Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development

Abstract

Pediatric drug development faces many difficulties. Traditionally, pediatric drug doses are simply calculated linearly based on the body weight, age, and body surface area of adults. Due to the ontogeny of children, this simple linear scaling may lead to drug overdose in pediatric patients. The physiologically based pharmacokinetic (PBPK) model, as a mathematical model, contributes to the research and development of pediatric drugs. An example of a PBPK model guiding drug dose selection in pediatrics has emerged and has been approved by the relevant regulatory agencies. In this review, we discuss the principle of the PBPK model, emphasize the necessity of establishing a pediatric PBPK model, introduce the absorption, distribution, metabolism, and excretion of the pediatric PBPK model, and understand the various applications and related prospects of the pediatric PBPK model.

Current situation of pediatric clinical trials in China: focus on trials for drug marketing application and administrative approval

“…Research and development of pediatric drug faces many difficulties, such as ethical issues, difficult to carry out informed consent effectively. Besides, as neonates, infants, children, and adolescents are in different physiological development stage, a drug may need to be studied separately in those groups, then, the complexity and high cost both lead to a lack of pediatric drug research [ 1 ]. Previously studies showed the approval process for a new drug in the United States took an average of 12 years but approval using in pediatrics need a lag time of another 8 ~ 10 years [ 2 ], and the lag time was about 1017 days in Japan and the European Union [ 3 ].…”

Physiologically Based Pharmacokinetic (PBPK) Model-Informed Dosing Guidelines for Pediatric Clinical Care: A Pragmatic Approach for a Special Population

“…PBPK modeling is increasingly applied in pre-market safety and efficacy studies to guide first-in-pediatric dose selection, its use being driven by the introduction of the Pediatric Study Plan (PSP) in the USA and the Paediatric Investigation Plan (PIP) in the European Union in the 2000s [ 18 , 19 ]. Both the US Food and Drug Administration (FDA) and the EMA support the use of PBPK models in regulatory submissions in conjunction with clinical studies [ 20 , 21 ].…”

“…PSP) in the USA and the Paediatric Investigation Plan (PIP) in the European Union in the 2000s[18,19]. Both the US Food and Drug Administration (FDA) and the EMA support the use of PBPK models in regulatory submissions in conjunction with clinical studies…”

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups - an Investigation using Physiologically based Pharmacokinetic Modelling

“…These changes include development of organ systems functions, maturation of cardiac output, organ perfusion and permeability, or glomerular filtration rate. Similarly, the ontogeny of cytochrome p450 (CYP) and non-CYP enzymes may result in differences in metabolic clearance [1,2]. Maturational and pathophysiological changes in children often co-exist, and this complicates drug treatment strategies.…”

“…Maturational and pathophysiological changes in children often co-exist, and this complicates drug treatment strategies. Though dosing design strategies commonly consider maturational changes occurring with age, there is usually less consideration on the impact of pathophysiology in patients, and their effects on drug disposition [1,2]. Cardiac output (CO) is one of these pathophysiological changes.…”