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.Electronic supplementary materialThe online version of this article (doi:10.1208/s12248-015-9819-4) contains supplementary material, which is available to authorized users.
Highlights
Therapeutic proteins (TPs) have been used clinically for many years (e.g. insulin, erythropoietin (EPO), growth hormone), and with the more recent development of monoclonal antibodies, fusion proteins, antibody-drug conjugates, etc. represent a fast-growing sector of pharmaceutical development [1,2]
The differential equations used to describe the movement of TP in the physiologically based pharmacokinetic (PBPK) model are shown below (Eqs. 1 to 5)
For smaller TPs, where diffusion through endothelial pores may have a larger contribution to distribution, this model potentially offers an advantage over PBPK models considering only convective movement
Summary
Therapeutic proteins (TPs) have been used clinically for many years (e.g. insulin, erythropoietin (EPO), growth hormone), and with the more recent development of monoclonal antibodies (mAbs), fusion proteins, antibody-drug conjugates, etc. represent a fast-growing sector of pharmaceutical development [1,2]. Therapeutic proteins (TPs) have been used clinically for many years (e.g. insulin, erythropoietin (EPO), growth hormone), and with the more recent development of monoclonal antibodies (mAbs), fusion proteins, antibody-drug conjugates, etc. Subcutaneous (SC) dosing is a common administration route for TPs, which cannot usually be given orally due to their poor bioavailability [3,4]. SC dosing delivers drugs into the interstitial space of the hypodermis, located between the skin and the muscle. The thickness and structure of the hypodermis varies between species and with body location [5]. There have been several reviews of the structure of the interstitial space and the transport of Electronic supplementary material The online version of this article (doi:10.1208/s12248-015-9819-4) contains supplementary material, which is available to authorized users
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