Avalyn Pharma, Inc., 701 Pike Street, Suite 1500, Seattle, WA, 98101, USA.
Respiratory Pharmacology, Charles River Laboratories, Edinburgh, EH33 2NE, UK.
Pulm Pharmacol Ther. 2020 Aug;63:101938. doi: 10.1016/j.pupt.2020.101938. Epub 2020 Aug 22.
Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF), Systemic Sclerosis-Associated Interstitial Lung Disease and Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype. While effective at slowing fibrosis progression, as an oral medicine nintedanib has limitations. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, inhalation was used as a tool to dissect the pharmacokinetic components required for nintedanib pulmonary anti-fibrotic activity. Following oral administration, nintedanib extensively partitioned into tissue and exhibited flip-flop pharmacokinetics, whereby resulting lung Cmax and AUC were substantially higher than plasma. By comparison, inhaled nintedanib was capable of delivering an oral-equivalent lung Cmax with lower local and systemic AUC. Using a multi-challenge bleomycin rat model, this distinct inhaled pharmacokinetic profile was dose responsive (0.05, 0.25 and 0.375 mg/kg), delivering oral-superior pulmonary anti-fibrotic activity with an equivalent delivered lung Cmax (QD inhaled 0.375 mg/kg versus BID oral 60 mg/kg). Possibly assisting this improvement, the infrequent high inhaled dose also improved bleomycin-challenged animal weight gain to levels equivalent to sham. By comparison, BID oral weight gain was substantially less than controls, suggesting a negative health impact on oral administered animals combating fibrosis. Both oral and inhaled administration exhibited anti-inflammatory activity, with oral achieving significance. In summary, inhalation (short-duration nintedanib lung Cmax without high local or systemic AUC) was well-tolerated and was effective reducing bleomycin-induced pulmonary fibrosis.
尼达尼布口服制剂已上市，用于治疗特发性肺纤维化（IPF）、系统性硬化症相关间质性肺病和具有进行性表型的慢性纤维化间质性肺病。尼达尼布作为一种口服药物，虽然能有效减缓纤维化进展，但也存在局限性。为了降低副作用并最大限度地提高疗效，尼达尼布被重新配方制成雾化吸入剂。为了预测尼达尼布治疗 IPF 的疗效，吸入被用作一种工具来剖析尼达尼布肺抗纤维化活性所需的药代动力学成分。口服后，尼达尼布广泛分布到组织中，并表现出翻转的药代动力学特征，导致肺 Cmax 和 AUC 显著高于血浆。相比之下，吸入尼达尼布能够以较低的局部和全身 AUC 达到与口服相当的肺 Cmax。在多剂量博莱霉素大鼠模型中，这种独特的吸入药代动力学特征具有剂量依赖性（0.05、0.25 和 0.375mg/kg），在达到与口服相当的肺 Cmax 时，具有优于口服的肺抗纤维化活性（QD 吸入 0.375mg/kg 与 BID 口服 60mg/kg 相比）。可能有助于改善这一情况的是，频繁给予高吸入剂量也改善了博莱霉素挑战动物的体重增加，使其达到与假手术组相当的水平。相比之下，BID 口服组的体重增加明显低于对照组，这表明口服药物治疗纤维化的动物健康状况受到负面影响。口服和吸入给药均表现出抗炎活性，其中口服给药具有显著意义。总之，吸入（短时间尼达尼布肺 Cmax 而无高局部或全身 AUC）具有良好的耐受性，并能有效减轻博莱霉素诱导的肺纤维化。
