Translational two-pore PBPK model to characterize whole-body disposition of different-size endogenous and exogenous proteins.

Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans.

Investigation of Antibody Pharmacokinetics in the Brain Following Intra-CNS Administration and Development of PBPK Model to Characterize the Data.

Despite the promising potential of direct central nervous system (CNS) antibody administration to enhance brain exposure, there remains a significant gap in understanding the disposition of antibodies following different intra-CNS injection routes. To bridge this knowledge gap, this study quantitatively investigated the brain pharmacokinetics (PK) of antibodies following intra-CNS administration. The microdialysis samples from the striatum (ST), cerebrospinal fluid (CSF) samples through cisterna magna (CM) puncture, plasma, and brain homogenate samples were collected to characterize the pharmacokinetics (PK) profiles of a non-targeting antibody, trastuzumab, following intracerebroventricular (ICV), intracisternal (ICM), and intrastriatal (IST) administration.

Construction of nursing-sensitive quality indicator system for cardiac rehabilitation of patients undergoing percutaneous coronary intervention based on structure-process-outcome model.

Background: Coronary heart disease (CHD) is a cardiovascular disease with high mortality. At present, percutaneous coronary intervention (PCI) is considered as the main effective treatment for CHD due to less trauma, shorter course of treatment, and better curative effect. However, PCI alone is not a permanent cure, so cardiac rehabilitation (CR) is needed for a supplement.

Expansion of platform physiologically-based pharmacokinetic model for monoclonal antibodies towards different preclinical species: cats, sheep, and dogs.

Monoclonal antibodies (mAbs) are becoming an important therapeutic option in veterinary medicine, and understanding the pharmacokinetic (PK) of mAbs in higher-order animal species is also important for human drug development. To better understand the PK of mAbs in these animals, here we have expanded a platform physiological-based pharmacokinetic (PBPK) model to characterize the disposition of mAbs in three different preclinical species: cats, sheep, and dogs. We obtained PK data for mAbs and physiological parameters for the three different species from the literature.

Pharmacokinetics of AAV9 Mediated Trastuzumab Expression in Rat Brain Following Systemic and Local Administration.

Introduction: Recombinant adeno-associated viruses(rAAVs) are an attractive tool to ensure long-term expression monoclonal antibody(mAb) in the central nervous system(CNS). It is still unclear whether systemic injection or local CNS administration of AAV9 is more beneficial for the exposure of the expressed mAb in the brain. Hence, we compared the biodistribution and transgene expression following AAV9-Trastuzumab administration through different routes.

PBPK model for antibody disposition in mouse brain: validation using large-pore microdialysis data.

The objective of this manuscript was to validate a physiologically-based pharmacokinetic (PBPK) model developed to characterize brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) using novel large-pore microdialysis data generated in mice. To support this objective, brain, CSF, and ISF PK of a human anti-tetanus toxin (TeTx) antibody was measured in mice following intraperitoneal (IP) administration. This antibody has no binding in mice.

Assessment of AAV9 distribution and transduction in rats after administration through Intrastriatal, Intracisterna magna and Lumbar Intrathecal routes.

Challenges in obtaining efficient transduction of brain and spinal cord following systemic AAV delivery have led to alternative administration routes being used in clinical trials that directly infuse the virus into the CNS. However, data comparing different direct AAV injections into the brain remain limited making it difficult to choose optimal routes. Here we tested both AAV9-egfp and AAV9-fLuc delivery via intrastriatal (IST), intracisterna magna (ICM) and lumbar intrathecal (LIT) routes in adult rats and assessed vector distribution and transduction in brain, spinal cord and peripheral tissues.

Effect of the Size of Protein Therapeutics on Brain Pharmacokinetics Following Systematic Administration.

