Inhalation: A means to explore and optimize nintedanib’s pharmacokinetic/pharmacodynamic relationship

Abstract

Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF). While effective slowing fibrosis progression, as an oral medicine nintedanib is limited. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, the nintedanib pharmacokinetic/pharmacodynamic relationship was dissected. Pharmacokinetic analysis indicated oral-delivered nintedanib plasma exposure and lung tissue partitioning were not doseproportional and resulting lung levels were substantially higher than blood. Although initial-oral absorbed nintedanib efficiently partitioned into the lung, only a quickly eliminated fraction appeared available to epithelial lining fluid (ELF). Because IPF disease appears to initiate and progress near the epithelial surface, this observation suggests short duration nintedanib exposure (oral portion efficiently partitioned to ELF) is sufficient for IPF efficacy. To test this hypothesis, exposure duration required for nintedanib activity was explored. In vitro, IPF-cellular matrix (IPF-CM) increased primary normal human fibroblast (nHLF) aggregate size and reduced nHLF cell count. IPF-CM also increased nHLF ACTA2 and COL1A expression. Whether short duration (inhalation mimic) or continuous exposure (oral mimic), nintedanib (1-100 nM) reversed these effects. In vivo, intubated silica produced a strong pulmonary fibrotic response.Once-daily (QD) 0.021, 0.21 and 2.1 mg/kg intranasal (IN; short duration inhaled exposure) and twice daily (BID) 30 mg/kg oral (PO; long duration oral exposure) showed that at equivalentdelivered lung concentrations, QD short duration inhaled nintedanib exposure (0.21 mg/kg IN vs. 30 mg/kg PO) exhibited equivalent-to-superior activity as BID oral (reduced silica-induced elastance, alpha-smooth muscle actin, interleukin-1 beta (IL-1β) and soluble collagen, and lung macrophage and neutrophils). An increased lung dose (2.1 mg/kg IN vs. 30 mg/kg PO) exhibited 3 increased effect by further reducing silica-induced elastance, IL-1β and soluble collagen. Neither oral nor inhaled nintedanib reduced silica-induced parenchymal collagen. Both QD inhaled and BID oral nintedanib reduced silica-induced inflammatory index with oral achieving significance.In summary, nintedanib pulmonary anti-fibrotic activity can be achieved using small, infrequent inhaled doses to deliver oral equivalent-to-superior therapeutic effect.

Galectin-3 levels are elevated following nintedanib treatment

“…In vivo silica mouse model Mouse studies were performed in collaboration with McMaster University using established protocols, as previously described. 21 Briefly, IPF was induced on day 1 in 20-22 g female C57BL/6 mice by a single intratracheal intubation of silica (2.5 mg/kg) or phosphate-buffered saline (PBS) control while animals were under isoflurane anesthesia. Nintedanib was delivered using intranasal (IN) administration of 50 µl formulation directly to the lung.…”

“…Nintedanib was delivered using intranasal (IN) administration of 50 µl formulation directly to the lung. 21,22 After acclimation, animals were randomized based upon body weight. On days 10-29, animals were lightly anesthetized with isoflurane and dosed once a day with 0.021, 0.21, or 2.1 mg/kg nintedanib (35 µl per dose) or inhaled vehicle.…”

“…In our recent work, 21 nintedanib was given to silica-exposed mice in three doses (0.021-2.1 mg/ kg) and was shown to inhibit the silica-induced expression of fibrotic markers (e.g. smooth muscle actin, collagen, and IL-1β).…”

“…We evaluated Gal-3 levels in those receiving nintedanib versus those not receiving nintedanib. Of these patients, 21 were diagnosed with IPF and 20 with non-IPF-ILD (e.g. nonspecific interstitial pneumonia, sarcoidosis).…”

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

“…For this aim, an inhaled version of nintedanib was recently described. Using two animal models [ 12 , 13 ], it was shown that oral-equivalent to superior effects could be obtained administering substantially reduced inhaled doses, with less adverse effects on general health. Moreover, the activity of inhaled pharmacokinetics were further supported using the in-vitro IPF-CM system wherein only short-duration nintedanib exposure was required to achieve similar effects [ 13 ].…”