Biologics Flashcards
(163 cards)
1
Q
What are the 4 broad categories of biologics for Psoriasis?
A
TNF
17
23
12/23
2
Q
List 5 TNF-alpha inhibitors:
A
Adalimumab/humira
Infliximab/remicade
Etanercept/Enbrel
Certolizumab/cimzia
3
Q
3) Given an example of an IL-12/23 inhibitor:
A
stelara/ustekinumab
4
Q
4) List 4 IL-17 inhibitors:
A
Ixekizumab-talz
Brodalumab- siliq
secukinumab- cosentyx
Bimekizumab (Bimzelx)
5
Q
5) List 3 IL-23 inhibitors:
A
Guselkumab (Tremfya)
Rizankizumab (Skyrizi)
Tildrakizumab (Ilumya)
6
Q
Humira - 1) What is the source and structure?
A
Fully human monoclonal IgG1 ab
7
Q
Humira- What is MOA?
A
a. Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF-expressing cells in vitro in thepresence of complement.
b. *unclear on membrane bound tnf alpha
8
Q
What is pregnancy category for humira, infliximab and etanercept
A
Class B
9
Q
7) List 7 FDA approved indications for humira
A
Psoriasis
HS
Chrons-adult and paediatric
UC
PsA
Ankylosing spondylitis
RA
polyarticular JIA
Uveitis
10
Q
List 5 off-label uses humira
A
PG
Behcets
Sarcoidosis
Vasculitis
PRP
11
Q
How is it supplied?
A
a. Single use pens or single use prefilled syringes, given SC
12
Q
10) What is the starting dosing? For Psoriasis vs. HS? What is the maintenance dose? for Humira
A
Psoriasis:
80 mg day 0, 40 at week 1, then 40 mg q2 weekly
HS: 160 day 0, then 80 week at 2 weeks, then 40 mg at 4 weeks, then 40 mg weekly
13
Q
What baseline blood work would you order before starting TNFs
A
CBC diff, Liver enzymes, Cr/urea
Hep B serology
Hep C serology
TBST + CXR or IGRA + CXR
Strongy serology
14
Q
12) What is the PASI-75 of Humira at 16 weeks?
Infliximab at 10 weeks? Etanercept at 10 weeks
A
Humira- 70%
Infliximab-80%
Etanercept- 50%
(12 weeks 50%, 24 wks60%)
15
Q
13) How quickly does humira work? Onset of response?
Infliximab?
Etanercept?
A
1-2 weeks Humira
2 weeks infliximab
4 weeks etanercept
16
Q
14) What is the bioavailability of humira? Inflximab? Etanercept?
A
64%- humira
100% - infliximab
58% etanercept
17
Q
15) After how long are peak levels achieved for humira? Infliximab? Etanercept
A
5.5 days- humira
infliximab-immediate post infusion
Etanercept 2 days
18
Q
Half life of humira? infliximab? Etanercept?
A
14 days- humira
7-9 days infliximab
5 days etanercept
19
Q
17) How is infliximab, humira and etanercept metabolized?
A
proteolysis
20
Q
18) How are humira, infliximab and etanercept excreted?
A
Fragments into bile and urine
21
Q
Infliximab - What is the source and structure?
A
a. 25% mouse, 75% human chimeric IgG1 monoclonal Ab
22
Q
What is the mechanism of action of infliximab
A
Binds to soluble and membrane bound TNF alpha
The antibodies also activate complement mediated cytotoxicity and induce cellular apoptosis.
