Antibody PK

Question 1

Applications of Mab

Answer 1

Alteration of toxin (immunotoxicotherapy) disposition
Elimination of cells
Alteration of cell function
Drug delivery

Question 2

Antibody PK general expectations

Answer 2

Good absorption following SQ or IM dosing
Bi-exponential disposition
Long terminal half-life and low rates of CL
Small Vd

Question 3

Elimination mechanisms for peptides and proteins (6 things)

Answer 3

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

Question 4

Phagocytosis may be a primary mechanism of elimination for proteins and aggregates of what size?

Answer 4

> 400 kDa

Question 5

Renal elimination and subsequent proteolysis is often a primary mechanism of elimination when MW is what?

Answer 5

<50 kDa

Question 6

How does prior treatment of Mab affect the PK?

Answer 6

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

Question 7

Features of FcRn receptor

6 things

Answer 7

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

Question 8

PK characteristics of target-mediated disposition (Vss and CL)

Answer 8

Vss decreases with increasing dose
CLd decreases with increasing dose
CL decreases with dose when the receptor binding leads to drug elimination

Question 9

Risk for ADA appears to be greatest for what types of antibodies?

Answer 9

Rodent

Question 10

Risk for ADA appears to be greatest in what route of administration?

Answer 10

SQ

Question 11

For fluid-phase endocytosis, phagocytosis, renal filtration, and catabolism, is elimination likely to be dose-dependent or dose-independent?

Answer 11

Dose-independent

Question 12

For drug-specific and component-specific processes, is elimination likely to be dose-dependent or dose-independent?

Answer 12

Dose-dependent

Question 13

IgG CL: target-mediated disposition vs. FcRn

Imagine that one graph where the line looks like a misshapen U idk lol

Answer 13

With increasing doses of IgG, there is an increase in CL due to saturation of the target (but at extremely high doses)

Question 14

Primary mechanism for monoclonal antibody distribution

Answer 14

Convection

Question 15

True or false: antibodies can be eliminated from sites that ARE NOT in rapid equilibrium with plasma

Answer 15

True

Question 16

Does variability in Fc-gamma-R3A explain inter-individual variability in mAb PK?

Answer 16

No, it’s not a big determinant of antibody PK in either plasma or tissue, but it’s important for PD

Question 17

Fc-gamma-R3A and rituximab

Answer 17

Patients with a variant in that receiving rituximab demonstrate superior responses

Question 18

Do ADAs contribute to the inter-individual variability of mAb PK?

Answer 18

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

Question 19

Do disease and DDIs contribute to the inter-individual variability in mAb PK? FcRn example

Answer 19

Patients with a higher concentration of endogenous Ab have a rapid elimination of the therapeutic antibody

Question 20

Properties of FcRn recycling

Answer 20

Capacity-limited and saturable

Question 21

Do disease and DDIs contribute to the inter-individual variability in mAb PK? ADA example

Answer 21

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

Question 22

Do disease and DDIs contribute to the inter-individual variability in mAb PK? Convection example

Answer 22

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

Question 23

Do disease and DDIs contribute to the inter-individual variability in mAb PK? Diabetic nephropathy and antibody PK example

Answer 23

Patients with T2DM nephropathy were shown to have nearly 20-fold high urinary levels of IgG

Question 24

Do disease and DDIs contribute to the inter-individual variability in mAb PK? Disease example

Answer 24

Lupus, PLE, RA all affect the PK of mAbs

Question 25

Major determinant of antibody elimination kinetics

Answer 25

FcRn

Question 26

Will FcRn saturation lead to non-linear PK for most therapeutic antibodies?

Answer 26

No, but is partly responsible for IVIG efficacy

Question 27

What will develop with chronic treatment

Answer 27

ADAs

Question 28

Is target-mediated elimination non-linear or linear?

Answer 28

Non-linear

Question 29

Antibody CL decreases as a function of what?

Answer 29

Increasing concentration/dose