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