23
Q
List 10 adverse effects of infliximab, humira and etanercept
A
Infusion reaction
Allergic reaction including anaphylaxis
Increased risk reactivation TB, HepB
Increased risk serious and OIs
Increased risk malignancy-NMSC and lymphoma
Increased risk of new onset or worsening demyelinating disease
Increased risk new onset or worsening CHF
Drug induced ANA+ and lupus
Drug induced vaculitis
Drug induced lupus
paradoxical pso
Cytopenias
Differences:
-increased risk AI hepatitis and hepatoxicity infliximab
-Etanercept high risk injection site reactions, increased risk demyelinating d/o
24
Q
What are absolute contraindications? List 3 for infliximab, humira and etanercept
A
Known hypersensitivity to infliximab or murine proteins
Concurrent administration with anakinra (IL-1 receptor antagonist)
Active infections/Chronic or localized infections—including TB
25
5) What are relative contraindication? List 2 for infliximab, humira and etanercept
Moderate to severe (New York Classification III or IV) congestive heart failure (OK with doses ≤5 mg/kg)
Family history of demyelinating disease (including multiple sclerosis)
26
7) List 5 FDA approved indications for infliximab
Pso
PsA
Chrons
Colitis
Ank Spond
RA
JIA
*Not HS, not Uveitis
27
8) List 10 off-label uses infliximab and etanercept
1, 2. Neutrophilic (PG, Behcets)
3, 4, 5 , 6Granulomatous (sarcoidosis, GA, granulomatous cheilitis, necrobiosis lipoidica diabetocorum),
7, 8Vasculitis ( GCA, GPA),
9,10Autoinflammatory keratinization d/o (HS, PRP),
11 AI-CTD (DM),
12-14. Others: Reactive arthritis, GVDH, multricentric reticulohistiocytosis
SJS/TEN
28
How is infliximab supplied
Lypophilized powder for reconstitution, single use vial, infusion IV
29
10) What is the starting dosing for infliximab? Maintenance?
3-5 mg/kg at 0,2,6,8 weeks then q8
30
20) Mean time to relapse after discontinuation infliximab
12 weeks
31
Source and structure etanercept
Fully human dimeric fusion protein: 2 binding domains of p75 receptor bound to Fc portion of IgG1
Produced in Chinese hamster ovaries
32
MOA etanercept
Binds TNF-alpha and TNF-beta, soluble and transmembrane
33
Name FDA indications etanercept
Pso
PsA
RA
JIA
Ank spond
*Not IBD
34
8) How is it supplied?
Prefilled syringes, autoinjector, lypophilized powder requiring reconstitution
35
Dosing for etanercepts
50 mg SC twice weekly x12 weeks then
50 mg SC weekly
36
19) Mean time to relapse after discontinuation? Etanercept
12 weeks
37
20) List 7 live vaccine:
Mumps
Measles
Rubella
Varicella
Yellow Fever
Intranasal flu
Old shingles (Zostavax)
BCG
Oral polio/typhoid
Rotavirus
38
What enzyme cleaves membrane bound TNF-alpha into its more potent soluble form?
TNF alpha converting enzyme
39
2) What are the two TNF-alpha receptors? Where are they found?
P55-most cells, epidermal cells --> tnf alpha action usually through this
P75- immune cells only
40
Which TNF highest risk injection site rxn
etanercept
41
4) Most likely to induce ANA positivity.
Inflix
42
5) Showed an increased incidence of serious infections when used with anakinra. *
a. Etancercept
43
6) Concomitant use of methotrexate can reduce its clearance by 44%.
Adalimumab
44
10) Mean terminal half-life is 14 day
Ada
45
11) Least likely to have associated tachyphylaxis.
Etanercept
46
12) Most likely to stimulate the development of human anti-human antibodies.
Ada
47
13) Least likely to cause hepatitis
Etanercept
48
15) Most associated with the development of histoplasmosis.
Infliximab
49
16) Least likely to have measurable anti-drug antibodies.
etaner
50
17) Least likely to reactivate tuberculosis.
Etaner
51
18) Mean terminal half-life is 7 days.a.
Infliximab
52
19) Does not fix complement binding both membrane and soluble forms of TNF
a. Certolizumab
53
When giving a live vaccine, should wait 42-70 days, give vaccine, wait another 10-14 days and then restart drug
a. Adalimumab
(half life 2 weeks
54
21) When giving a NON live vaccine, must wait 10-14 days, give vaccine, wait another 10-14 days and then restart
adalimumab
55
22) Binds to lymphotoxin B.
Etanercept
56
23) Results in a PASI75 of 80% at week 10 with over one half of patients achieving a PASI90.
infliximab
57
MOA CERTO, STRUCTURE AND FUNCTION
Certolizumab pegol (CZP) is a recombinant, humanized antibody fragment composed of a Fab’ antibody fragment conjugated with polyethylene glycol (PEG) that acts by neutralizing both membrane-bound and soluble TNF-α.
*DOES NOT FIX COMPLEMENT (DIFFERS FROM others)
58
MOA ALL 4 TNF inhibitors:
Adalimumab:
-Binds soluble TNF-alpha, "prevents interaction with p55/-75 TNF transmembrane receptor"
-fixes complement and it can lyse cells that express TNF-α on their surface
*unclear re: membrane bound tnf alpha"
Infliximab:
- Solublizes soluble TNF alpha and blocks membrane bound TNF-alpha,
-fixes complement and can lyse cells that express TNF-α on their surface
Etanercept:
-Binds soluble AND transmembrane TNF-alpha + also binds TNF-beta.
