Pharmacokinetic, pharmacodynamic and biodistribution following oral

Pharmacokinetic, pharmacodynamic and biodistribution following oral

1. Pharmacokinetic, pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs Prepared by: Osaid Al Meanazel Ph.D. student, King Saud University, Saudi Arabia

2. Contents Introduction Absorption The influence of physicochemical properties on NPs ADME profile Pharmacokinetic(PK) pharmacodynamic (PD) data following oral administration of p/p loaded nanoparticles Biodistribution Physiologically-based pharmacokinetic modelling(PBPK) as a predictive tool for oral administration of NPs Regulatory considerations Conclusions and future perspectives

3. 1. Introduction non-invasive, relative ease of administration and correspondingly higher patient compliance. Compared to parenterals , oral formulations are less expensive to produce and are amendable to self administration. Following oral absorption insulin would be transported via the portal vein to the liver where it can regulate hepatic glucose production thus mimicking the natural endogenous fate of insulin in contrast to SC administration which delivers insulin into the peripheral circulation. the oral route is a very hostile environment for peptide- and protein-like drugs (p/p ).

4. The objectives of this review are: to examine how orally administered NP formulations can alter the PKPD profiles of p/p, and to provide insights into emerging in silico approaches that more may accurately interpret and predict PKPD of NPs.

5. 2. Absorption Oral absorption can generally be classified into three potential scenarios : N anocarriers may be absorbed intact along with the cargo into the systemic circulation. N anocarriers fuse or directly interact with the intestinal membrane aiding the absorption of the cargo but without absorption of the nanocarrier . T he nanocarrier prematurely releases the cargo in the gut lumen prior to interacting with the intestinal membrane thus leading to degradation of the p/p. In case of A&B, the two major barriers to absorption are the mucus layer secreted by the goblet cells and the intestinal epithelial membrane.

6. The gastrointestinal mucus barrier The major impacts of mucus are related to the highly viscous nature which can reduce NP diffusion and the negative charge which may hinder transport of charged particles. Recently NP surface characteristics have been modified to optimize mucoadhesion thus prolonging contact, gastrointestinal (GI) retention time and enhance mucus penetration thereby promoting cellular up take in the GI tract.

7. Mechanistic studies at the membrane/cellular level The extent of transcytosis will be influenced by cell adhesion, cellular uptake and intracellular trafficking and exocytosis . It is frequently reported that both phagocytic (M cells) and endocytic (enterocytes) pathways are involved in NP uptake from the GIT. the increased understanding regarding phagocytosis and non-phagocytic transport mechanisms has been successfully exploited to design NP with the capacity to harness these transport mechanisms and enhance drug delivery . Endocytosis of NPs was shown to involve clathrin , lipid raft/ caveolae and macropinocytosis and also incorporated different proteins such as actins , protein tyrosine kinase (PTK) and cyclooxygenase (COX).

8. 3. The influence of physicochemical properties of NPs on ADME profiles Size  ↓;↑Abs , ↑; avoidance of 1 st pass metabolism, ↓; ↑ recycling time, ↓(<6 nm); ↑ renal eliminaation Charge aggregation, luminal residence time (LRT), Protein interaction in plasma (+) Surface polarity Stability (Stealth) by pegylation Bioadhesive properties ↑ the LRT; ↑ Abs. turnover of guts ↓abs Functional modification-targeted NPSreceptor ligand, Smart NPs

9. 4. Pharmacokinetic (PK) pharmacodynamic (PD) data following oral administration of p/p loaded nanoparticles Comparison of the PK/PD data for oral versus SC showed that while oral aspart -insulin NPs produced a more prolonged hypoglycaemic effect versus SC administration of aspart -insulin, the oral NP profile was similar to that of the SC administered NPH-insulin (intermediate-acting insulin product). These results indicate that the oral chitosan NP could be used for maintaining basal insulin levels in diabetic patients. Nanoparticles using inorganic materials for oral delivery — silica  Need more work in order to mimic the action of IV Gold NPs  Infancy depending on the functional grp or attached polymer to its surface

10. 5. Biodistribution Role of the intestinal lymphatic system Bypass the 1 st pass metab . possibility of a more controlled kinetics of distribution into the systemic blood circulation possibility of treating diseases such as certain cancers or infectious disease (e.g. HIV) that spread via the lymphatics

11. II. Whole body distribution

12. Physiologically-based pharmacokinetic modelling (PBPK) as a predictive tool for oral administration of NPs PBPK modelling of therapeutic proteins and NPs is relatively new and additional information is required to facilitate the prediction of pharmacokinetics from orally administered p/p-loaded NPs; this may be feasible given appropriate in vitro and in vivo preclinical models to elucidate the many unknown parameters.

13. 7. Regulatory considerations In particular, the safety and toxicological assessment of the NPs remain central to evaluation of the benefit/risk analysis. However, there is a lack of thorough systematic toxicity studies on NPs which are needed to reliably assess toxicity/efficacy and support the regulatory decisions regarding risks associated with NP . Due to the potential for variation in the ADME profiles of nanomedicines and the complex nature of the formulations, often containing a variety of excipients, new regulatory frameworks are required to assess the quality, safety, and efficacy of these complex products. Many of the clinical evaluation studies to date have utilised ‘ generally recognised as safe’ (GRAS) listed excipientswith the hope of facilitating the licensing process of resulting products.

14. 8. Conclusions and future perspectives A detailed understanding of the pharmacokinetics and pharmacodynamics of orally administered p/p is currently limited by a lack of studies that comprehensively assess PK/BD/PD in reliable in vivo models . Furthermore such analysis of p/p formulated as oral NPs is almost completely absent. The lack of comprehensive studies makes a critical analysis of the mechanisms of absorption difficult . In the field of biopharmaceuticals , nano -formulations undoubtedly have advantages as drug delivery systems and the application of such technologies to the oral route is exciting . The need to illustrate a positive benefit to risk ratio for orally administered NPs will become even more critical as newer more ‘bioactive’ excipients are employed in these formulations.

15. 9. Reference Griffin, B.T., Guo , J., Presas , E., Donovan, M.D., Alonso, M.J. and O'driscoll , C.M., 2016. Pharmacokinetic, pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs.  Advanced drug delivery reviews ,  106 , pp.367-380.