Molecular Attributes Affecting Subcutaneous Absorption

For the summer of 2019, I was co-advised by John Chung, Marissa Mock, and Francis Kinderman at Amgen's Thousand Oaks campus.  The project we were working on was studying the molecular attributes that impact absorption into the body via the subcutaneous route.  Due to company policy, I will give a brief background of the field and some techniques used.

Pharmacokinetics is study of the time course of a drug moving into, through, and out of the body.

The subcutaneous drug delivery system is more patient-centric, allows for self-administration. However, one drawback of subcutaneous delivery is wide variability in bioavailability.

In order to engineer solutions at the molecular level, a thorough understanding of the significant molecular attributes is necessary.  A drug must be designed to be stable upon introduction to the SubQ space.  These conditions are:

  • pH 7.4 

  • Temperature = 34C

  • Compatible with the components within the extracellular matrix.

Our hypothesis and data are omitted for privacy, but below are some pre-established methods that were used:

 

SCISSOR:

Subcutaneous Injection Site Simulator

  • Mimics an in vivo subcutaneous site injection and gain insight of the rate of drug diffusion from injection site to lymph.

RP HPLC:

Reverse Phase High Performance Liquid Chromatography

  • Separates compounds on the basis of polarity

AC-SINS: 

Affinity-Capture Self-Interaction Nanoparticle Spectroscopy

  • Observe the effects Fab-Fab self-interactions that could lead to antibody aggregation.

  • Since nanoparticles emit light based on their size, self-interaction would lead to a greater-sized nanoparticle which is observable via wavelength shift. 

DLS-kD: 

Dynamic Light Scattering - Diffusion Interaction Parameter

  • Observe how diffusion coefficients change as a function of concentration.

SEC-HPLC: 

Size-Exclusion Chromatography - High Performance Liquid Chromatography

  • Separate components on the basis of size.

Molecular Modeling

  • Provide a 3D representation of the antibody in order to see its physiochemical attributes.

Sample molecule from Google Search‚Äč