25 - PK of Biologics Flashcards
What are Biologics
- Genetically derived from LIVING Material
- Very complex and and unpredictable
-
CDER
- examples
- NOT INSULIN
- Cytokines / Enzymes
- Growth Factors
- Monoclonal Antibodies
- Vaccines / Blood products
- examples
Biosimilar
- Analytical Evidence
- SImilar to a biologic
- Approved based on being HIGHLY SIMILAR to an FDA approved biologic
- no meaningful differences in safety/effectiveness
- MUCH SMALLER AND EASILY REPRODUCIBLE
-
7 current products approved
- Cytokines / AB’s / Fusion Proteins
Bioassay of Biologics
-
PK Assays:
-
LCMS
- = MOST COMMONLY USED FOR SM
-
ELISA / RIA
- Most commonly used for biologics
-
LCMS
-
ADA = Anti Drug Antibodies
- specific for biologics
Immunogenicity
Ability to provoke an immune response
- Consequences:
-
INCREASE in clearance of mAB’s
- monoclonal antibodies cleared out
-
DECREASE in capacity for target binding
- less binding
-
INCREASE in clearance of mAB’s
Biologics Absorption
MAINLY SC / IV
no oral biologics
HIGH MW –> INCREASE Tmax
If MW > 16k Da –> LYMPHATIC
following SC absorption
Higher the MW –> Greater % goes to the lymph
Physicochemical Properties of Biologics
LARGE MW and SIZE
limited solubility
hydrophilicity / shape / charge
GI degradation / stability
Lymphatic System
-
One-Way Transport system
- transports them from interstitial space –> blood
-
100-500x SLOWER/LESS THAN
- the net rate of flow of blood
- Also a major transport route for immune cells & macromolecules
Distribution
of biologics
LImited & Slow Tissue distribution
-
2 Steps
- Extravasations from circulation –> interstitial space
- –> diffusion through EC matrix to cell surface
-
VERY MW / CHARGE DEPENDENT
- determines how fast it gets to the target
- Key Mechanisms of distribution
- CONVECTION
- PINOCYTOSIS/trancytosis
Volume of Distribution
PK’s
ALMOST ALWAYS NON-LINEAR
- Estimations of Vd are NOT appropriate
- unless CL is all from central compartment
-
Non-Linear distribution / metabolism
-
Binding is STRONG / SPECIFIC
- SATURABLE
- receptor mediated uptake
-
Binding is STRONG / SPECIFIC
Elimination PK
of biologics
Elimination may be NON-LINEAR
MANY PATHWAYS
- Immunogenicity
- Catabolism / Proteolysis
- Degraded after binding
- Renal / Hepatic
- Receptor mediated
- FcRn Salvage Pathway
Half Life of Antibodies
VARIENT
-
The more “Real” the antibody is
- –> INCREASE IN HALF LIFE
- if chimeric / fake
- –> low half life
-
How the body views the antibody matters
-
Biosimilars vs Biologic
- biosimilars can have a poor half life
-
Biosimilars vs Biologic
Hepatic Uptake / Metabolism
of biologics
These receptors internalize the ligands
through endocytic pathway –> LYSOSOMAL DEGRADATION
-
ASGPR = asialoglycoprotein receptors
- Recognizes galactose / n-acyl
- primary expression on hepatocytes
-
Mannose Receptor
- expressed on kupfer cells/macrophages
FcRn Salvage Pathway
for IgG
Neonatal Fractional Component
-
Prolongs IgG half Life!
- by recycling endocytosed IgG back to circulation
-
pH dependent
- low pH results in recycling
- Discovered in neonatal rats
Renal Elimination
of biologics
Not Very possible for biologics b/c VERY LARGEK
GSC only takes MW <69 kDa
But if it does:
Brush-Border Catabolism
Reuptake/secretion
Target Mediated Clearance of mABs
HIGHLY DOSE DEPENDENT
IN ORDER TO SATURATE TARGETS
small changes in dose highly effect the therapeutics and clearance
Strategies to Improve
HALF LIFE
Glycosylation
PEG-ylation
FcRn Binding
(Fc engineer / Fc Fusion proteins)
To allow for less frequent dosing
