Assessing the impact of cystic fibrosis on the antipyretic response of ibuprofen in children: Physiologically‐based modeling as a candle in the dark
Year: 2020
Type: article
Abstract: AIM: The goal of this study is to present the utility of quantitative modelling for extrapolation of drug safety and efficacy to underrepresented populations in controlled clinical trials. To illustrate this, the stepwise development of an integrated disease/pharmacokinetics/pharmacodynamics model of antipyretic efficacy of ibuprofen in children with cystic fibrosis (CF) is presented along with therapy optimization suggestions. METHOD: Published clinical trials, in vitro data, and drug physiochemical properties were used to develop an ibuprofen-mediated antipyresis model for febrile children also having CF. Workflow included first developing a mechanistic absorption model using in vitro-in vivo extrapolation followed by physiologically-based pharmacokinetic (PBPK) modelling. The verified PBPK model was then scaled to paediatric patients with CF. Once verified, the PBPK model was linked to an indirect response model of antipyresis for simulation of the overall antipyretic efficacy of ibuprofen in CF children. RESULTS: and AUC decreased by 39% (32-46%) and 44% (36-52%), respectively, in patients. Further, and in agreement with literature reports, predicted pharmacodynamics time courses suggest a slower onset and faster offset of action in patients compared to healthy children, 30 and 60 minutes, respectively. Exploratory simulations suggest an increase in dosing frequency for CF children as a better therapeutic strategy. CONCLUSION: Model-informed approaches to leveraging knowledge obtained throughout the life cycle of drug development may play a key role in extrapolating drug efficacy and safety to underrepresented populations.
DOI: 10.1111/bcp.14326
Institution: University of Florida
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3019246176