Certolizumab:
- binds both membrane-bound and soluble TNF-α.
-does NOT fix complement bc it does NOT contain Fc
59
most associated AI hepatitis
infliximab
60
25) Given subcutaneously at 80 mg followed by 40 mg one week later and then 40 mg every two weeks thereafter.
ada
61
x26) Contraindicated in patients with a hypersensitivity to murine proteins
inflicting
62
27) Full human monoclonal antibody that can fix complement and inhibits binding to transmembrane TNF-alpha
ada
63
28) Binds both membrane-bound and soluble forms of TNF-alpha and binds complement
influx and ADA
64
31) Produced in Chinese hamster ovary cells.
Etan
65
32) Associated with human anti-chimeric antibodies.
Inflixi
66
33) Second most-likely to cause histoplasmosis.
Ada
67
35) Uses limited use code 417 under the Trillium benefits Program in Ontario
Ada
68
36) Uses LU code 418
Etan
69
37) Uses LU code 471
Infliximab
70
38) Least associated with acute liver failure
Etan
71
39) Gives a PASI75 of 49% at 12 weeks and 59% at 24 weeks
Etanercept
72
1) What is the source and structure of ustekinumab
a. Fully human IgG1 monoclonal antibody against the P40 subunit shared between IL-12/23
73
MOA ustekinumab
Binds to common P40 subunit of IL-12/23, prevents interaction with receptor IL-12RB1, prevents differentiation of T-helper cells into Th1 and Th17.
74
3) List 6 adverse effects ustekinumab
a. Increased risk infections-MC nasopharyngitis, pneumonia
b. TB reactivation
c. Injection site reactions
d. Hypersensitivity-e.g. anaphylaxis, angioedema, skin rashes
e. Reversible posterior leukoenceophalopathy-rare
f. Worsening psoriasis
g. Headache
nasopharyngitis
*no malignancy risk
75
4) What are absolute contraindications to ustekinumab
known hypersensitivity
uncontrolled infection
76
pregnancy category ustekinumab
b
77
FDA indications stelara
pso 6 yrs
psa 6 yrs
IBD
78
7) How is it supplied? uste
prefilled syringe
single use vial
79
What is dosing for Stelara for pso for <100 kg, >100 kg,
< 100 kg: 45 mg SC 0, week 4 then q12
>100 kg: 90 sC 0, week 4 then q12
80
10) What baseline blood work would you order before starting?
a. CBC, liver, kidney, TBST, HepB/C
81
PASI75 ustekinumab at 12 weeks
a. 66% at 12 weeks in phoenix trials phase 3
82
12) What are 4 Risk factors for poor response when using Stelera?
a. Psoriatic arthritis
b. Long history psoriasis
c. Obese
d. Resistance to other biologics
83
13) How quickly does it work? Onset of response?
2 weeks onset, max at 6 mo
84
14) What is the bioavailability stelara
~60%
85
half life stelara
3 weeks
86
how is stelara metabolized or exerted
unknown
87
20) What is the size of the common sub-unit shared by IL-12 and IL-23 that is targeted by ustekinumab?
40
88
22) What cytokine inhibited by ustekinumab is critical for expanding the TH17 cell population?
23
89
23) From the PHOENIX2 trial data, how would you dose escalate a 130 kg patient who has only a partial response at 90 mg at week 48?
a. Increase to 90 mg q8weeks
90
24) What serious adverse event caused the early termination of phase 3 studies for the IL-12/23 inhibitor Briakinumab and has had a questionable signal with early studies of Ustekinumab?
MACE
91
25) What were the two most common adverse effects of ustekinumab in the Phase 3 studies?
HA
nasopharyngitis
92
26) What condition had been reported in one patient after 12 doses of ustekinumab where the patient presented with headache, seizure and confusion in the setting of alcohol abuse and recovered with no residual CT-scan changes after 1 week and hence made it into the product monograph?
a. Reversible posterior leukoencephalopathy
93
27) What is the age above which ustekinumab is approved for the treatment of psoriasis in Canada?
6 and above is approved
94
28) What is the dosing and frequency of ustekinumab for a patient that weighs 120 kg?
