Pharmacology Flashcards
(203 cards)
1
Q
Anthracyclines MOA -4
A
nonspecific: Inhibits topoisomerase II.
prevents the religation of DNA during DNA replication causing DNA strand breaks.
Intercalations between base pairs in the DNA -> more breaks.
Form oxygen free radicals->inc cytotoxicity. (except mitoxantrone, so less cardiomyopathy)
2
Q
Anthracylines DLTs -2
A
myelosuppression (primarily leukopenia),
chronic cardiomyopathies
3
Q
Anthracylines ADRs -4
A
Dose dependent nausea and vomiting,
alopecia,
radiation recall,
turns urine red (except mitoxantrone turns urine blue)
4
Q
Anthracylines DAs -4
A
Hepatic.
50% dec if bili 1.2-3.0
75% dec if bili > 3.0
generally omitted if bilirubin > 5.0 mg/dL.
5
Q
Anthracylines administration issues. How do you manage? -3
A
potent vesicants.
Apply cold ice pack and evaluate for antidote use
(99% DMSO 1-2 ml applied to site every 6 hours for 7-14 days) or Totect®.
6
Q
Etoposide MOA -4
A
G2 specific:
Forms a complex with topoisomerase II
- > inhibits enzyme
- > single stranded DNA breaks
7
Q
Etoposide DLTs -1
A
myelosuppression- primarily leukopenia
8
Q
Etoposide ADRs -2
A
nausea and vomiting (with oral dosing),
alopecia
9
Q
Etoposide Administration Issues -3
A
IV infusion should be infused over 30-60 minutes to avoid hypotension.
Oral dose is 2x greater than the IV.
conc <0.4mg/ml (stability)
10
Q
Camptothecins MOA -4
A
synthesis cycle specific:
Inhibit topo I
- > “cleavable complexes” stabilized
- > reversible single stranded DNA breaks
11
Q
Camptothecins DLTs -topo -2 irino -1
A
leukopenia and thrombocytopenia (topotecan);
diarrhea (irinotecan)
12
Q
Camptothecins ADRs -4
A
neutropenia,
nausea, vomiting, diarrhea
alopecia,
increased liver enzymes
13
Q
Irinotecan Diarrhea Concepts -4
A
SN-38 active metabolite broken down by UGT1a1.
Both early and late.
Treat early with anticholinergics (atropine) (cholinergic syndrome resulting from the inhibition of acetylcholinesterase activity by irinotecan).
Treat late with loperamide.
14
Q
Vinca Alkaloids MOA -3
A
M phase specific:
Bind to Tubulin,
inhibits polymerization and thus Microtubule formation.
15
Q
Vinca Alkaloids DLTs -4
A
leukopenia and thrombocytopenia (vinblastine and vinorelbine),
neurologic toxicity,
constipation,
paralytic ileus (vincristine)
16
Q
Vinca Alkaloids ADRs
A
Neurologic toxicity,
constipation,
abdominal cramps (much less than vincristine)
vincristine ONLY -rare bone marrow suppression and SIADH
17
Q
Vinca Alkaloids DAs -4
A
Hepatic.
50% dec if bili 1.5-3.0
75% dec if bili > 3.0
generally omitted if bilirubin > 5.0 mg/dL.
18
Q
Vinca Alkaloids administration issues. How do you manage? -2
A
potent vesicants
#apply warm pack and administer hyaluronidase
19
Q
M phase specific (3pts)
A
drugs that work in mitosis (vincas, taxanes, ixabepilone)
20
Q
S phase specific (2pts)
A
DNA synthesis (antimetabolites and tecan’s)
21
Q
G2 phase specific (2pts)
A
after mitosis, before synthesis (bleomycin, etoposide)
22
Q
G1 phase specific (2pts)
A
after synthesis, before mitosis (steroids, asparaginase)
23
Q
nonspecific cell cycle agents
A
cell kill proportional to dose (kill both nml and malignant cells to the same extent)
everything else (alkylating agents, anthracyclines, antitumor antibiotics, nitrosureas, misc)
24
Q
cell phase/cycle specific agents -2
A
preferentially kill proliferating cells
admin as “continuous infusion”
25
targeted therapy agents -3
effect on specific "tumor cells"
prevent from entering cell cycle
target signals that trigger cell growth, metastasis, and immortality
26
alkylating agent DLT -1
myelosuppression (usually neutropenia)
27
mechlorethamine administration issues -2
potent vesicant.
extravasation= 4mL 10% sodium thiosulfate + 6mL sterile water for injection inject SQ around site
28
what is the cyclophos ADR that you always forget?
