Antibody PK Flashcards
Applications of Mab
Alteration of toxin (immunotoxicotherapy) disposition
Elimination of cells
Alteration of cell function
Drug delivery
Antibody PK general expectations
Good absorption following SQ or IM dosing
Bi-exponential disposition
Long terminal half-life and low rates of CL
Small Vd
Elimination mechanisms for peptides and proteins (6 things)
Fluid-phase endocytosis (and catabolism)
Renal filtration (and catabolism or excretion)
Phagocytosis
“Component-specific”-receptor mediated endocytosis
“Component-specific”-receptor mediated protection
“Drug specific”-receptor mediated endocytosis
Phagocytosis may be a primary mechanism of elimination for proteins and aggregates of what size?
> 400 kDa
Renal elimination and subsequent proteolysis is often a primary mechanism of elimination when MW is what?
<50 kDa
How does prior treatment of Mab affect the PK?
When you wipe out the cells from the first dose, there’s less target-mediated elimination from the first dose. Subsequent doses will have a higher AUC because there’s less target-mediated elimination
Features of FcRn receptor
6 things
AKA the Brambell receptor
Transient, saturable GI absorption in neonates
Saturable maternofetal transfer
Very long plasma half-life
Concentration-dependent elimination
Inhibiting FcRn increases the elimination of antibodies which helps autoimmunity
PK characteristics of target-mediated disposition (Vss and CL)
Vss decreases with increasing dose
CLd decreases with increasing dose
CL decreases with dose when the receptor binding leads to drug elimination
Risk for ADA appears to be greatest for what types of antibodies?
Rodent
Risk for ADA appears to be greatest in what route of administration?
SQ
For fluid-phase endocytosis, phagocytosis, renal filtration, and catabolism, is elimination likely to be dose-dependent or dose-independent?
Dose-independent
For drug-specific and component-specific processes, is elimination likely to be dose-dependent or dose-independent?
Dose-dependent
IgG CL: target-mediated disposition vs. FcRn
Imagine that one graph where the line looks like a misshapen U idk lol
With increasing doses of IgG, there is an increase in CL due to saturation of the target (but at extremely high doses)
Primary mechanism for monoclonal antibody distribution
Convection
True or false: antibodies can be eliminated from sites that ARE NOT in rapid equilibrium with plasma
True
Does variability in Fc-gamma-R3A explain inter-individual variability in mAb PK?
No, it’s not a big determinant of antibody PK in either plasma or tissue, but it’s important for PD
Fc-gamma-R3A and rituximab
Patients with a variant in that receiving rituximab demonstrate superior responses
Do ADAs contribute to the inter-individual variability of mAb PK?
Patients who have more AAAs from taking adalimumab will have a lower amount of drug in the body because the antibodies are also clearing the drug out
Do disease and DDIs contribute to the inter-individual variability in mAb PK? FcRn example
Patients with a higher concentration of endogenous Ab have a rapid elimination of the therapeutic antibody
Properties of FcRn recycling
Capacity-limited and saturable
Do disease and DDIs contribute to the inter-individual variability in mAb PK? ADA example
Cotreatment of MTX with a biologic response decreases the antibody response which leads to higher concentrations of the antibody and decreases the CL of the biologic
Do disease and DDIs contribute to the inter-individual variability in mAb PK? Convection example
Giving bevacizumab and another antibody to treat cancer won’t allow it to get to the tumor to provide benefit and will lead to DDIs
Do disease and DDIs contribute to the inter-individual variability in mAb PK? Diabetic nephropathy and antibody PK example
Patients with T2DM nephropathy were shown to have nearly 20-fold high urinary levels of IgG
Do disease and DDIs contribute to the inter-individual variability in mAb PK? Disease example
Lupus, PLE, RA all affect the PK of mAbs
Major determinant of antibody elimination kinetics
FcRn
Will FcRn saturation lead to non-linear PK for most therapeutic antibodies?
No, but is partly responsible for IVIG efficacy
What will develop with chronic treatment
ADAs
Is target-mediated elimination non-linear or linear?
Non-linear
Antibody CL decreases as a function of what?
Increasing concentration/dose
