Date Published: September 25, 2015
Publisher: Springer US
Author(s): Katherine L. Gill, Iain Gardner, Linzhong Li, Masoud Jamei.
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 tmax 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. tmax 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 Cmax values, although a general trend for underprediction of tmax was observed. No clear trend between prediction accuracy of tmax 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.
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). Subcutaneous (SC) dosing is a common administration route for TPs, which cannot usually be given orally due to their poor bioavailability (3,4).
In the current study, a whole-body PBPK model has been developed to describe the tissue distribution and SC absorption rate of TPs. Movement of TPs within the model is based on the 2-pore hypothesis (10), with hydrodynamic radius being the only drug-specific parameter used to predict the rate of absorption and the extent of tissue distribution. Use of the 2-pore model will have minimal impact for the prediction of mAb distribution compared to previously published models where distribution is described by convection alone. 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. In addition to the usual physiological data required for PBPK models (organ weights, blood flows etc.), lymph flow and pore sizes in each tissue were needed to describe the disposition of TPs. Obtaining accurate estimates of lymph flow from different organs in humans is challenging as the clinical measurement of lymph flow is an invasive procedure and as such is not usually conducted in healthy individuals. Obtaining reliable estimates of lymphatic flow is also difficult because lymph cannulation may lead to changes in flow, making it difficult to get an estimate of the unperturbed lymph flow (62). In the model developed here, we used physiological estimates of lymph flow for the different tissues. Unsurprisingly, when used in the context of the PBPK model, these lymph flow values in addition to the optimised pore sizes were suitable to accurately capture the steady-state tissue lymph/plasma concentration ratios of TPs with a large size range (Fig. 2). Sensitivity analysis showed that the steady-state lymph/plasma concentration ratios were not sensitive to individual tissue lymph flows, whereas interstitial fluid tmax was (Supplemental Material Figures 2–3). Although most of the observed lymph/plasma concentration ratio data are taken from animals for those proteins where human data are also available, large interspecies differences are not evident, indicating that the animal data may be suitable to use for model development and validation where human data are lacking.
A mechanistic whole-body PBPK model has been developed to predict absorption rate of TPs following SC dosing via both direct diffusion through capillaries into blood and through lymphatic absorption. The model provided reasonable prediction of SC absorption using a bottom-up approach based on TP molecular size as the model input. One third to half the Cmax and tmax predictions fell within 0.8–1.25-fold of the observed values. Although a general trend for underprediction of tmax was observed, no correlation with molecular size or pI was apparent. Further enhancement in the future to include mechanistic prediction of distribution at the injection site and through the interstitial space as well as pre-systemic elimination will allow a true bottom-up approach for prediction of TP SC absorption.