SIADH
29
bendamustine renal dosing
DO NOT USE if CrCl <40
30
thiotepa and excretion in sweat -3
for high dose BMT doses:
bath 3-4 times daily
no tight clothes, to prevent skin breakdown
31
dacarbazine unique ADRs -3
inc LFTs
flu-like sx
injection site pain
32
platinum MOA
form a reactive electrophile that covalently binds to DNA (alkylating-like)
33
crcl calculation
((140-age) x wt in kg) / (SCr x 72) (x0.85 for females)
34
cisplatin DLT -1
N/V (acute and delayed)
35
carboplatin DLT -1
myelosuppression (thrombocytopenia)
36
platinum ADR -6
nephrotox,
hypomag,
hypoK,
ototox,
peripheral neuropathies,
myelosuppression
carbo=less of all but myelos
oxal=minimal nephrot, otot
37
oxaliplatin and peripheral neuropathy -3
cummulative..."stop and go"
acute= 1st 2 days, resolves within 14d, primarily peripheral sx, often exacerbated by cold
persistent= >14d, daily activities effected (writing, buttoning, swallowing), sx may improve on drug d/c
38
taxane MOA -3
M phase specific:
Bind to micotubules, Stabilizes polymerization, prevents Microtubule to Tubulin breakdown;
(niche for cabazitaxel is poor affinity for p-gp->?less drug resistance, activity in D resistant cells)
39
taxane DLT -1
leukopenia
40
taxane ADR -6
WHAT IS INF RX DIFFERENCE?
hypersensitivity rxn (P, premed (rare for D)),
allopecia,
cardiac tox (P),
PN,
mucositis (P),
peripheral edema (D, pre and post med)
41
taxane administration issues -4
administer prior to platinums to reduce myelosuppression
#P cremophor hypersensitivity rxn- premed dex 20, diphen 50, ranit 50 iv
#D - fluid retention/peripheral edema - pre and post med - dex 8bid 1 day prior 2 days post
#C - diphen 25, dex 8, ranit 50
42
nab-albumin paclitaxel administration issues -1
does not contain cremophor->less hypersensitivity reactions
43
taxane DAs -3
#hepatic
#D: bili >ULN, AST or ALT >1.5 ULN, AlkP >2.5 ULN -do NOT give
#P: AST/ALT 10xULN, bili >5 ULN do NOT use
44
epothilones (ie. ixabepilone) MOA -3
M phase specific.
similar to taxanes but distinct microtubule binding. activity in paclitaxel-resistant cell lines.
poor p-gp substrates->?overcome resistance
45
epothilones (ie. ixabepilone) DLT -2
leukopenia
PN
46
epothilones (ie. ixabepilone) ADR -6
anemia,
thrombocytop,
diarrhea,
fatigue,
myalgia,
alopecia
47
epothilones (ie. ixabepilone) admin issues -1
premed with diphen 50, ranit iv 50 (or cimet iv 300)
| no steroid needed
48
miscellaneous tubulin agent (ie eribulin) MOA -2
marine macrolide halichondrin B, synthetic,
inhibits tubulin polymerization
49
miscellaneous tubulin agent (ie eribulin) ADR -2
neutropenia,
neuropathy (less than vincristine)
50
miscellaneous tubulin agent (ie eribulin) DA -2
both renal and hepatic dose adjustments
51
antimetabolite general MOA (4pts)
S phase specific:
inhibit cell growth and proliferation
#1 compete for binding sites on enzymes
#2 incorporate directly into DNA or RNA
52
folate antagonist (methotrexate and pemetrexed) MOA -3
S phase specific:
inh conversion of FA to tetrahydrofolate by inh enzyme dihydrofolate reductase
-> blocks thymidylate and purine synthesis which inhibits DNA synthesis
53
folate antagonist (methotrexate and pemetrexed) DLT -2
leukopenia
thrombocytopenia
54
folate antagonist (methotrexate and pemetrexed) ADR -5
renal tubular necrosis (high doses),
pulmonary pneumonitis,
alopecia,
stomatitis, mucositis
#watch third spacing
55
leucovorin rescue -4
initiate with 42 hours
MOA: reduced folate, enters cell by passive diffusion thus high doses needed
po bioavailability good <35mg, above that ranges 5-50%
t 1/2=3hr
56
pemetrexed premeds -3
folic acid and vitamin b12
reduce myelosuppression
57
methotrexate DDI (3pts)
#1 highly protein bound drugs may displace MTX from albumin and inc tox (ie. sulfonamides, salicylates, phenytoin, tetracycline)
#2 NSAIDS compete for renal excretion
#3 vitamin c acidifies urine
58
purine analogue thioguanine (6-TG) and mercaptopurine (6-MP) MOA -2
S cycle specific.
structural analogues of guanine that are incorporated into DNA.
