Understanding the metabolic processes and degradation of therapeutic proteins after subcutaneous administration

Subcutaneous (SC) route is important for administration of various therapeutic proteins (TPs) like monoclonal antibodies (mAbs), human growth hormone (hGH), insulin, and recombinant subunit vaccines. The SC route has advantages like shorter clinical visits for patients, the possibility of self-administration, and its less invasive nature compared to the intravenous (IV) route. However, SC route has a challenge of incomplete bioavailability for various TPs, especially mAbs (52-80%). After SC administration, the mAbs travel through the lymphatic vessels and lymph nodes (LNs) before reaching the systemic circulation. Proteolysis at the SC injection site and within the lymphatic system may be partially responsible for the reduced bioavailability of mAbs. Chapter 2 of this dissertation describes a top-down mAb physiologically based pharmacokinetic (PBPK) model which was used to estimate the lymphatic trunk-LN clearance using the human SC pharmacokinetic (PK) data from published clinical trials. Iron oxide nanoparticles (IONPs) may originate from equipment used in the manufacturing of TPs or from needles during the SC injection. The IONPs may alter the secondary structure and the degree of oxidation of TPs. Therefore, Chapter 3 of this dissertation looks at the effect of IONPs on the TP stability. In Chapter 4, midazolam (MDZ) metabolism and PK were reported in the healthy and inflammatory disease condition in mice. Finally, a bottom-up minimal PBPK model was used to predict MDZ PK in the disease state

Understanding the monoclonal antibody disposition after subcutaneous administration using a minimal physiologically based pharmacokinetic model

This record contains an article, several datasets, an OpenGL Shader Builder Project (sbproj) file, and supplementary data.PURPOSE: Monoclonal antibodies (mAbs) are commonly administered by subcutaneous (SC) route. However, bioavailability is often reduced after SC administration. In addition, the sequential transfer of mAbs through the SC tissue and lymphatic system is not completely understood. Therefore, major objectives of this study were a) To understand absorption of mAbs via the lymphatic system after SC administration using physiologically based pharmacokinetic (PBPK) modeling, and b) to demonstrate application of the model for prediction of SC pharmacokinetics (PK) of mAbs. METHODS: A minimal PBPK model was constructed using various physiological parameters related to the SC injection site and lymphatic system. The remainder of the body organs were represented using a 2-compartment model (central and peripheral compartments), with parameters derived from available intravenous (IV) PK data. The IV and SC clinical PK data of a total of 10 mAbs were obtained from literature. The SC PK data were used to estimate the lymphatic trunk-lymph node (LN) clearance. RESULTS: The mean estimated lymphatic trunk-LN clearance obtained from 37 SC PK profiles of mAbs was 0.00213 L/h (0.001332 to 0.002928, 95% confidence intervals). The estimated lymphatic trunk-LN clearance was greater for the mAbs with higher isoelectric point (pI). In addition, the estimated clearance increased with decrease in the bioavailability. CONCLUSION: The minimal PBPK model identified SC injection site lymph flow, afferent and efferent lymph flows, and volumes associated with the SC injection site, lymphatic capillaries and lymphatic trunk-LN as important physiological parameters governing the absorption of mAbs after SC administration. The model may be used to predict PK of mAbs using the relationship of lymphatic trunk-LN clearance and the pI. In addition, the model can be used as a bottom platform to incorporate SC and lymphatic in vitro clearance data for mAb PK prediction in the future

A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

This is the author's accepted manuscript.Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs