Population Pharmacokinetics and Exposure-Response Model-Based Bayesian Extrapolation of FVC-Based Efficacy Endpoints...

Nintedanib reduces the rate of decline in forced vital capacity (FVC) in adult patients with idiopathic pulmonary fibrosis (IPF), chronic progressive-fibrosing interstitial lung diseases (ILDs) and systemic sclerosis-associated ILD (SSc-ILD). A pediatric Phase 3 trial (InPedILD) has been conducted in children 6-17 years, and partial extrapolation from adults to pediatrics was performed to support dose selection and benefit-risk assessment in pediatric patients with progressive-fibrosing ILDs. Previously developed population pharmacokinetic (popPK) and efficacy exposure-response (ER) meta-models across all non-oncologic pulmonary indications of nintedanib in adults were used as a basis for partial extrapolation to pediatric patients. Data from InPedILD and its open-label extension trial (InPedILD-ON) were incorporated and a Bayesian approach was utilized to extrapolate PK and FVC-based efficacy endpoints. PK of nintedanib was adequately described using a similar structure as the adult popPK model. The weight-based dosing scheme applied in InPedILD resulted in exposures similar to those in adult patients receiving the approved dose of nintedanib 150 mg twice daily. The ER models for FVC %predicted and FVC Z-score were similar to those developed in adults. Compared to adults, pediatric patients showed a slower estimated rate of decline for both endpoints. The estimated EC50 and Emax values in children and adolescents were comparable to those in adults. Partial extrapolation from adult to pediatric patients showed that the pre-defined pediatric dosing regimen resulted in similar nintedanib exposures compared to the efficacious exposures in adults. ER models suggested a similar beneficial treatment effect of nintedanib on FVC in children and adults.