90 0, 4 weeks, 12 weeks
95
29) What is the dosing for a 15 year old weighing 38 kg? Stelara
0.75 mg/kg 0, 4 , q12
0,75 mg/kg 28.5 mg 0, 4, q12weeks
96
1) What is the source and structure cosentyx
a. Fully human IgG1k monoclonal Ab
97
2) What is the mechanism of action cosentyx
a. Binds and neutralizes IL-7A
98
3) List 10 adverse effects cosentyx
injection site rxn
hypersensitivity rxn
increased risk infections
TB reactivation
headache
GI upset
nasopharyngitis*
rhinitis*
worsening or new onset IBD*
neutropenia*
MACE events*
99
4) What are absolute contraindications to cosentyx? List 3
a. Known hypersensitivity (including latex)--> this is really the only one
b. Active or serious infection e.g. Tb
c. IBD
100
Pregnancy category cosentyx
b
101
7) List the FDA approved indications for cosentyx
PsO (6 yrs), PsA (2 yrs),
Ank spond, non radiographic AS, enthesitis arthritis
102
8) How is it supplied? cosentyc
pre filled pen or refilled syringe
103
Dosing for secukinumab
300 mg SC weekly x4 then q4 weeks
104
12) What is the PASI-75 at 12 weeks? secu
PASI 90?
84%
55% PASI90
105
How quickly secukinumab works
3 weeks
106
bioavailability secu
55-75
107
16) After how long are peak levels achieved? secu
5-6 days
108
1/2 life secukinumab
27 days
109
Source and structure ixekizumab
a. Humanized IgG4 monoclonal antibody
110
MOA ixe
binds and neutralizes il 17A
111
List 9 AE to ixe
a. URTI: Nasopharyngitis, rhinitis, pharyngitis,
b. Headache
c. GI upset-diarrhea
d. Candida
e. HSV
f. Tinea
g. Injection site reaction
h. Hypersensitivity reaction-urticaria, anaphylaxis
i. New or worsening IBD
j. Neutropenia
k. TB reactivation
No mace?
112
Metabolism 17s?
drugs are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
113
Indication for broadlumab
adult Pso
114
Aboluste contraindication to 17s? Relative?
Absolute: hypersensitivity
Relative:
a. IBD=personal or stron fam hx
b. Pregnancy
c. Breastfeeding
d. Receiving live vaccines
e. Chronic or recurrent infections
f. Active or latent TB
115
Pregnancy category secu
B
116
FDA indications ixekizumab
Pso (6 yrs +)
PsA
AS
Radio negative spondylitis
117
How is ixe supplied
pre filled syringe or autoinjetor
118
Dosing for ixe
160 mg at week 0,
80 mg at week 2, 4, 6, 8, 10, 12 then q4
119
12) What is the PASI-75 at 12 weeks? ixe
PASI 90? PASI 100
90%
70%
35% 100
120
Bioavailability ixe
60-80%
121
Ixe how long till peak levels
5 days
122
Half life ixe
13 days
123
source structure broda
a. Fully human IgG2
124
2) What is the mechanism of action broad
Bind to IL-17RA --> prevents binding of IL-17 A/F, E, C
125
Dosing broda
210 mg SC at 0, 1, 2 weeks then 210 q2 weeks
126
5) PASI 75 and 90 at 12 weeks Broda
86% and 70%
127
6) Name 2 drugs whose levels or effects would need to be monitored with blood tests in patients while being treated with IL-17 inhibitors according to the label?
a. Warfarin and cyclosporin although I checked all 3 product monographs for 22 and no monitoring is recommended currently?
128
7) What are eight possible adverse reactions that are common to interleukin 17 inhibitors?
nasopharyngitis
rhinitis
h/a
gi upset
injection site rxn
allergic rxn
infections-viral urti, tinea, Hsv
candida
ibd
neutropenia
tb reactivation theoretical
129
8) What are 8 relative contraindications to IL-17 inhibitors?
receiving live vaccines
immunocomp/predisposed to infections
active or latent tb
active or serious infections
pregnant
breasfeeding
ibd- personal
ibd- fam hx strong
Depression-broda only
130
9) Which IL-17 inhibitor is more likely to have neutralizing anti-drug antibodies at 1 year?
a. Ixekizumab
secukinumab 50% neutralizing but only 1% overall,
ixe 22% developed Ab’s with 9% being neutralizing= 2% neutralizing)
131
GUSELKUMAB 1) What is the source? What is the structure?
