Inhaled Nintedanib May Reduce Side Effects of Oral Formulation, Rat Study Shows

Inhaled Nintedanib May Reduce Side Effects of Oral Formulation, Rat Study Shows
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An inhaled formulation of nintedanib — the active ingredient in Ofev — demonstrated enhanced antifibrotic effects after short-duration doses compared to oral formulations given at a higher dose in a rat model with induced idiopathic pulmonary fibrosis (IPF), a study shows. 

These findings support the further development of the inhaled formulation to reduce the side effects reported with oral Ofev treatment, while maintaining or improving its effectiveness. 

The study, “Inhaled Nintedanib is Well-Tolerated and Delivers Key Pharmacokinetic Parameters Required to Treat Bleomycin-Induced Pulmonary Fibrosis,” was published in the journal Pulmonary Pharmacology & Therapeutics

Ofev, developed and marketed by Boehringer Ingelheim, is an oral therapy approved for the treatment of IPF. Its approval was supported by clinical trials showing Ofev helps to reduce the decline in lung function and the number of acute exacerbations (sudden worsening of symptoms). 

Despite its efficacy, Ofev can produce side effects such as diarrhea in up to 63% of patients and increased liver enzymes in the blood, a sign of liver damage, according to clinical trial data. Most side effects are managed by either reducing the dose, interrupting the therapy, or stopping treatment altogether. 

Furthermore, after being absorbed into the bloodstream from the digestive tract, the fast metabolism of oral Ofev leaves less therapy to reach the lungs. 

To address these issues, Ofev’s active ingredient — nintedanib — was reformulated as a liquid solution to be inhaled directly into the lungs. Because inhaled medicines avoid the digestive tract, this approach may reduce side effects seen in oral formulations. Moreover, fewer side effects means higher, more effective doses may be used. 

To test the potential of this reformulation, scientists at Avalyn Pharma in Washington, along with investigators at Charles River Laboratories in the U.K., assessed the impact of an inhalable solution of nintedanib in rats with induced IPF.

“The objective of this study was to dissect the nintedanib properties required for anti-fibrotic activity in the lung and predict the effectiveness of inhaled therapy in treating IPF,” the scientists wrote. 

First, the team used healthy rats to establish lung exposure after dosing with inhaled nintedanib. The solution was applied to the animals’ pharynx at the back of the throat or directly into the windpipe (trachea) at doses of 0.1 and 0.5 mg/kg.

The results indicated that both routes of inhaled administration efficiently delivered nintedanib to the lung in a dose-dependent manner. As the inhaled solution applied at the back of the throat was better tolerated, this method was chosen for further experiments. 

Compared to a 60 mg/kg oral dose of nintedanib delivered directly into the stomach, the small doses of inhaled nintedanib delivered similar levels of the therapy to the lungs. 

Next, tolerability tests were conducted in IPF-induced rats to establish conditions that would allow daily inhaled nintedanib treatment for 20 consecutive days, and ensure that delivering the medicine into an inflamed IPF-induced lung would not affect its efficacy. 

Based on these experiments, 0.375 mg/kg was selected as a high dose, which delivered a similar amount of nintedanib to the lungs as the 60 mg/kg oral formulation; 0.25 mg/kg was selected as a mid-dose; and 0.05 mg/kg was the low dose. All doses were well-tolerated. 

Finally, the efficacy of the inhaled solution compared to an oral formulation was assessed. 

Compared to healthy controls, the average body weight of IPF-induced rats was significantly reduced. While low- and mid-dose inhaled nintedanib did not affect body weight gain compared to IPF animals without treatment, the high-dose inhaled solution improved body weight gain similar to healthy controls. 

In contrast, 60 mg/kg of orally administer nintedanib significantly reduced body weight gain compared to healthy controls, “suggesting a negative health impact on oral administered animals combating fibrosis,” the researchers wrote. 

Following inhaled nintedanib treatment, scores that measure the extent of fibrosis in the lungs followed a dose-dependent reduction. The median (middle) score was 2.5 for untreated IPF-induced animals, and it was significantly lower at 1.5 in rats treated with the inhaled solution. Microscope analysis found less fibrosis in the lungs of treated rats than in controls. 

The fibrosis score was also reduced in rats that received oral nintedanib, but the difference was not statistically significant. 

Inflammation scores for rats exposed to the inhaled solution showed a dose-response trend, but the differences were not significant. In turn, the inflammation score of orally-treated rats was significantly reduced compared to controls. 

The levels of hydroxyproline, a major component of collagen that’s used to evaluate tissue fibrosis, were found to be reduced in rats treated with inhaled nintedanib in a dose-dependent manner after adjusting for lung weight-to-body weight ratio. Orally dosed animals also showed significantly reduced hydroxyproline compared with induced controls.

Overall, the data suggested that short-duration nintedanib was well-tolerated and effective at reducing induced pulmonary fibrosis.

“Because very small inhaled doses achieved this [effect] while largely avoiding the [gastrointestinal] tract, liver and systemic exposure, oral-observed side effects are predicted to be substantially reduced,” the researchers wrote.

According to the team, “although human studies are required to confirm these observations will translate to IPF, the promise for inhalation to reduce nintedanib side effects with possible treatment benefit should motivate such activities.”

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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