Insmed Incorporated, 202/206 North, Bridgewater, NJ, 08807, USA.
Insmed Incorporated, 202/206 North, Bridgewater, NJ, 08807, USA.
Pulm Pharmacol Ther. 2021 Feb;66:101983. doi: 10.1016/j.pupt.2020.101983. Epub 2020 Dec 17.
Treprostinil palmitil (TP) is an inhaled long-acting pulmonary vasodilator prodrug of treprostinil (TRE) that has been formulated for delivery as a suspension (treprostinil palmitil inhalation suspension; TPIS) and as a dry powder (treprostinil palmitil inhalation powder; TPIP). In humans, tachyphylaxis is frequently observed with continuous intravenous (IV) or subcutaneous (SC) infusion of TRE and requires dosage escalation to maintain activity. The aim of the present study was to determine whether tachyphylaxis occurs with repeat daily administration of inhaled TPIS.
Experiments were performed in male Sprague-Dawley rats prepared with a telemetry probe implanted into the right ventricle to measure the change in right ventricular pulse pressure (ΔRVPP) induced by exposure to a 10% oxygen gas mixture. TPIS (6 mL) at concentrations of 0.25, 0.5, and 1 mM was given by nose-only inhalation using an Aeroneb Pro nebulizer, either as a single administration or daily for 16 or 32 consecutive days. In studies involving consecutive daily administrations of TPIS, the delivered TP dosage was 140.3 μg/kg at 1 mM and ranged from 40.2 to 72.2 μg/kg at 0.5 mM. A separate cohort of telemetered rats received continuous IV infusion of TRE via an Alzet mini-pump at a dosage rate of 250 ng/kg/min for 16 days. Blood and lung tissue samples were obtained, and the concentration of TRE in the plasma and TRE and TP in the lungs were measured approximately 1 h after TPIS administration.
Dose-response studies with TPIS administered as a single administration inhibited the hypoxia-induced increase in RVPP in both a concentration-dependent (0.25, 0.5, and 1 mM) and time-dependent (1-24 h) manner. TPIS, given QD or BID at inhaled doses ranging from 40.2 to 140.3 μg/kg for 16 or 32 consecutive days, produced statistically significant (P < .05) inhibition of the increase of RVPP due to hypoxia over the full duration of the dosing periods. By contrast, the inhibition of the hypoxia-induced increase in RVPP observed with IV TRE infusion (250 ng/kg/min) disappeared after 16 days of infusion. The plasma concentrations of TRE were significantly higher after IV TRE (range, 2.85-13.35 ng/mL) compared to inhaled TPIS (range, 0.22-0.73 ng/mL) CONCLUSIONS: There was no evidence of tachyphylaxis with repeat daily dosing of TPIS for a period of up to 32 days. The absence of tachyphylaxis with TPIS is likely related to its local vasodilatory effects within the lungs, combined with an absence of sustained high plasma concentrations of TRE.
曲前列尼尔棕榈酸酯（TP）是曲前列尼尔（TRE）的一种吸入长效肺动脉扩张剂前体药物，已被制成混悬液（曲前列尼尔棕榈酸酯吸入混悬液；TPIS）和干粉（曲前列尼尔棕榈酸酯吸入粉；TPIP）两种剂型。在人体中，持续静脉（IV）或皮下（SC）输注 TRE 时经常观察到快速耐受现象，需要增加剂量以维持疗效。本研究的目的是确定重复每日吸入 TPIS 是否会发生快速耐受现象。
雄性 Sprague-Dawley 大鼠接受了实验，这些大鼠通过将遥测探头植入右心室来制备，以测量暴露于 10%氧气混合气后右心室脉搏压力（ΔRVPP）的变化。使用 Aeroneb Pro 雾化器以鼻吸入方式给予浓度为 0.25、0.5 和 1 mM 的 TPIS，单次或连续 16 或 32 天每天一次给药。在涉及连续每日给予 TPIS 的研究中，在 1 mM 时给予的 TP 剂量为 140.3μg/kg，在 0.5 mM 时的剂量范围为 40.2 至 72.2μg/kg。另一组遥测大鼠通过 Alzet 微型泵以 250ng/kg/min 的剂量率连续静脉输注 TRE，持续 16 天。大约在给予 TPIS 后 1 小时，获得血液和肺组织样本，并测量血浆中 TRE 的浓度以及肺组织中 TRE 和 TP 的浓度。
单次给予 TPIS 的剂量反应研究表明，TPIS 以浓度依赖性（0.25、0.5 和 1 mM）和时间依赖性（1-24 小时）方式抑制缺氧诱导的 RVPP 增加。TPIS，以每天 40.2 至 140.3μg/kg 的吸入剂量 QD 或 BID 连续给予 16 或 32 天，在整个给药期间产生统计学显著（P<.05）的抑制缺氧诱导的 RVPP 增加。相比之下，静脉输注 TRE（250ng/kg/min）引起的缺氧诱导的 RVPP 增加抑制作用在输注 16 天后消失。与静脉注射 TRE（范围 2.85-13.35ng/mL）相比，血浆中 TRE 的浓度明显更高TPIS（范围，0.22-0.73ng/mL）。
在长达 32 天的时间内，重复每日给予 TPIS 没有证据表明发生快速耐受现象。TPIS 没有发生快速耐受现象可能与它在肺部的局部血管扩张作用有关，同时也没有持续的高浓度 TRE 血浆浓度。
