Application of Pharmacokinetic-Pharmacodynamic Modeling in Drug Delivery: Development and Challenges.

With the advancement of technology, drug delivery systems and molecules with more complex architecture are developed. As a result, the drug absorption and disposition processes after administration of these drug delivery systems and engineered molecules become exceedingly complex. As the pharmacokinetic and pharmacodynamic (PK-PD) modeling allows for the separation of the drug-, carrier- and pharmacological system-specific parameters, it has been widely used to improve understanding of the behavior of these complex delivery systems and help their development. In this review, we summarized the basic PK-PD modeling theory in drug delivery and demonstrated how it had been applied to help the development of new delivery systems and modified large molecules. The linkage between PK and PD was highlighted. In particular, we exemplified the application of PK-PD modeling in the development of extended-release formulations, liposomal drugs, modified proteins, and antibody-drug conjugates. Furthermore, the model-based simulation using primary PD models for direct and indirect PD responses was conducted to explain the assertion of hypothetical minimal effective concentration or threshold in the exposure-response relationship of many drugs and its misconception. The limitations and challenges of the mechanism-based PK-PD model were also discussed.