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Kinetics > Ex. 2 L7: PK of Biological drugs > Flashcards

Ex. 2 L7: PK of Biological drugs Flashcards

1
Q

What are biologics

A

Generally derived from living material (human, animal, microorganism)
Complex in structure and this not fully characterized

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2
Q

Biologics examples

A

Monoclonal antibodies (mAb) for in vivo use
-Monospecific antibody that is identical because they are produced by immune cells of a single type
-They are clones of a single parent cell (identical)
Cytokines, growth factors, enzymes, immunomodulators Proteins intended for therapeutic use that are extracted from animals or microorganisms
Other non-vaccine therapeutic immunotherapies
Vaccine, blood products and gene therapy

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3
Q

Mabs

A

Many people use MaB injections/drugs
More and more biologics on market

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4
Q

Monoclonal antibodies (mAb)

A

VERY Target specific

Companies LOVE MAbs – spend a lot of money on them

We do see side effects from exaggerated pharmacological effects = drug works too well, causes effects

Antibodies – Y shaped protein

unit: Nm

Thickness of membrane – it is impossible to diffuse into cell – NO PASSIVE DIFFUSION DUE TO SIZE

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5
Q

Small molecule drugs

A

Small molecule drugs go everywhere because they can diffuse easily across biological membranes

Many off target/non-target effects

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6
Q

Immunoglobulin as drugs:

A

antibodies used as drugs belong to immunoglobulin G (igG) class
IgG accounts for 75-80% of naturally occurring antibodies
Second most common protein in plasma (5-13 g/L)’ albumin 35-50 g/L

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7
Q

Structure of IgG

A

Two heavy chains

Two light chains

Connected by disulfide bonds

Variable region provides the specificity

Variable region contains CDR (complementarity-determining region; not shown here)

Variable recognize antigen – specificity

FAB and Fc

Fraction of antigen binding : Most important region for recognizing antigen

Fraction of crystallizable

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8
Q

IgG action and structure

A

When it binds to its target through Fab region, it can bring in different cells (NK, etc. -**Relisten

Can also bring in different complement to initiate CDC (Complement dependent cytotoxicity)

FC region is important in initiating activation of immune cells

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9
Q

Fc Receptor types

A

FcyR
FcRn (neonatal FcR)

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10
Q

FC receptors: FcyR

A

Crystallized structure

Y shape

L, light, H, heavy, V variable

IMPORTANT: FC region

Contains binding site for Fc receptor expressed on immune cells: Fcy receptor

Also binds to C1Q
Responsible for binding to certain immune cells for cytotoxicity - relisten

Involved in mediating immune responses
Expressed on immune cells

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11
Q

FC receptors: FCRN

A

Different FC receptor: FcRN

FC

R = receptor

N = neonatal

Expressed on endothelial cells and immune cells

Involved in uptake into cells

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12
Q

mAb function

A

Targets of mAb are either on the cell membrane or circulating in the blood

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13
Q

mAb function: targeting on cell membrane:

A

MAB binding to protein called HER2

HER2 – protein expressed on cell membrane

Expressed on breast

Give MAB to a breast cancer patient, bind to HER2, get internalized, and lead to lysosomal degradation = decreased HER expression

OR antibody undergoes antibody dependent cytotoxicity – brings in different immune cells

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14
Q

mAb function: Circulating target

A

TNF-a

Cytokine mediating inflammation

Once it binds to target – initiates binding that leads to inflammation

Infliximab

Binds to TNFa – falls into it

Decreased level of TNF-a that binds with target = decreased inflammation

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15
Q

mAb: Absorption

A

Cannot be taken orally due to instability in GI tract and difficult in permeating the intestinal epithelium

Must be given parenterally (e.g. IV, SC, or IM)

Reach systemic circulation by **convective flow of the interstitial fluids into lymphatic capillaries into lymphatic channels **

CANNOT give orally – body will be treated as big protein, used as nutrient source

Out of three methods: subq is preferred because patient can administer themselves

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16
Q

Lymphatic system

A

One-way transport system for fluid and proteins by collecting them from interstitial space returning them to blood circulation
Lymph flow rate is 100-500 times slower than that of blood
The protein composition of lymph is nearly equivalent to that of interstitial fluid
Serves as a major transport route for immune cells and macromolecules

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17
Q

mAB absorption process

A

Put drug into interstitial space

Small molecule drug as subq – typically go through lipid bilayer – small, can cross by passive diffusion

Typical route for small molecule absorption

Pass through capillary membrane

Mabs are too thick, cannot go through membrane

18
Q

Lymphatic system explained

A

Relatively high blood pressure

Because of that – some liquids squeeze through blood membranes and reach interstitial fluid area

Fluid accumulation – bad

Lymphatic – collects accumulated fluid back to the blood system

Takes care of extra fluid in interstitial space

Flow happens due to differences in pressure = Convective flow (fluid moving down the gradient)

19
Q

Major pathway for mAb

A

Convective flow of the interstitial fluid into lymphatic channel

20
Q

Minor pathway for mAbs

A

Diffusion through interstitial fluid and transport across blood capilary
(for small proteins (<5kD size)

