Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice.

Here we have investigated whole-body pharmacokinetics (PK) of exogenously administered T cells in a mouse model of melanoma and have developed a physiologically based pharmacokinetic (PBPK) model to quantitatively characterize the data. T cells were isolated from the spleen of tumor-bearing mice, activated, and labeled with chromium-51 to facilitate the quantification. Labeled T cells were injected in the tumor-bearing mice, and PK was measured in 19 different tissues. It was found that T cells disappear from the blood rapidly after administration and accumulate in the tissues to various extents. Spleen, liver, lung, kidney, bone, and lymph nodes accounted for more than 90% of T cells in the body. The distribution of T cells in solid tumors was found to be very low, hovering below 1%ID/g (percent of injected dose per gram of tissue) during the entire study. However, this observation may differ for targeted TCR-T and CAR-T cells. Observed PK profiles also suggest that T-cell-based therapies may be more successful in treating cancers of the lymphatic system and bone marrow metastases compared to solid tumors. A PBPK model was developed to characterize the whole-body PK of T cells, which incorporated key processes such as extravasation, elimination, and recirculation of T cells via lymph flow. Retention factors were incorporated into the spleen, liver, and kidney compartment to adequately capture the PK profiles. The model was able to characterize observed PK profiles reasonably well, and parameters were estimated with good confidence. The PK data and PBPK model presented here provide unprecedented insight into the biodistribution of exogenously administered T cells.

Target-Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy.

Bispecific antibodies (BsAbs) bind to two different targets, and create two binary and one ternary complex (TC). These molecules have shown promise as immuno-oncology drugs, and the TC is considered the pharmacologically active species that drives their pharmacodynamic effect. Here, we have presented a general target-mediated drug disposition (TMDD) model for these BsAbs, which bind to two different targets on different cell membranes. The model includes four different binding events for BsAbs, turnover of the targets, and internalization of the complexes. In addition, a quasi-equilibrium (QE) approximation with decreased number of binding parameters and, if necessary, reduced internalization parameters is presented. The model is further used to investigate the kinetics of BsAb and TC concentrations. Our analysis shows that larger doses of BsAbs may delay the build-up of the TC. Consequently, a method to compute the optimal dosing strategy of BsAbs, which will immediately create and maintain maximal possible TC concentration, is presented.

Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1.

Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i.e., T-DM1) in rats was characterized using platform PBPK model for antibody. Both the PBPK models were combined via degradation and deconjugation processes. The degradation of conjugated antibody was assumed to be similar to a normal antibody, and the deconjugation of DM1 from T-DM1 in rats was estimated using plasma PK data. The rat PBPK model was translated to humans to predict clinical PK of T-DM1. The translation involved the use of human antibody PBPK model to characterize the PK of conjugated trastuzumab, use of allometric scaling to predict human clearance of DM1 catabolites, and use of monkey PK data to predict deconjugation of DM1 in the clinic. PBPK model-predicted clinical PK profiles were compared with clinically observed data. The PK of total trastuzumab and T-DM1 were predicted reasonably well, and slight systemic deviations were observed for the PK of DM1-containing catabolites. The ADC PBPK model presented here can serve as a platform to develop models for other ADCs.

Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1).

A mathematical model capable of accurately characterizing intracellular disposition of ADCs is essential for a priori predicting unconjugated drug concentrations inside the tumor. Towards this goal, the objectives of this manuscript were to: (1) evolve previously published cellular disposition model of ADC with more intracellular details to characterize the disposition of T-DM1 in different HER2 expressing cell lines, (2) integrate the improved cellular model with the ADC tumor disposition model to a priori predict DM1 concentrations in a preclinical tumor model, and (3) identify prominent pathways and sensitive parameters associated with intracellular activation of ADCs. The cellular disposition model was augmented by incorporating intracellular ADC degradation and passive diffusion of unconjugated drug across tumor cells. Different biomeasures and chemomeasures for T-DM1, quantified in the companion manuscript, were incorporated into the modified model of ADC to characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When the cellular model was integrated with the tumor disposition model, the model was able to a priori predict tumor DM1 concentrations in xenograft mice. Pathway analysis suggested different contribution of antigen-mediated and passive diffusion pathways for intracellular unconjugated drug exposure between in vitro and in vivo systems. Global and local sensitivity analyses revealed that non-specific deconjugation and passive diffusion of the drug across tumor cell membrane are key parameters for drug exposure inside a cell. Finally, a systems pharmacokinetic model for intracellular processing of ADCs has been proposed to highlight our current understanding about the determinants of ADC activation inside a cell.

Integration of bioanalytical measurements using PK-PD modeling and simulation: implications for antibody-drug conjugate development.

Recent technological advances have enabled precise quantitation of various bioanalytical measurements pertaining to antibody-drug conjugates (ADCs). However, availability of bioanalytical data alone cannot guarantee the provision of correct go/no-go decisions at different stages of ADC development. Integration and comprehension of all the available data at each stage of ADC development is necessary to make a well informed and objective decision about moving the ADC forward to the clinic. In this manuscript, we have reviewed the application of PK-PD modeling and simulation for quantitative integration of diverse bioanalytical data available from different stages of ADC development. We have also elaborated on how similar bioanalytical data can be characterized using different models to gain distinct insights into ADC development.