ABSTRACT
Gastric pH is an important factor that affects drug absorption, as gastric pH may lead to lower bioavailability, especially for weak-base drugs. Acid-reducing agents (ARAs) such as antacids, histamine-2 receptor antagonists, and proton pump inhibitors, are susceptible to drug-drug interactions (DDIs), potentially resulting in the loss of efficacy. Physiologically based pharmacokinetic (PBPK) modeling is an important tool for the evaluation of oral drug-drug interactions and the most commonly used models include the advanced comparative absorption and transport (ACAT) model and the advanced dissolution, absorption and metabolism (ADAM) model. These models can be used for adjustment of the dosage regimen and the screening of candidate drugs in drug development by simulating the change of gastric pH to predict the change in drug absorption. This review summarizes the theoretical basis, the most common PBPK models used to predict drug absorption, and the effects of different kinds of ARAs drugs on gastric pH. Some successful applications of PBPK modeling in predicting the effects of gastric pH on drug absorption are also presented.
ABSTRACT
Oral transmucosal drug delivery can be defined as the administration of drug through the oral mucosa to achieve systemic effects. It has the advantages of high bioavailability and rapid drug response. In this review, we introduce the physiology of oral mucosa, and analyze the factors affecting the pharmacokinetic properties of oral transmucosal drug delivery in detail, such as physiological barriers, different administration sites, physicochemical properties of drugs, dosage forms, and formulation strategies. In addition, we describe the methods to evaluate the pharmacokinetic properties of this delivery systems, including in vitro permeability studies, buccal absorption studies, in vivo pharmacokinetic studies and physiologically based pharmacokinetics (PBPK) modeling, which provide methods and reference for the development of oral transmucosal drug delivery systems.
ABSTRACT
Physiologically based pharmacokinetic (PBPK) modeling is an important tool to predict pharmacokinetic or pharmacodynamic profiles in special populations, especially in children and infants where designing and conducting clinical studies is difficult. The application of PBPK modeling can effectively promote the development of pediatric drugs and their clinical use. At present, PBPK modeling of pediatric populations is mainly applied in clinical trial design, drug-drug interaction (DDI) risk assessment, and dose selection in children. This review discusses the advantages of PBPK modeling in pediatric drug research and summarizes how to extrapolate a PBPK model from adults to children. The theoretical basis for pediatric PBPK models, the modelling process and important physiological parameters during the modeling process are introduced. Some successful applications of PBPK modeling in pediatric drug research and development are also presented. This review also analyzes the current limitations and future directions of pediatric PBPK modeling.