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Exposure-Efficacy Meta-Model of Nintedanib in Adult Patients With Chronic Fibrosing Interstitial Lung Diseases
Sonja Hartmann1, Julie Janssen2, Jakob Ribbing2
1Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
Abstract:
The tyrosine kinase inhibitor, nintedanib, reduces the rate of decline in forced vital capacity (FVC) in a comparable manner in patients with idiopathic pulmonary fibrosis (IPF), other forms of progressive pulmonary fibrosis (PPF), and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib in all indications is 150 mg twice daily (BID). Data from Phase II and III trials in IPF, PPF, and SSc-ILD were incorporated into a meta-model to holistically investigate the relationship between nintedanib exposure and efficacy. Using data from 2642 patients with IPF, PPF, or SSc-ILD treated with nintedanib doses ranging from 50 to 150 mg BID, disease progression models with a maximum drug effect on the annual rate of change in absolute FVC (i.e., mL), FVC %predicted, and FVC Z-score were developed. The estimated plasma concentration producing 50% of the maximum drug effect (EC50) ranged from 6.21 to 10.4 nM (with respect to nintedanib trough concentration) across the explored FVC-based endpoints. While the disease progression for absolute FVC (mL), FVC %predicted, and FVC Z-score was different between IPF and PPF patients compared to SSc-ILD patients, the relative treatment effect of nintedanib, described by a disease-modifying Emax effect, was comparable across indications. The majority of patients achieve exposure levels at or exceeding the EC50 with the approved starting dose of 150 mg BID.
Insights
Nintedanib effectively slows lung function decline in idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF), and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Most patients reach therapeutic drug levels with the standard 150 mg twice-daily dose.
Area of Science:
- Pharmacology
- Pulmonology
- Clinical Trials
Background:
- Idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF), and systemic sclerosis-associated interstitial lung disease (SSc-ILD) are progressive fibrotic lung diseases.
- Nintedanib is a tyrosine kinase inhibitor used to treat these conditions.
Purpose of the Study:
- To investigate the relationship between nintedanib exposure and its efficacy across IPF, PPF, and SSc-ILD.
- To determine the dose-exposure-response relationship for nintedanib in these fibrotic lung diseases.
Main Methods:
- A meta-model incorporating data from Phase II and III trials of 2642 patients treated with nintedanib (50-150 mg BID).
- Development of disease progression models analyzing the effect of nintedanib on annual changes in forced vital capacity (FVC) metrics.
- Estimation of the EC50 (plasma concentration for 50% maximal effect) for nintedanib trough concentration.
Main Results:
- The EC50 values ranged from 6.21 to 10.4 nM across FVC-based endpoints.
- Disease progression differed between IPF/PPF and SSc-ILD, but nintedanib's relative treatment effect (Emax) was comparable across all indications.
- The approved dose of 150 mg BID generally achieves nintedanib exposure levels at or above the EC50 for most patients.
Conclusions:
- Nintedanib demonstrates a comparable relative efficacy across IPF, PPF, and SSc-ILD.
- The standard 150 mg BID dose is likely to provide therapeutic exposure for the majority of patients in these indications.
