Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice.

摘要

AIMS AND OBJECTIVES: (i) To describe an example of the development work required for building a 'pediatric physiologically based pharmacokinetic' (P-PBPK) model (Simcyp Pediatric ADME Simulator), (ii) to replicate pediatric clinical studies and undertake theoretical studies to show the potential applications of mechanistic PBPK in pediatric drug clinical investigation and practice, with emphasis on pediatric anesthesia. BACKGROUND: PBPK models draw together the physiological and biochemical information that determine drug absorption, distribution, metabolism, and excretion and then link them in a physiologically realistic 'systems' model. Incorporating the emerging additional information on developmental physiology and biochemistry has resulted in the creation of P-PBPK. There has been a renewed interest in the application of such modeling by the pharmaceutical industry to improve the efficiency of drug development, especially in populations where designing and conducting clinical studies is more challenging, such as pediatric patients. METHODS: P-PBPK was used to simulate a number of published clinical studies and clinical case scenarios with the aim of highlighting the potential applications. RESULTS: Changing the P-PBPK model parameters in a number of 'what if' simulations were used to explore the likely underlying reasons for observed pharmacokinetic (PK) behavior of drugs in critically ill children. In addition, the use of P-PBPK models to predict complex drug-drug interactions (DDI) highlighted disparities with adult populations. DISCUSSION: The examples highlight the use of prior knowledge of in vitro drug attributes and biology of the system (human body) to simulate PK and multiple DDI scenarios not infrequently encountered in critically ill pediatric patients.