Abstract
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 in vivo 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.
Highlights
The research field of drug delivery focuses on the development of new techniques to manipulate drug absorption and disposition to achieve a desirable effect (Anselmo and Mitragotri, 2014; Asiri and Mohammad, 2018)
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
As for the modification of large molecules related to drug delivery, such as PEGylated protein, Fc-modified monoclonal antibody (mAb) and antibody-drug conjugate (ADC), modeling technique has been widely used in both preclinical studies and clinical trials, providing valuable information for the animal-tohuman translation and dose regimen selection in clinical trials (Mager et al, 2005; Zheng et al, 2011; Krzyzanski et al, 2013; AitOudhia et al, 2017; McSweeney et al, 2018)
Summary
The research field of drug delivery focuses on the development of new techniques to manipulate drug absorption and disposition to achieve a desirable effect (Anselmo and Mitragotri, 2014; Asiri and Mohammad, 2018). As for the modification of large molecules related to drug delivery, such as PEGylated protein, Fc-modified mAbs and antibody-drug conjugate (ADC), modeling technique has been widely used in both preclinical studies and clinical trials, providing valuable information for the animal-tohuman translation and dose regimen selection in clinical trials (Mager et al, 2005; Zheng et al, 2011; Krzyzanski et al, 2013; AitOudhia et al, 2017; McSweeney et al, 2018). In the development of the drug delivery system, PK-PD modeling could guide the formulation design and dosing regimen selection based on the preclinical and clinical data. This technique connects the drug dose to the physiological response, related to the properties of the drug delivery system and physiological system. The limitations and challenges of the mechanism-based PK-PD model are discussed
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