21
Q

Vd of mAb range

A

lies between that of plasma (0.04L/Kg) and extracellular water (0.23 L/kg)
-mAbs too big to cross - stuck in blood and plasma

22
Q

mAb disposition:

A

Bioavailability – not 100%

There are _ to take care of Mabs when you inject

Relatively low at injection site: proteolysis at injection site

RESULT: Small protein and _ = become nutrients

Peak time: 3days – 1 week

Much slower time

Only relevant to IM and subq – IV fast

Half life – unit of days, weeks, or sometimes months

Antibodys hang in body for pretty long time due to FCrn recycling
revisit table

23
Q

FcRn (neonatal Fc receptor)

A

Originally identified as a receptor for transporting maternal IgG to neonates via maternal milk
Expressed in many tissues including placenta syncytiotrophoblast and vascular endothelium
Serves as trasnport mechanism for IgG from maternal to fetal

24
Q

IgG salvage by FcRn

A

The endothelial cells internalize serum IgG which binds to FcRn in an acidic endosomal compartment. FcRn then recycles IgG back into circulation, extending its serum half-life
FcRn in endothelial cells protects IgG from catabolism

25
Q

IgG salvage by FcRn deeper explanation

A

Leads to endocytosis

Leads to endosome

LogpH solidifies this interaction between receptor and antibody

FCRN recycles – after getting through cell, go back to cell membrane = BRING ANTIBODIES WITH because binding is strong due to pH

When exposed to blood – binding is weaker because pH is higher – antibody gets released

IgG goes through cycles over and over – leads to half life of IgG

26
Q

Q: T/F: The absence of FcRn leads to faster elimination of mAb

A

True

27
Q

mAb elimination: IgG salvage by FcRn

A

FcRn gene knockout (KO) significantly decreases mAb half-life
FcRn binding delays mAb elimination and prolongs mAb half life

Revisit graph

28
Q

mAb: Elimination - Phase I and II

A

Hepatic metabolism by phase I and II enzymes plays NO ROLE in mAb elimination

29
Q

Renal elimination and mAb

A

Renal elimination of mAb is insignificant (glomerular filtration threshold ~60kDa)

30
Q

mAbs are mainly eliminated through

A

Proteolytic degradation, resulting in smaller peptides and amino acids

31
Q

Clearance from circulation is via nonspecific or specific pathway

A

Nonspecific clearance pathway (proteolysis by reticuloendothelial system, RES)

Specific clearance pathway (target-mediated clearance)

Other (antidrug antibody-mediated clearance)

32
Q

mAb elimination: Reticuloendothelial system (RES)

A

Mononuclear phagocyte system (part of immune system)
Consists of the phagocytic cells located in reticular connective tissue (e.g. liver, bone marrow, and lymphoid organs)
Nonspecific uptake by cells via pinocytosis and subsequent protein catabolism

33
Q

mAb elimination: Nonspecific clearance by RES

A

mAb bound to circulating antigen or free mAb is eliminated by RES

Slow but large capacity (not saturated at typical mAb doses)

Endogenous IgG half life: 21 days

Dose-independent” (ie, linear PK)

34
Q

mAb elimination: Target mediated clearance

A

Elimination of mAbs through its antigen specific interaction

After mAbs bind to a specific antigen, they may be internalized or catabolized through lysosomal degradation as an antibody-antigen complex

More rapid than nonspecific clearance and most prominent for membrane-bound antigen

At high doses of mAb, this pathway is saturated, leading to dose dependent (nonlinear PK)

35
Q

Example of Target mediated clearance mAb elimination:

A

Efalizumab:

Binds to CD11a on lymphocyte membrane and inhibits lymphocyte activation

36
Q

Nonlinearity in mAb PK: High dose

A

Slow elimination
By RES mainly because target -mediated clearance is saturated
Linear clearance (unpredictable clearance)

37
Q

Nonlinearity in mAb PK: Low dose

A

Rapid elimination
By RES + target mediated clearance
Nonlinear clearance (unpredictable clearance)

38
Q

mAb: immunogenecity

A

Both neutralizing and non-neutralizing ADA form circulating ADA-mAb immune complex that is cleared by RES
SC admin elicits a higher likelihood compared to IM or IV admin, potentially secondary to aggregate formation at the injection site

39
Q

mAb: antidrug antibodies

A

mAbs may trigger an immune response, i.e. formation of antidrug antibodies (ADA), in patients
Increased fraction of nonhuman sequence in the protein molecule leads to more immune response

40
Q

Immunogenecity: As duration of treatment lengthens, the chances to elicit an immune response

A

also increases

41
Q

Immunogenecity: ADA-mAb complex formation may

A

Increase mAb clearance

42
Q

Disposition of mAb

A

Interstitial fluid
(some are lost at the local injection site)
Lymph
Blood
FcRN Mediated recycling
(Extends mAb half-life)
Elimination by RES or binding to membrane targets

Kinetics (20 decks)

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