A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins

Abstract

Abstract. The ability to predict subcutaneous (SC) absorption rate and tissue distribution of therapeutic proteins (TPs) using a bottom-up approach is highly desirable early in the drug development process prior to clinical data being available. A whole-body physiologically based pharmacokinetic (PBPK) model, requiring only a few drug parameters, to predict plasma and interstitial fluid concentrations of TPs in humans after intravenous and subcutaneous dosing has been developed. Movement of TPs between vascular and interstitial spaces was described by considering both convection and diffusion processes using a 2-pore framework. The model was optimised using a variety of literature sources, such as tissue lymph/plasma concentration ratios in humans and animals, information on the percentage of dose absorbed following SC dosing via lymph in animals and data showing loss of radiolabelled IgG from the SC dosing site in humans. The resultant model was used to predict t max and plasma concentration profiles for 12 TPs (molecular weight 8-150 kDa) following SC dosing. The predicted plasma concentration profiles were generally comparable to observed data. t max was predicted within 3-fold of reported values, with one third of the predictions within 0.8-1.25-fold. There was no systematic bias in simulated C max values, although a general trend for underprediction of t max was observed. No clear trend between prediction accuracy of t max and TP isoelectric point or molecular size was apparent. The mechanistic whole-body PBPK model described here can be applied to predict absorption rate of TPs into blood and movement into target tissues following SC dosing.

Pharmacokinetics of Monoclonal Antibodies

“…4,55 The outlined concepts have successfully been implemented in recent PBPK modeling attempts for mAb disposition after s.c. administration. 56…”

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

“…69 However, similar quantitative information about the metabolic processes of TPs in the SC or ID injection sites and lymphatic system is not available. 2,[70][71][72][73] Therefore, it is difficult to use the in vitro TP metabolic data from currently available models in the prediction of PK after SC or ID administration. In this section, in vitro techniques used to study proteolysis and bioavailability of TPs are summarized.…”

“…Therefore, bioavailability cannot be mechanistically estimated using the available in vitro systems. 73 These quantitative data can be used to define the rate of metabolism from the ID or SC injection sites and the lymphatic system. To develop in vitro system for quantitative understanding of bioavailability, it is necessary to understand various types of cells such as macrophages, lymphocytes, and SC tissue cells to which the TPs are exposed.…”

Repository Describing an Aging Population to Inform Physiologically Based Pharmacokinetic Models Considering Anatomical, Physiological, and Biological Age-Dependent Changes

“…Data regarding the composition of lipids and proteins of tissues are generally sparse in humans and no age-dependency was found in the literature, but total body water, total extracellular water and total body cell mass have been reported in aging subjects [26,37,65,[182][183][184][185][186][187][188][189][190]. Age-independent fraction of tissue volumes [191] coupled with age-dynamic tissue volumes have been used to calculate the vascular and interstitial space of tissues (representing the extracellular water) and the intracellular space minus the intracellular water (representing the cell mass). Organ densities to convert organ weight obtained from the derived functions to volumes have been used from the ICRP database [192,193].…”