59
thioguanine (6-TG) and mercaptopurine (6-MP) DLT -2
leukopenia and thrombocytopenia
60
thioguanine (6-TG) and mercaptopurine (6-MP) ADRs -4
liver tox and jaundice (much higher with 6-MP),
stomatitis, mucositis,
rash,
N/V
61
mercaptopurine (6-MP) DDI -2
metabolized by xanthine oxidase.
75% dose reduction with allopurinol.
62
other purine analogues names (3pts) and ADR
cladribine, fludarabine, pentostatin
unique myelosuppression of t-helper cells->often requires abx px
63
pyrimidine analogues names (2pts) and MOA -4
S cycle specific.
cytarabine and gemcitabine.
structural analogues of nucleosides cytidine and deoxycytidine.
inhibit DNA polymerase.
64
pyrimidine analogues DLT -2
leukopenia and thrombocytopenia
65
pyrimidine analogues ADR -9
N/V,
mucositis,
diarrhea,
flu-like sx,
rash,
TLS (often give with allopurinol)
#for high dose araC: excess BM depression, CNS tox, conjunctivitis (steroid eye gtts)
66
"false" pyrimidine analogues names (2pts) and MOA -5
S cycle specific.
5-FU and capecitabine.
#1inhibit formation of base thymidine by inhibiting enzyme thymidylate synthase (rate limiting step).
#2 5-FU metabolites may incorporate into RNA inhibiting its synthesis.
#3 last conversion step of cape->5-FU utilizes thymidine phosphorylase which is higher in tumor cells than nml cells thus limiting systemic exposure
67
"false" pyrimidine analogues DLT -5
5-FU: leukopenia and thrombocytopenia.
anemia (bolus inf),
HFS and diarrhea (continuous inf)
cape: HFS,
diarrhea
68
"false" pyrimidine analogues ADR -7 (3+4)
5-FU: skin discoloration,
nail changes,
photosensitivity,
neurologic tox
cape: N/V,
fatigue,
rash
69
hypomethylating pyrimidine analogues names (2pts) and MOA. -5
S cycle specific.
azacytidine and decitabine.
direct incorporation into DNA, inhibit DNA methyltransferase.
hypomethylation of DNA->cell differentiation and apoptosis.
ALSO covalent bonds of drug-DNA methyltrasferase
70
hypomethylating pyrimidine analogues DLT -1
myelosuppression
71
hypomethylating pyrimidine analogues ADR -2
mild GI tox
infx's
72
bleomycin MOA -2
binds to DNA producing single and double stranded DNA breaks through the generation of free radicals
indx: testicular, hodgkins, NHL
73
bleomycin DLT -1
fatal lung disease
MAX DOSE is 400 units!!
74
bleomycin ADR
hyperpigmentation,
rashes,
fever,
rare allergic rxns
75
omacetaxine MOA -3
inhibits protein translation preventing the initial elongation step of protein synthesis.
protein synthesis and tumor growth inhibited independent of BCR-ABL binding (can use in T315I mutation)
indx: resistant CML
76
omacetaxine ADR -10
thrombocytopenia,
inc risk of hemorrhage,
anemia, neutropenia, lymphop
diarrhea, N,
fatigue,
```
asthenia,
inj site rxn,
pyrexia,
infx,
hyperglycemia
```
77
antiestrogens - tamoxifen MOA -2
#inhibits nuclear binding of estrogen to estrogen receptor.
#tamoxifen-R complex translocates to the nucleus->inh DNA synthesis.
78
antiestrogens - tamoxifen ADR -8
#menopausal sx (hot flashes, N/V),
vaginal bleeding,
bone pain,
menstrual irregularities,
HA,
depression.
#RARE: retinal tox, thromboembolic events
#endometrial CA risk 3x normal
79
antiestrogens - nonspecific aromatase inhibitor name (1pt) and MOA -4
aminoglutethimide:
"medical adrenalectomy",
inhibits cholesterol->pregnenolone conversion.
inhibits production of estradiol BUT ALSO glucocorticoids, mineralcorticoids, and androgens
80
antiestrogens - nonspecific aromatase inhibitor ADRs -5
N/V,
leukopenia, thrombocytop
#neuro - lethargy, nystagmus, dizziness
#derm - allergic rash with fever,malaise (responds to dose red)
#endo - facial swelling, hyponatremia (replace adrenal and mineralo-corticoids= hydrocort 20 bid, fludrocort 0.1 qod)
81
antiestrogens - nonsteroidal aromatase inhibitor name (3pts) and MOA -3
anastrazole, letrazole, and exemstane
selective inhibition that block both testosterone-> estradiol AND androstenedione->estrone conversion.