Here, we have investigated the effect of size of protein therapeutics on brain pharmacokinetics (PK) following systemic administration in rats. All tested proteins were derived from trastuzumab that do not bind to any targets in rats. PK data generated with F(ab)(100 kDa), Fab (50 kDa), and scFv (27 kDa) fragments of trastuzumab, along with published PK data for FcRn non-binding and wild-type trastuzumab (150 kDa), were used to establish a relationship between the protein size and brain exposure.

Algorithmic multiscale analysis for the FcRn mediated regulation of antibody PK in human.

A demonstration is provided on how algorithmic asymptotic analysis of multi-scale pharmacokinetics (PK) systems can provide (1) system level understanding and (2) predictions on the response of the model when parameters vary. Being algorithmic, this type of analysis is not hindered by the size or complexity of the model and requires no input from the investigator. The algorithm identifies the constraints that are generated by the fast part of the model and the components of the slow part of the model that drive the system within these constraints.

Towards a translational physiologically-based pharmacokinetic (PBPK) model for receptor-mediated transcytosis of anti-transferrin receptor monoclonal antibodies in the central nervous system.

In this manuscript, we present a translational physiologically-based pharmacokinetic (PBPK) model to characterize receptor-mediated transcytosis (RMT) of anti-transferrin receptor (TfR) monoclonal antibodies (mAbs) in the central nervous system (CNS). The model accounts for the state-of-the-art knowledge of the brain's anatomy and physiology, and physiological parameters were fixed according to different species. By estimating a few parameters associated with the TfR concentration, the TfR turnover, and the internalization rate, the model simultaneously characterizes plasma, whole brain, interstitial fluid (ISF), and cerebrospinal fluid (CSF) PK of unbound and bound anti-TfR mAbs with different binding affinities in mice, rats, and monkeys obtained from various literature sources within a threefold prediction error.

Brain pharmacokinetics of anti-transferrin receptor antibody affinity variants in rats determined using microdialysis.

Receptor-mediated transcytosis (RMT) is used to enhance the delivery of monoclonal antibodies (mAb) into the central nervous system (CNS). While the binding to endogenous receptors on the brain capillary endothelial cells (BCECs) may facilitate the uptake of mAbs in the brain, a strong affinity for the receptor may hinder the efficiency of transcytosis. To quantitatively investigate the effect of binding affinity on the pharmacokinetics (PK) of anti-transferrin receptor (TfR) mAbs in different regions of the rat brain, we conducted a microdialysis study to directly measure the concentration of free mAbs at different sites of interest.

Current progress and limitations of AAV mediated delivery of protein therapeutic genes and the importance of developing quantitative pharmacokinetic/pharmacodynamic (PK/PD) models.

While protein therapeutics are one of the most successful class of drug molecules, they are expensive and not suited for treating chronic disorders that require long-term dosing. Adeno-associated virus (AAV) mediated in vivo gene therapy represents a viable alternative, which can deliver the genes of protein therapeutics to produce long-term expression of proteins in target tissues. Ongoing clinical trials and recent regulatory approvals demonstrate great interest in these therapeutics, however, there is a lack of understanding regarding their cellular disposition, whole-body disposition, dose-exposure relationship, exposure-response relationship, and how product quality and immunogenicity affects these important properties.

Determination of ADC Cytotoxicity in Immortalized Human Cell Lines.

Cytotoxicity assays are a necessary first step to triage ADC molecules before moving them forward to relatively time-consuming and expensive in vivo studies. When cells are exposed to ADC molecules, antigen expressing cells can effectively take up those molecules and eventually die as a result of the released payload. This cytotoxic property of ADCs can be evaluated by measuring the percentage of living cells at the end of the incubation period.

A translational platform PBPK model for antibody disposition in the brain.

In this manuscript, we have presented the development of a novel platform physiologically-based pharmacokinetic (PBPK) model to characterize brain disposition of mAbs in the mouse, rat, monkey and human. The model accounts for known anatomy and physiology of the brain, including the presence of distinct blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier. CSF and interstitial fluid turnover, and FcRn mediated transport of mAbs are accounted for.