Two recent publications in CPT: Pharmacometrics & Systems Pharmacology—resulting from a strategic collaboration between Boehringer Ingelheim and Pharmetheus—exemplify how Model-Informed Drug Development (MIDD) can successfully extrapolate results from approved adult indications to pediatric patients suffering from rare diseases.
Nintedanib is a well-established standard of care for adults with several chronic fibrosing interstitial lung diseases (ILDs), including Idiopathic Pulmonary Fibrosis (IPF), Systemic Sclerosis-associated ILD (SSc-ILD), and other forms of Progressive Pulmonary Fibrosing ILDs (PPF). These diseases are marked by irreversible lung scarring, progressive loss of lung function, respiratory failure, and high mortality.
In contrast, Childhood Interstitial Lung Disease (chILD) encompasses over 200 rare disorders. While distinct from adult forms, some pediatric cases develop a progressive fibrosing phenotype similar to adult disease, with substantial morbidity and mortality. Designing dosing regimens for these patients poses a unique challenge: the rarity makes traditional, large-scale efficacy trials unfeasible.
Bridging the gap
To address these challenges, the authors present a robust quantitative framework that bridges the gap between abundant adult data and limited pediatric data:
- In the first analysis, a model was developed using data from 2,642 adult patients with IPF, SSc-ILD, and PPF across five clinical trials. The results showed that although disease progression rates differed by indication, the treatment effect of nintedanib Emax on Forced Vital Capacity (FVC) was comparable across all groups. The same conclusion was reached for FVC% predicted and FVC Z-score (alternative endpoints suitable for extrapolation, as they are adjusted for factors such as age, sex, and height).
- Building on the adult meta-model, the second analysis applied a Bayesian approach to partial extrapolation for the pediatric InPedILD trial. The modeling confirmed that the weight-based dosing regimen in children (6–17 years) results in exposures similar to those achieved with the efficacious adult dose of 150 mg BID.
- The exposure-response models suggested a similar beneficial treatment effect across pediatric and adult patients for the two FVC-based endpoints that were investigated across both patient groups: FVC% predicted and FVC Z-score, supporting the benefit-risk assessment for this younger population.
This work is an example of the application of pharmacometrics to regulatory decision-making, particularly in rare diseases, where extrapolation is essential for efficient drug development and a pediatric label.
Co-authored by Sonja Hartmann, Anna Chan Kwong, Julie Janssen, Jakob Ribbing, Martina Gahlemann, Susanne Stowasser and Julia Korell, this work demonstrates the power of Model-Informed Drug Development (MIDD) in bridging knowledge gaps between adult and pediatric populations, particularly for rare diseases where extrapolation is essential for efficient drug development and regulatory approval.