DO NOT BLOCK gluco-,mineralo-corticoids or androgen formation
82
antiestrogens - nonsteroidal aromatase inhibitor ADR -5
GI disturbances,
hot flashes,
thromboembolic events,
wt gain,
edema
83
luteinizing hormone-releasing hormone analogs (2pts) names and MOA -8
goserelin and leuprolide
competitive binding to hypothalamus receptor
- >initial surge in FSH and LH
- >stimulate adrenal gland, testes, ovaries
- > surge in E and T production which stimulate down regulation of receptor via negative feedback loop
- > decrease in further LH
- > decrease in androgen AND estrogen production.
T reduced ~75% by day 14, then ~100% by day 28
84
luteinizing hormone-releasing hormone analogs and antagonists=GnRH antagonist ADR (7pts)
```
hot flashes,
impotence,
reduced libido,
GI disturbances (N/V/ constipation),
injection site pain,
gynecomastia,
peripheral edema
#tumor flare: from initial T increase->bone pain (treat with antiandrogens prior to Tx OR use degarelix)
```
85
luteinizing hormone-releasing hormone antagonists = gonadotropin releasing hormone antagonist (1pt) names and MOA. -6
Degarelix
blocks GnRH receptors in anterior pituitary
- > decrease FSH and LH release
- >decrease in androgen and estrogen production
#NO tumor flare.
T reduced ~90% in 24hours
86
antiandrogens name (3pts) and MOA and use -3
flutamide 250tid, bicalutamide 50qd, nilutamide 300qd x1mo,150qd
nonsteroidal, competitively Inh binding of androgens (T) to peripheral R,
use in combo with LHRH analogs
87
antiandrogen ADR (7pts)
gynecomastia,
hot flashes,
inc LFTs,
N/V,
diarrhea,
visual disturbances
88
abiaterone MOA -4
selective, irreversible Inh of CYP17.
blocks pregnenolone and progesterone
-> androgens DHEA and androstenedione (these are further converted to T and DHT downstream.
DO NOT significantly affect hydrocortisone levels
89
abiaterone administration -3
250mgx4 daily = 1000mg WITH pred 5bid
1hr before or 2hr after meals
90
abiaterone DA'S -2
child-pugh class B= reduce to 250qd
if hepatoxic develops, ALT/AST >5x ULN or billi >3x HOLD and reduce dose
91
abiaterone ADR -15
Know serious adr
```
joint swelling of discomfort,
hypoK,
edema,
muscle discomfort,
hot flush,
diarrhea,
UTI,
cough,
htn,
arrythmia,
urinary frequency,
nocturia,
dyspepsia,
URI
SERIOUS: CHF, arrhythmias, liver tox, adrenal insuff
```
92
abiaterone DDI
CYP2D6 Inh
CYP3A4 substrate
93
misc hormonal agents - enzalutamide MOA -3
Inh nuclear translocation of the androgen R, DNA binding, and coactivator recruitment.
greater affinity for receptor.
No known agonistic effects.
94
misc hormonal agents - enzalutamide ADR -13
```
asthenia,
diarrhea,
arthralgia,
muscle pain,
hot flashes,
peripheral edema,
infx,
HA,
dizziness,
spinal cord compression,
hematuria,
htn
RARE: seizure
```
95
misc hormonal agents - enzalutamide DDI -2
CYP3A4, 2C9, 2C19 inducer (warfarin)
CYP3A4, 2C8 substrate
96
misc hormonal agents - estramustine MOA
thought was alkylating agent linked to estradiol BUT seems to work via Inh of microtubule assembly and disassembly.
give 1hr before or 2hr after food
97
misc hormonal agents - estramustine ADR (6pts)
```
N/V,
edema,
CV tox,
thromboembolic events,
gynecomastia
```
98
monoclonal Ab MOA (4pts)
antibody dependent cellular cytotoxicity (ADCC)
CDCC - complement dependent
??
