Re-Assessing PK/PD Issues for Oral Protein and Peptide Delivery

Randall J Mrsny,Tahir A Mahmood

doi:10.3390/pharmaceutics13071006

Abstract

Due to a lack of safe and effective oral delivery strategies for most protein and peptide therapeutics, pharmaceutical drug developers have focused on parenteral routes to administer these agents. Recent advances in delivery technologies have now shown clinical validation for a few of these biopharmaceuticals following oral administration. While these initial opportunities have provided more than just a glimmer of hope within the industry, there are important aspects of oral biopharmaceutical delivery that do not completely align with pharmacokinetic (PK) parameters and pharmacodynamics (PD) outcomes that have been learned from parenteral administrations. This commentary examines some of these issues with the goal of presenting a rationale for re-assessing methods, models, and success criteria to better measure oral protein or peptide delivery outcomes related to PK/PD events.

Highlights

For over 100 years, since the first documented description in 1922, extensive efforts have been made to identify safe, effective strategies for the successful oral delivery of insulin [1]
PK from what was identified from parenteral administration. These two examples further suggest that it may be time to re-think targeting and actions within the intestine and associated tissues based upon the therapeutic goal. The premise of this commentary is not to suggest that the outcomes observed for all orally delivered protein and peptides therapeutics will be dramatically different from what has been observed for parenteral administration
PK/PD outcome to that observed for parenteral administration; such an outcome would theoretically simplify development efforts in the transition from an injectable to an oral dosage form

Summary

Background

For over 100 years, since the first documented description in 1922, extensive efforts have been made to identify safe, effective strategies for the successful oral delivery of insulin [1]. Despite the likelihood of many duplications across these searches, the numbers demonstrate the extensive interest in this area Scanning these publications highlights the wide range of approaches that have been described, including various types of chemical enhancers, cell-penetrating peptides, chelating agents, chemical surfactants, bile salts, mucoadhesive platforms and hydrogels, proteolytic protectants, liposomes, microspheres, and nanoparticles, as well as robotic systems and needle-protruding devices [5,6,7]. Modifications made to the GLP-1 molecule, such as lipidation and amino acid exchanges, resulted in dramatically longer serum half-lives that have resulted in commercially successful products, with some reductions in dose-limiting side effects that include nausea, diarrhea, and vomiting [13] While such chemical modifications led to successful clinical products for parenteral administration, these modified molecules were not necessarily optimized for patient safety and clinical efficacy following oral delivery.

Relative distribution of a of bioFigure

Gut and Liver

Findings

Summary