a. Human IgG1lamba
132
2) What is the MOA guselkumab
a. Binds to and neutralizes P19 subunit of IL-23
133
3) What is the half life guselkumab
Brodalumab
17 days for Guselkumab
11 Days broadlumab
134
4) List 7 adverse effects guselkumab
a. Hypersensitivity
b. Injection site reaction
c. TB reacrtivation
d. Infections
i. Viral URTI* most common
ii. Candida
iii. HSV/VZV
iv. Tinea
v. Gastroenteritis
e. H/A/migraine
f. Diarrhea
g. Arthralgias
135
5) What are some drug interactions? with guselkumab
Live vaccines
CYP 450 substrates - e.g. metoprolol
Tremfya
other immune suppressants
136
6) List 3 contraindications: guselkumab
hypersensitivity
active serious infection e.g. TB
Live vaccines
137
7) What is the FDA approved indication? guselkumab
adult pso and spa
138
How is tremfua supplied
profiled syringe or auto injector
139
Dosing guselkumab
100 mg SC 0, week 4, then q 8 weeks
140
11) What is the PASI 75, 90 and 100 at week 16? guselkumab
87%,, 70%, 35%
141
PASI 90 guslekumab at week 24
77%
142
1) What is the source and structure dupilumab
fully human IgG4
143
2) What is the MOA of Dupilumab?
Bind to IL-4R alpha subunit on IL-4 and 13 receptors (blocks recptor), blocks 4/13 signallong
144
3) What is the bioavailability of Dupilumab?
66%
145
4) List 7 side effects of Dupilumab:
Dry eye
Ulcers-HSV
Peripheral Eos
Injection site rxn-MC
Like reaction-serum sickness
U-?
MF worsening
Alopecia areata
Blepharitis, keratitis
146
List 2 contraindications dupilumab
Hypersensitivity
Pregnant/BF
Pre-existing eye diseases
Parasitic infections
147
How is dupixent supplied
profiled syringes
148
Dosing for dupixent for adults
Adults:
600 mg SC day 0, 300 q 2weeks
149
Dosing dupixent 6-18
>60 same as adults
30-60 kg: 400 SC then 200 q2 weeks
15-30 kg: 600 SC then 300 q 4 weeks
150
Dosing dupixent 6 mo-5 yrs
15-30 kg: NO LOAD, 300 q 4 weeks
5-15 kg: NO LOAD< 200 q 4 weeks
151
8) What baseline blood work would you do for dupixent
none required,
152
9) List the name of 3 studies where Dupilumab was tested:
SOLO1, SOLO2, chronos (+ steroids)
153
10) What was the EASI 75 and 90 in the SOLO 1, 2 and Chronos?
a. SOLO1: EASI75- 51% EASI90- 35%
b. SOLO2: EASI75- 44% EASI90- 30%
c. CHRONOS: EASI75-69% EASI90- 40%
154
11) What are components of the EASI? Max sore?
Body surface area
erythema
lichenification
excoriation
edema/papules
Max score 72
155
12) What are components of the PASI? Max score?
a. Max score 72
b. BSA + erythema, induration/thickness, scale
156
Compare and contrast time of onset:
Etanercept 6.3 weeks
Ustekinumab 4 weeks (just over)
Guselkumab 4 weeks
Adalimumab and infliximab 4 weeks (just under)
Secukinumnab 3
Ixe and broda 2
157
Drug interactions tnfs
Etan: Abatacept, Anakinra, ?cyclophosphamide
In: Abatacept, Anakinra, CYP450 substrates
ada: Abatacept, Anakinra, CYP450 substrates, MTX
158
Certoloziumab structure
Recombinant humianized antibody Fab fragment conjugated to polyethyelen glycol
159
eta percept Peds dosing
"25-50mg SC twice weekly x 12 wks
Rotate injection sites ≥1 inch apart
Peds dosage (recent RCT > 6y/o) = 0.8mg/kg/dose SC
Approved over the age of 4 "
160
Skyrizi indications
Adult Pso
Adult PsA
Chrons -new!
161
Tildrakizumab indications
Adults with Pso
162
How many and which biologics can treat kids with psoriasis and psA
Adalimumab 4+ -> JIA, not psoriasis.
Etanercept 4+ PsO and poly JIA
Ustekinumab 6+ PsO and PsA
Cosentyx 2+ PsA, 4+ ERA, 6+ PsO
Ixekizumab Pso only 6+
163
Which biologics can be used for PsA in adults
All TNFs
Ustekinumab
Guselkumab
Rizankizumab
Secukinumab
Ixekizumab
(basically not Tildra, not Broda)