99
- zumab
- ximab
- umab
- momab
```
zumab= humanized
ximab= chimeric
umab= human
momab= murine
```
100
alemtuzumab MOA and indx -3
#CD52 on malignant lymphocytes (binding induces cell lysis)
```
#CD52 also on nml lymphocytes, monocytes, NK cells, some
granulocytes, some nml bone marrow cells
```
#CLL
101
alemtuzumab administration -3
#3mg, then 10mg, then 30mg as tolerated
#premed diphen 50, APAP 650, add hydrocort 200 for previous severe inf events
#PJP and HSV px to continue until minimum of 2 months after last dose OR until CD4 >200
102
alemtuzumab ADR -3
serious, prolonged, sometimes fatal heme tox (avg neutropenia duration 28d, thrombocyto 21d),
infusion related rigors,
hypotension
103
brentuximab vedotin MOA -2 and indx -3
#CD30 antibody linked to monomethylauristatin (MMAE) which Inh microtubule polymerization
#may induce apoptosis by Inh NF-KB activation
#decrease T-cell regulatory activity
#HL post autoHSCT, HL not autoHSCT candidates after >2 multiagent chemo regimens, anaplastic large cell and >1 regimen
104
brentuximab vedotin ADR. -15
```
neutrop,
PN,
fatigue,
N,
anemia,
URI,
diarrhea,
pyrexia,
rash,
thrombocytop,
cough,
V
```
SERIOUS: progressive multifocal leukoencephalopathy (PML), TLS, steven's johnson
105
brentuximab vedotin dose and administration issues -2
1.8mg/kg q3wk up to 16c
premed for infusion rxns
106
rituximab MOA. -3
#CD20 binding and apoptosis
#ADCC
#CDCC: activity correlated with amount of CD20 present
107
rituximab ADR -5
```
infusion rxns (fever, chills/rigors, hypot, N) (premed),
TLS,
mucocutaneous rxns,
hepatitis B reactivation,
PML
```
108
ofatumumab MOA -3 and indx -1
#ADCC
#CDCC: correlates to amount of CD20 present
#may target different epitope than ritux, slower off time
#refractory CLL
109
ofatumumab dose and administration issues -4
#300mg D1, 2000mg D8 weekly x7, then 4 wks later 2000mg q4wk x4 doses
#premed: APAP 1000mg, ranit iv 50 (cetirizine 10), methylpred iv 100mg
#may reduce steroid if tolerated
#start slow and titrate
110
ofatumumab ADR -6
```
infusion rxns (fever, chills/rigors, hypoT, N),
neutrop,
thrombocytop,
bacterial or fungal infx,
hepatitis b reactivation,
PML
```
111
ibritumomab tiuxetan MOA -3 indx -1
CD20.
chelate tiuxetan binds to In-111 and Y-90.
beta emission from Y-90 induces cellular damage by formation of free radicals.
CLL
112
ibritumomab tiuxetan dosing and DA -4
step 1- ritux 250
step 2- 7-9d later, 2nd ritux 250 prior to 0.4mCi/kg Y-90 irbitumomab
REDUCE to 0.3 if plt 100-149k
HOLD if plt <100k
113
ibritumomab tiuxetan ADR -2
thrombocytop (61%),
| neutrop
114
tositumomab MOA -4 indx -1
CD20 antibody LINKED to I-131
gamma XRT->imaging purposes
beta XRT->cytotoxic
#ritux refractory FL
#only one dose due to murine origin
115
tositumomab ADR -4
hypersensitivity rxn (anaphylaxis),
prolonged and severe neutrop and thrombocytop (nadir 4-7wks, 30d duration),
preg category X (I-131 can damage fetal thyroid tissue),
secondary malignancies (8%)(MDS, AML)
116
tositumomab administration issues -2
#premed APAP, diphen
thyro-protective regimen at least one day prior to tx
117
ipilimumab MOA -3
CTL4, a negative regulator of T cell function
-> Inc T-cell stimulation and antitumor reaction
#may also antagonize CTLA-4 on regulatory T cells to limit their ability to suppress the antitumor T cell effector response
118
ipilimumab dose -1
3mg/kg over 90 min q3wk x4
119
ipilimumab ADR -3
skin, liver, GI, pituitary (endocrinopathy) GVHD,
neuropathy
most during tx, but also weeks to months after
120
trastuzumab MOA
binds to Her-2/neu oncogene (25% of breast CA)
-> antibody dependent cellular cytotoxicity (ADCC)
IHC 2-3, FISH (+)
121
trastuzumab dose - 1
qwk schedule: 4mg/kg week 1, then 2mg/kg q3wk schedule: ??
122
trastuzumab ADR -5
CHF,
infusion related sx
Others: rash,
myelosuppression,
GI tox (diarrhea)
123
pertuzumab MOA. -3
#Her-2 receptor on extracellular domain blocking ligand dependent HER2, HER3 ligand dimerization.
#Synergistic with trastuzumab.
#ADCC
124
pertuzumab dosing -1
```
840mg load then 420mg q3w
flat dosing (not wt or BSA-based)
```
125
pertuzumab ADR (10pts)
```
diarrhea,
N,
alopecia,
rash,
neutrop,
fatigue,
PN,
embryo-fetal tox,
LV dysfunction,
infusion related rxn
```
126
cetuximab MOA -4
#cell surface epidermal growth factor receptor (EGFR-1) preventing EGF and TGF-alpha binding and signal transduction.
Blocks PI3K-Akt-mTOR and STAT 3/5 (survival) and Ras-Raf-MEK-MAPk (proliferation) pathways.
