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. For a comprehensive analysis, these intra-CNS injection datasets were juxtaposed against our previously acquired intravenous (IV) injection data obtained under analogous experimental conditions. Our findings highlighted that direct CSF injections, either through ICV or ICM, resulted in ~ 5-6-fold higher interstitial fluid (ISF) drug exposure than IV administration. Additionally, the low bioavailability observed following IST administration indicates the existence of a local degradation process for antibody elimination in the brain ISF along with the ISF bulk flow. The study further refined a physiologically based pharmacokinetic (PBPK) model based on new observations by adding the perivascular compartments, oscillated CSF flow, and the nonspecific uptake and degradation of antibodies by brain parenchymal cells. The updated model can well characterize the antibody PK following systemic and intra-CNS administration. Thus, our research offers quantitative insight into antibody brain disposition pathways and paves the way for determining optimal dosing and administration strategies for antibodies targeting CNS disorders.

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. METHODS AND RESULT: In-house generated AAV9-Trastuzumab vectors were administered at 5E+11 Vgs/rat through intravenous(IV), intracerebroventricular(ICV), intra-cisterna magna(ICM) and intrastriatal(IST) routes. Vector and trastuzumab blood/plasma concentrations were assessed at different time points up to the terminal time point of 21 days. Different brain regions in addition to the spinal cord, cerebrospinal fluid(CSF) and interstitial fluid(ISF), were also analyzed at the terminal time point. Our results show that vector biodistribution and Trastuzumab expression in the brain could the ranked as follows: IST>ICM>ICV>IV. Rapid clearance of vector was observed after administration via the ICM and ICV routes. The ICV route produced similar expression levels across different brain regions, while the ICM route had better expression in the hindbrain and spinal cord region. The IST route had higher expression in the forebrain region compared to the hindbrain region. A sharp decline in trastuzumab plasma concentration was observed across all routes of administration due to anti-trastuzumab antibody response. CONCLUSION: In this study we have characterized vector biodistribution and transgene mAb expression after AAV9 vector administration through different routes in rats. IST and ICM represent the best administration routes to deliver antibody genes to the brain.

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. We were able to describe the PK of mAbs following intravenous (IV) or subcutaneous administration in cats, IV administration in sheep, and IV administration dogs reasonably well by fixing the physiological parameters and just estimating the parameters related to the binding of mAbs to the neonatal Fc receptor. The platform PBPK model presented here provides a quantitative tool to predict the plasma PK of mAbs in dogs, cats, and sheep. The model can also predict mAb PK in different tissues where the site of action might be located. As such, the mAb PBPK model presented here can facilitate the discovery, development, and preclinical-to-clinical translation of mAbs for veterinary and human medicine. The model can also be modified in the future to account for more detailed compartments for certain organs, different pathophysiology in the animals, and target-mediated drug disposition.

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. In addition, there is a lack of quantitative studies to support the development of pharmacokinetic-pharmacodynamic models, which can support the discovery, development, and clinical translation of this delivery system. In this review, we have provided a state-of-the-art overview of current progress and limitations related to AAV mediated delivery of protein therapeutic genes, along with our perspective on the steps that need to be taken to improve clinical translation of this therapeutic modality.