Dataset Information

Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model.

ABSTRACT: 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.

SUBMITTER: Varkhede N

PROVIDER: S-EPMC6613546 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model.

Varkhede Ninad N Forrest Laird ML

Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 20180101 1s

<h4>Purpose</h4>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 a ...[more]

PMID: 30011390

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Dataset Information

Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model.

Publications

Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model.

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