#kras wt (b/c Ras signal is downstream of egfr receptor)
#IgG1
127
cetuximab dose -1
400mgm2 load then weekly 250
128
cetuximab ADR (9pts)
```
infusion related rxns required dose mods,
skin rash,
asthenia/malaise,
diarrhea,
N/V,
interstitial lung dz,
hypoMg
```
129
panitumumab MOA -2
EGFR-1 (same as cetux)
IgG2
130
panitumumab dose -1
6mg/kg q2wk
131
panitumumab ADR (4pts)
skin rash,
infusion related rxns,
interstitial lung dz,
hypoMg
132
bevacizumab MOA -4
#binds to VEGF ligand-> prevents binding to receptor.
#antiangiogenesis
#may inc levels of chemo delivered to tumor
#colon, breast, NSCLC, brain, renal cell
133
bevacizumab dose and administration issues -2
#usually 5mg/kg q2wk
#because of long half-life separate from surgery by 4-6wks
134
bevacizumab DLT (3pts)
HTN,
bleeding episodes,
thrombotic events (MI, PE, DVT)
135
bevacizumab ADR -3
rare perforation of bowel,
proteinuria
Wound healing
136
VEGF diagram
SEE PG 776
137
erlotinib and gefitinib MOA -3
#EGFR-TKI (blocks intracellular phosphorylation)
#dec growth, invasion, metastasis, angiogenesis, and resistance to apoptosis
#mutations in TK domain may predict response to be worse
138
erlotinib and gefitinib indications
#E 1st or 2nd line NSCLC, panc, maintenance NSCLC
#G 3rd line NSCLC
139
erlotinib and gefitinib ADR -6
```
diarrhea,
rash (MAY BE IMPORTANT),
acne,
dry skin,
N/V
#RARE but serious: interstitial lung dz (1%, but 33% fatal in these cases)
```
140
erlotinib and gefitinib DDI -2
CYP3A4 substrate
increased INR with warfarin
141
lapatinib MOA and dose -3
TKI of both EGFR and Her-2
#MBC in combo with cape
#1250mg (5 tabs) daily
142
lapatinib ADR (5pts)
diarrhea (common),
dec LVEF,
QT prolongation,
rash,
HFS
143
lapatinib DDI -2
CYP3A4 and 2C8 inhibitor
144
lapatinib DA -1
hepatic
145
imatinib, dasatinib, nilotinib, bosutinib, ponatinib MOA -5
#Bcr-Abl TKI -> apoptosis of Bcr-Abl (+) cells
#binding capacities vary
#D inh SRC, c-KIT, PDGFR
#B inhibits SRC kinases
#P effective in T315I mutation, also inhibits VEGFR, PDGFR, SRC, c-KIT, and FLT3
146
imatinib, dasatinib, nilotinib, bosutinib, ponatinib drug resistance -2
#1 Bcr-Abl point mutation ->dec binding (dependent resistance)
#2 alternate lesion than Bcr-Abl (independent resistance)
147
imatinib, dasatinib, nilotinib, bosutinib, ponatinib DLT -1
myelosuppression (mostly leukop and thrombocytop)
148
imatinib, dasatinib, nilotinib, bosutinib, ponatinib ADR (7pts) -ponatinib additional ADR (3pts)
```
N/V,
fluid retention,
elevated transaminases or bili,
muscle cramps,
fever,
bleeding
#P peripheral and arterial thrombosis,
severe and fatal hepatotox,
pancreatitis (monitor LFTs, serum lipase)
```
149
imatinib, dasatinib, nilotinib, bosutinib, ponatinib DA -1
hepatic (mostly)
150
imatinib, dasatinib, nilotinib, bosutinib, ponatinib DDI
#CYP3A4 substrate and inhibitors
#I also CYP2C19, 2D6 inhibitor
#avoid antacids and PPI
Nilotinib without food
151
CYP3A4 and general DDI -3
inducer (phenytoin)
inhibitor (cimetidine, itraconazole)
substrates (simvastatin, cyclosporine)
152
sunitinib MOA, indx and dose -3
multi-R TKI: PDGFR, EGFR, stem cell factor R, others
#refractory GIST, advanced RCC
#50mg qd 4 weeks ON, 2 weeks OFF
153
sunitinib ADR -12
common:
diarrhea, N/V,
stomatitis, dyspepsia,
skin discoloration
```
others:
fatigue,
HTN,
bleeding,
swelling,
mouth pain,
taste disturbance,
CHF
```
154
sunitinib DDI. -1
CYP3A4 substrate
155
sorafinib MOA and dose -3
#multi-R TKI: PDGFR, VEGFR, stem cell factor R, raf/mek pathway kinases
#400mg bid without food
#adv RCC, HCC
156
sorafinib ADR -4
common: diarrhea
others: rash,
HTN,
HFS
157
sorafinib DA -1
HFS
158
sorafinib DDI. -2
CYP3A4, UGT1A9 substrate (increases AUC of SN-38)
159
pazopanib MOA and dose
