Current Practices, Gap Analysis and Proposed Roadmaps for PBPK Modeling of Cytochrome P450 Induction: An Industry Perspective

The International Consortium for Innovation and Quality (IQ) Physiologically Based Pharmacokinetic modeling (PBPK) Induction Working Group (IWG) conducted a survey across participating companies around general strategies for PBPK modeling of induction, including experience with; its utility to address various questions, regulatory interactions, and regulatory acceptance. The results highlight areas where PBPK modeling is used with high confidence and identify opportunities where confidence is lower and further evaluation is needed. To enhance the survey results, the PBPK-IWG also collected case studies and analyzed recent literature examples where PBPK models were applied to address CYP3A induction-mediated drug-drug interactions. PBPK modeling of induction has evolved and progressed significantly and has great potential to accelerate drug discovery and development. With the aim of enabling optimal use for new molecular entities that are either substrates and/or inducers of CYP3A, the PBPK-IWG proposes initial roadmaps for PBPK application, discusses future trends, and identifies gaps that need to be addressed

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling—A Contribution from the ConcePTION Project

Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for “non-lactating” adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage

Pediatric Pharmacokinetics and Dose Predictions: A Report of a Satellite Meeting to the 10th Juvenile Toxicity Symposium

On April 24, 2019, a symposium on Pediatric Pharmacokinetics and Dose Predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. This symposium brought together scientists from academia, industry, and clinical research organizations with the aim to update each other on the current knowledge on pediatric drug development. Through more knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically-based pharmacokinetic (PBPK) models, we have gained a more integrated understanding of age-related differences in pharmacokinetics (PKs), Relevant examples were presented during the meeting. PBPK may be considered the gold standard for pediatric PK prediction, but still it is important to know that simpler methods, such as allometry, allometry combined with maturation function, functions based on the elimination pathway, or linear models, also perform well, depending on the age range or the mechanisms involved. Knowledge from different methods and information sources should be combined (e.g., microdosing can reveal early read-out of age-related differences in exposure), and such results can be a value to verify models. To further establish best practices for dose setting in pediatrics, more in vitro and in vivo research is needed on aspects such as age-related changes in the exposure-response relationship and the impact of disease on PK. New information coupled with the refining of model-based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials.Pharmacolog

Pediatric pharmacokinetics and dose predictions: a report of a satellite meeting to the 10th Juvenile Toxicity Symposium

On the 24th of April 2019 a symposium on Pediatric pharmacokinetics and dose predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. The aim of this meeting was to bring together scientists from academia, industry and clinical research organizations to update each other on the current knowledge on pediatric drug development. The increased knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically based pharmacokinetic (PBPK) models has allowed a more integrated understanding of age-related differences in PK, for which examples were given during the meeting. PBPK may be considered the gold-standard for pediatric PK prediction, but still it is important to know that simpler methods like allometry, allometry combined with maturation function, functions based on the elimination pathway or linear models also perform well depending on the age range or the mechanisms involved. It is important to combine knowledge from different methods and information sources; e.g. techniques like microdosing can gain early read-out of age-related differences in exposure and in addition such results can be value to verify models. To further establish best practices for dose setting in pediatrics more in vitro and in vivo research is needed on such aspects as age related changes in the exposure response relationship and also the impact of disease on PK. New information coupled with the refining of model based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials