Physiologically-based pharmacokinetic (PBPK) modeling has proven invaluable in drug development, especially for pediatric populations, because of its ability to reduce and potentially eliminate the need to conduct clinical trials in this special population. However, much of the early research into pediatric PBPK models has concentrated on the North European and American populations. Growing interest in using PBPK for international clinical trials and tropical disease medicines requires developing specific ethnic pediatric PBPK models. This blog explores recent developments in the field, focusing on the Japanese pediatric population model.
The Demand for Ethnically Diverse Pediatric PBPK Models:
Existing pediatric PBPK models have been instrumental in supporting regulatory submissions and dose and formulation extrapolations from adult populations as well as drug-drug interaction (DDI) risk prediction. Still, there is a growing awareness that inter-ethnic physiological differences should be considered in these models.
A recent publication1 has highlighted drug development cases involving neonates, infants, and children where ethnicity and disease were not fully accounted for using this approach, with many cases only reporting using a pediatric population based on a North European population, and with few examples where any other specific ethnicity is included. The draft ICH (International Council for Harmonisation) E11 guideline on pediatric extrapolation mentions PBPK modeling and states that “the specific characteristics of the target population should be incorporated into the model” (read more about the ICH E11 guideline in this blog.) Therefore, developing PBPK models that account for inter-ethnic physiological differences for bridging pediatric ethnic groups is needed.
The Development of the Japanese Pediatric PBPK Model:
In response to the need for ethnically diverse models, the Simcyp pediatric team developed the Japanese pediatric population PBPK model for version 19 of the Simcyp Simulator. Collaborating with Dr. Chie Emoto from Showa Pharmaceutical University in Tokyo, they utilized data from literature and Japanese public databases to optimize underlying demographics and equations to develop and verify this model.
The model’s outputs successfully represented the Japanese pediatric population. Model verification was performed using 14 different drugs including 5 eliminated by CYP3A4 and 4 renally; all cases performed well in the virtual adult Japanese population prior to using in pediatrics.
Validation and Performance:
The performance of the Japanese pediatric PBPK model was encouraging. For PK parameters, 44 out of 62 predictions (AUC (Areas Under the Curve), Cmax, clearance) were reasonably close to observed values. Importantly, qualification of specific pathways enhances the likelihood of regulatory acceptance of these models. Multiple verification examples and ultimately qualification of specific pathways is important to enable the models to be accepted by regulators in relation to similar drugs. Results for the five CYP3A4 substrates showed all cases were reasonably predicted. When comparing the Japanese and North European pediatric populations against Japanese clinical data, incorporating representative population data was important to prediction accuracy.
Future Outlook:
To further establish the credibility of these models, ongoing efforts include expanding the study to include other drugs and routes of elimination. This endeavor necessitates collaboration with experts from academia, industry, PBPK model providers, and regulatory bodies. Given the increasing regulatory reliance on pediatric PBPK models in drug development, expanding their scope to include other ethnic groups is crucial. Notably, the team has already developed a Chinese pediatric population model and plans to introduce additional models, including a racially mixed pediatric US population soon.
Conclusion:
Developing pediatric PBPK models for differing ethnic populations is essential to optimize drug development for diverse patient groups. The progress achieved with the Japanese pediatric model exemplifies the potential of these models in addressing inter-ethnic variations. By fostering collaboration and inclusivity, the pharmaceutical industry can embrace the power of PBPK models to improve drug efficacy and safety for pediatric populations worldwide.
Take a deeper dive into the development of the PBPK model for the Japanese pediatric population by reading our latest article with the full case study. Click here to access the article.
Explore the in-depth research and innovative solutions driving pediatric drug development with Simcyp’s cutting-edge PBPK modeling in our accompanying white paper titled “Advancing Pediatric Drug Development and Regulatory Acceptance Using Simcyp PBPK: from Birth to Young Adult.”
- Small BG, Johnson TN, Rowland Yeo K. Another Step Toward Qualification of Pediatric Physiologically Based Pharmacokinetic Models to Facilitate Inclusivity and Diversity in Pediatric Clinical Studies. Clin Pharmacol Ther. 2023;113(3): 735-745.