```
#multi-R TKI: PDGFR, VEGFR, c-Kit, IL-2 R inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, transmembrane, glycoprotein R TK
#adv RCC, adv STS
#800mg qd without food
```
160
pazopanib ADR
common: diarrhea
others: HTN, inc LFTs, prolonged QT, arterial thrombosis, hemorrhagic events, proteinuria, hypothyroidism
161
axitinib MOA
```
#multiR TKI: similar to pazopanib with enhanced potency and selectivity to all VEGFR, minor against PDGFR and c-KIT
#adv RCC
#5mg q12h
```
162
axitinib ADR
diarrhea, rash, HFS, bleeding, thrombotic events, HTN, hepatotox, hypothyroidism, proteinuria, GI perforation, fatigue
RARE: PML
163
axitinib DA and DDI
hepatic - decrease for Childs-Pugh B
CYP3A4 substrate
164
vandetanib MOA and dose
```
VEGFR, EGFR, RET TK
#progressive medullary thyroid CA
#300mg qd
```
165
vandetanib ADR
black box: QT prolongation (monitor lytes, EKG)
others: skin rxns, stevens-johnson, ILD, ischemic c/v events, hemorrhage, CHF, diarrhea, hypothyroidism, HTN, RPLS
166
vandetanib DA and DDI
#renal: CrCl <50 reduce to 200
#hepatic: AVOID if childs-pugh B or C
#CYP3A4 substrate
#avoid QT prolonging drugs
167
cabozantinib MOA and dose
```
#multi-R TKI: most important rearranged during transfection receptor (RET), VEGFr-2, and MET membrane R
#progressive medullary thyroid CA
#140mg qd
```
168
cabozantinib ADR (23pts)
black box: hemmorrhage, fistulas, GI perforation
others: diarrhea, stomatitis, HFS, weight loss, dec appetite, N, fatigue, oral pain, hair color changes, dysgeusia, HTN, abd pain, constipation, inc LFTs, proteinuria, lymphop, neutrop, thrombocytop, hypoCa, hypophos
169
cabozantinib DDI
CYP3A4 substrate
170
regorafenib MOA and dose
```
#multi-kinase inh: VEGFR, c-KIT, RET, RAF1, BRAF, PDGFR, fibroblast growth factor R (FGFR)
#colon CA
#160mg daily D1-21 of 28days, take with low fat breakfast
```
171
regorafenib ADR
black box: hepatotoxicity
others: asthenia, fatigue, dec appetite, HFS, diarrhea, mucositis, wt loss, infx, htm, dysphonia, hemorrhage
172
regorafenib DDI
CYP3A4 substrate
173
bortezomib and carfilzomib MOA and dose
```
#Inh 26S proteasome, which is a intracellular protease responsible for protein catabolism. IkB accumulates which leads to increased inhibition of NF-kB (transcription factor). NF-kB decreases expression of adhesion molecules and various growth, survival and angiogenic factors.
#C irreversible and rapid binding (use in bortezomib resistance, after 2 tx including bortezomib)
#B MM, mantle cell
```
174
bortezomib DLT
thrombocytop or neuropathies (PN dec with SQ admin)
175
bortezomib ADR (5pts)
thrombocytop, fatigue, PN, TLS, neutrop
176
carfilzomib ADR (13pts)
fatigue, anemia, thrombocytop, N, diarrhea, dyspnea, pyrexia, inf related rxns
RARE: cardiac arrest, MI, CHF, hepatotox, TLS
177
bortezomib and carfilzomib dose and admin issues
```
#C 20mg/m2 1st C, then 27mg/m2 subsequent C, D1-2, 8-9, 15-16 of 28d cycle
premed with Dex
#B 1.3mg/m2 D1,4,8,15 q21d OR D1,8,15,22 q35d
```
178
temsirolimus and everolimus MOA
```
#Inh mTOR signaling pathway-> cell cycle arrest, dec expression of proteins VEGF, PDGF, transforming growth factor (TGF) and others involved in angiogenesis and cell growth
#adv RCC (T 1st line, E post TKI failure)
```
179
temsirolimus and everolimus dose and admin issues and DDI
```
#T 25mg iv weekly (diphen premed)
#E 10mg qd
```
#both CYP3A4 substrates
180
temsirolimus and everolimus ADR
common: rash, asthenia, mucositis, N, edema, anorexia
lab abnormalities: anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, inc LFTs, inc SCr, lymphop, hypophos, thrombocytop, leukop
MGMT: treat both hyperglycemia and hyperlipidemia
181
crizotinib MOA and dose
