Determination of Pharmacokinetic Parameters of a Four-Armed, Guanidinium-Rich Structurally Nanoengineered Antimicrobial Peptide Polymer: A Research Protocol

Introduction: Antibacterial resistance has accentuated the need for the development of novel, efficacious pharmaceuticals. Structurally nanoengineered antimicrobial polypeptide polymers (SNAPPs) have shown promise as a candidate for a new antibacterial pharmaceutical class which may help overcome the problem of antibacterial resistance in humans or animals.  Particularly, the SNAPP with a chemical formula (RGRGRGRGRGRG)4K2K-NH2 (4R6G6) has been shown to exhibit negligible hemolysis while retaining low minimal inhibitory concentrations against bacteria. An important consideration in drug development is pharmacokinetic studies, however, there have been no prior pharmacokinetic studies involving SNAPPs. Therefore, the objective of this study is to determine the pharmacokinetic parameters of 4R6G6. Methods: 4R6G6 will be synthesized and purified according to previously reported methods. 4R6G6 will be administered to BALB/c mice intravenously, serial blood samples will be taken from 0-48 hours after SNAPP administration and serum 4R6G6 concentrations will be quantified over time by liquid chromatography mass spectrometry. This information will be used to calculate key pharmacokinetic parameters using Pmetrics. Results: We expect that the half-life of elimination will be on the order of hours and will exceed 3 hours, while the volume of distribution will be equal to the plasma volume of a mouse (1.2 mL/mouse) Discussion: The half-life of elimination of 4R6G6 will influence its desirability as a future drug target. Additionally, the volume of distribution is expected to indicate a distribution into plasma, and can be used to calculate the desired dose for a certain plasma concentration in future studies. Conclusion: Given the expected half-life of elimination on the order of hours, we expect 4R6G6 to be a strong candidate for further translational study in the race to combat antibacterial resistance. Future directions include the quantification of the safety of the drug by determining the therapeutic index in vivo.