Mechanistic Modeling of Antibody Drug Conjugate Pharmacokinetics

Linzhong Li

Antibody Drug Conjugates (ADCs) are constructed by attaching a small molecule drug to an antibody via a linker. The antibody selectively targets tumor cells and releases the cytotoxic drug within the cells to kill cancerous cells while sparing healthy tissue. Although some ADCs have been approved, many unanswered questions¬†remain, such as drug-drug interactions (DDIs) and […]

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

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

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 […]

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Prediction of the Pharmacokinetics, Pharmacodynamics, and Efficacy of a Monoclonal Antibody, Using a Physiologically Based Pharmacokinetic FcRn Model

Although advantages of¬†physiologically¬†based¬†pharmacokinetic¬†models (PBPK) are now well established, PBPK models that are linked to pharmacodynamic (PD) models to predict¬†pharmacokinetics¬†(PK), PD, and¬†efficacy¬†of¬†monoclonal¬†antibodies (mAbs) in humans are uncommon. The aim of this study was to develop a PD¬†model¬†that could be linked to a¬†physiologically¬†based¬†mechanistic¬†FcRn¬†model¬†to predict PK, PD, and efficacy¬†of efalizumab. The mechanistic¬†FcRn¬†model¬†for mAbs with target-mediated drug disposition within […]

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Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model

Compared to small chemical molecules,¬†antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behavior characterized by relatively poor cellular permeability,¬†minimal¬†renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A¬†minimal¬†physiologically¬†based¬†pharmacokinetic (PBPK)¬†model¬†to describe the¬†pharmacokinetics¬†of mAbs in¬†humans¬†was developed. Within the¬†model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The […]

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