#EML4-ALK fusion oncogene TKI (blocks activation downstream Ras pathway, which inhibits apoptosis)
#2-10% of NSCLC pts (need to test for mutation)
#250mg bid
182
crizotinib ADR
#severe: pneumonitis, hepatotox, QT prolongation
#common: N/V, diarrhea, vision changes
183
crizotinib DA and DDI
#HOLD or REDUCE for hepatotox, QT prolongation, or myelosuppression
#CYP3A4 substrate and inhibitor
184
vemurafenib MOA and dose
```
#Inhibits MAP kinase signaling pathway through inhibition of mutated BRAF (V600E) -> prevents downstream activation of MEK and ERK
# metastatic melanoma
#960mg bid
```
185
vemurafenib ADR
common: arthralgia, rash, alopecia, fatigue, photosensitivity rxn, N, pruritis, skin papilloma
#24% SQUAMOUS CELL CANCER
#RARE: SJ sx, QT prolong, opthalmitic rxn, hepatotox, hypersensitivity rxn
186
vemurafenib DDI
CYP3A4 substrate and inducer
CYP1A2 moderate Inh
CYP2D6 weak Inh
increases warfarin levels
187
thalidomide and lenalidomide MOA
```
#not fully understood
#immune modulation (inc T-helper cells)
#cytokine inhibition (TNF-alpha)
#antiangiogenesis
```
188
thalidomide dose
#pharmacies and prescribers need to enroll in STEPS program
#200mg qd MAY increase by 200mg q14d to MAX 800mg qd
189
lenalidomide dose
#patients, pharmacies, prescribers need to enroll in RevAssist
#10mg qd
190
thalidomide ADR
common: somnolence/drowsiness, constipation, dizziness/orthostatic, hypotension, rash, PN
RARE: neutrop
SERIOUS: teratogenicity (pregnancy test)
191
lenalidomide ADR
common: neutrop, thrombocytop, thrombotic issues
| MUCH less somnolence, PN than thalidomide
192
ziv-aflibercept MOA, indx, and dose
#soluble recombinant fusion protein designed to block angiogenesis. fused VEFR-1 and -2 immunoglobulin domains to Fc portion of human IgG1. Blocks VEGF and PIGF by "trapping" ligands before they get to transmembrane receptors.
```
#colon CA in combo with FOLFIRI after oxal-based regimen progression
#4mg/kg IV q2wks
```
193
ziv-aflibercept ADR
black box: hemorrhage, GI perf, compromised wound healing
others: neutop, diarrhea, proteinuria, inc transaminases, stomatitis, fatigue, thrombocytop, htn, wt loss, dec appetite, epistaxis, abd pain, dysphonia, SCr inc, HA, arterial thrombotic events, fistula formation
194
vismodegib dose and MOA
#Hedgehog signaling pathway inhibitor. Pathway abnormally activated in solid tumors. Binds to SMO.
```
#basal cell carcinoma that is untreatable with surgery or XRT
#150mg qd
```
195
vismodegib ADR
black box: embryo-fetal death and severe birth defect (hedgehog pathway used in nml tissue here)
others: muscle spasms, alopecia, dysguesia, ageusia, wt loss, fatigue, n/v/d, dec appetite, constipation, arthralgia
196
vismodegib DDI and donating blood
#AVOID pgp inhibitors and drugs that alter gastric pH
#pt can not donate blood for at least 7 months post tx
197
denileukin difitox MOA
#recominant protein of IL-2 receptor + diptheria toxin fragments A and B. binds with high affinity to IL-2 receptors on T-lymphocytes, is internalized into cell by fragment B, then fragment A is cytotoxic
#peripheral T-cell lymphoma
198
denileukin difitox admin issues
#premed with pred 20 or dex iv 8 to lower hypersensitivity rxns
#tumor MUST be CD-25 (+) (IL-2 receptor)
199
denileukin difitox ADR
capillary leak sx (hypotension, edema, hypoalbuminemia) occurs within 2 wks and get worse with each infusion. hypersens rxns, flu-like sx
200
vorinostat MOA
#histone deacetylase (HDAC) inhibitor. leads to accumulation of acetylated histones which induces cell cycle arrest or apoptosis
#progressive, recurrent cutaneous T-cell lymphoma
201
vorinostat ADR
PE, VTE, n/v/d, dose related thrombocytop and anemia
202
RENAL DOSE ADJUSTMENTS
see pg 790
203
HEPATIC DOSE ADJUSTMENTS
see pg 791
