μg）并使用活性炭阻断、口服溶液（1000μg）和静脉注射（100μg）莫西利胍的药代动力学。（口服和静脉剂量在研究的第1部分中选定。）研究2是一项为期8天的随机、单盲、安慰剂对照、多剂量递增研究，每日一次吸入莫西利胍（480、1000和2000μg）。研究3是一项为期2周的多剂量、随机、安慰剂对照、单盲研究，每日一次吸入1000μg莫西利胍。
在研究1（第2部分）中，吸入莫西利胍无活性炭阻断时的绝对生物利用度为18.8%，有活性炭阻断时为16.3%。口服莫西利胍的绝对生物利用度为23.1%。药代动力学参数显示受试者间变异性低至中等。吸入后达到最大血浆浓度（t）的时间为2.0小时，口服给药后为1.0小时；半衰期分别为15.1小时和4.4小时。根据研究2中的蓄积率，在第8天，各剂量下浓度-时间曲线下面积（AUC）和最大血浆浓度（C）分别增加了45 - 51%和15 - 21%。在研究2中，多次给药时吸入莫西利胍在1000和2000μg剂量下的半衰期分别为57.4小时和42.3小时。数据显示AUC和C存在中等变异性（研究3第1天的几何变异系数分别为26.6%和24.7%）。谷浓度在研究2（第8天）的蓄积率为1.7 - 2.1，在研究3（第14天）为2.5。在所有三项研究中，莫西利胍耐受性良好，对心率或血压无重大全身影响。
吸入莫西利胍的t和半衰期比口服莫西利胍长。蓄积数据表明在肺部形成了莫西利胍贮库，并持续转移至体循环，表明随着治疗时间延长蓄积率增加。
