exam 3 lecture 7

Question 1

biologics

Answer 1

meds derived from living organisms
recombinant proteins, peptides, blood factors, vaccines, oliognulceotides, cell-based therapy
biotech drugs or biopharmaceuticals

Question 2

importance of biologics

Answer 2

top 200 drug sales 2018 –> 73 were biologics
top 100 drug sales in 2003 –> 5 were biologics

Question 3

monoclonal antibodies (mAb)

Answer 3

two light chains (L)
two heavy chains (H)
linked by SS bonds
antigen binding occurs through variable domain(V) at (CDR)

Question 4

antibody drug conjugates

Answer 4

trojan horse
linker on ADC attaches to cytotoxic agent
combine target specificity of mAb with efficacy of small molecule drugs
can use mAb fragments rather than whole mAb

Question 5

cytokines

Answer 5

IL, INF
neulasta, epogen, avonex, rebif, humatrope

Question 6

insulins

Answer 6

a-chain and b-chain linked by ss bonds
alpha helical structure –> readily associates to form dimers, hexamers

Question 7

insulin analogs

Answer 7

lispro insulin: fast acting insulin analog, lys and pro on c-terminus are reversed
aspar insulin: fast acting insulin analog, pro on c-terminus of b-chain mutated to asp
glargin insulin: long acting, asn on a21 mutated to gly

Question 8

peptides

Answer 8

short proteins less than 50 AAs
some secondary structure, no higher order structure
some chemical modifications
peptide vs peptide analog

Question 9

peptidomimetic (telaprevir)

Answer 9

peptide like structure

Question 10

vaccines

Answer 10

types: inactivated, attenuated, toxoid, conjugate, subunit
differ widely in size and structure
can be much larger than other biologics

Question 11

cell therapies –> new biologics

Answer 11

car-t cell therapies
- remove immune cells from patient’s blood,
- genetically program to fight cancer cells,
- multiplied + infused into patient,
- newly programmed car-t cells kill cancer cells

Question 12

oligonucleotides –> new biologics

Answer 12

used to treat spinal musclar atrophy

Question 13

dosage forms for biologics

Answer 13

dosing is usually parenteral: except oral vaccines
peptides and proteins cannot be given orally
common dosage forms:
- solution for injection, pen/autoinjector, pre-filled syringe, lyphilized powder

Question 14

solution formulation

Answer 14

simple and least expensive
convienent for patients and hospital bc they don’t need reconstitution
can be inspected prior to administration

Question 15

clinical concerns for solutions

Answer 15

efficacy, sterility, side effects (dose-limiting immune response)
pain from injection

Question 16

formulation concerns solutions

Answer 16

all clinical concerns
stability: aggregation, chem stability, shelf-life, storage conditions
manufacturing: cost, manufacturing time

Question 17

formulation variables solutions

Answer 17

solution properties: ph, ionic strength, drug conc., volume, excipients.
container: materials
Storage conditions: refrigerator vs room, frozen

Question 18

formulation variables: pH

Answer 18

rate of sCT degradation depends on pH
pH of maximum stability is 3-4 –> not a pH for injection
additive makes stability worse

Question 19

formulation variables: concentration

Answer 19

beta lactoglobulin is a milk protein
higher concentration of it results in increased and greater aggregation
SC delivery required small volumes –> mAb concentrations risk aggregation

Question 20

formulation variables: excipients

Answer 20

stabilize proteins
promote interactions with water and stabilize native protein structure
excipients that bind to proteins can lead to denaturation
exception: protein binding to ligands can stabilize native structure

Question 21

Eythropoetin

Answer 21

erythropoetin (EPO, Epoetin) is used to treat anemia in renal disease

Question 22

anti-EPO antibodies

Answer 22

reduces drug effect and that of any naturally occur EPO

Question 23

Pure red cell aplasia (PRCA)

Answer 23

results in sudden onset anemia, death
increasesd PRCA has been associated with change in container closure (stopper)

Question 24

what if solution formulation does not work

Answer 24

store at fridge temperature
freeze
freeze-dry or spray-dry to create dried powder for reconstitution
re-engineer protein molecule
abandon drug candidate

Question 25

practical considerations

Answer 25

store at reccommended temp protect from light avoid agitation examine vial for particulates prior to admin be aware of adverse immune response

Question 26

prefilled syringes, autoinjectors, pens

Answer 26

prefilled syringes, pens, autoinjectors are not formulations pen is a medical device solution inside pen is formulation together "combination product"

Question 27

advantages prefilled, pens, auto

Answer 27

ease of use ease of transport discrete increased pt compliance reduced risk of dosage error and product contamination

Question 28

disadvantages prefilled, pens, autos

Answer 28

higher cost than vials + syringes cannot mix two drugs drug waste bc of priming greater surface-volume ratio, presence of lub, induce aggregation of protein drugs

Question 29

prefilled syringe components

Answer 29

syringe barrel leur lock finger grip plunger gasket top cap

Question 30

insulin pen components

Answer 30

cap outer needle inner needle needle protective seal rubber seal insulin reservoir dose window dosage knob injection button

Question 31

common features pen, prefilled, autos

Answer 31

solution dosage forms within a device for admin common features: drug solution, needle, piston/plunger, housing

Question 32

special concerns prefilled, pens, autos

Answer 32

when compared to vials: higher surface-to-volume ratio lower total volume syringe lubes + oils

Question 33

aggregation in syringe

Answer 33

proteins are surfactants that can unfold when exposed to surfaces or interfaces on wall of syringe there is lubricant, which can cause proteins to unfold and dimerize then aggregate

Question 34

advantages lyphilized powders

Answer 34

reduced rates of chem + physical degradation improved drug stability + longer shelf-life refrigerated storage not usually needed can use lyophilized formulations in prefilled, pens, autos

Question 35

disadvantages lyophilized powders

Answer 35

must be reconstituted prior inj less convenient than solutions more expensive and time consuming

Question 36

lyophilized powders

Answer 36

freeze drying removes water by sublimation occurs @ low temp + low pressure gentler than other methods of moving water same for foods

Question 37

lyophilization can cause instability

Answer 37

freeze-concentration can promote aggregation disulfide bond scrambling can be accelerated by freezing and drying protein structure can be perturbed by lyophilization - excipients to inhibit this: lyoprotectants + cryoprotectants aggregated and/or degraded protein can be observed on reconstitution

Question 38

clinical considerations

Answer 38

biologics are usually marketed in lyophilized form because they are unstable in solution use caution: reconsitution, storing + handling, when administering ; visually inspect for particulates