Pharmacology Flashcards
Anthracyclines MOA -4
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)
Anthracylines DLTs -2
myelosuppression (primarily leukopenia),
chronic cardiomyopathies
Anthracylines ADRs -4
Dose dependent nausea and vomiting,
alopecia,
radiation recall,
turns urine red (except mitoxantrone turns urine blue)
Anthracylines DAs -4
Hepatic.
50% dec if bili 1.2-3.0
75% dec if bili > 3.0
generally omitted if bilirubin > 5.0 mg/dL.
Anthracylines administration issues. How do you manage? -3
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®.
Etoposide MOA -4
G2 specific:
Forms a complex with topoisomerase II
- > inhibits enzyme
- > single stranded DNA breaks
Etoposide DLTs -1
myelosuppression- primarily leukopenia
Etoposide ADRs -2
nausea and vomiting (with oral dosing),
alopecia
Etoposide Administration Issues -3
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)
Camptothecins MOA -4
synthesis cycle specific:
Inhibit topo I
- > “cleavable complexes” stabilized
- > reversible single stranded DNA breaks
Camptothecins DLTs -topo -2 irino -1
leukopenia and thrombocytopenia (topotecan);
diarrhea (irinotecan)
Camptothecins ADRs -4
neutropenia,
nausea, vomiting, diarrhea
alopecia,
increased liver enzymes
Irinotecan Diarrhea Concepts -4
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.
Vinca Alkaloids MOA -3
M phase specific:
Bind to Tubulin,
inhibits polymerization and thus Microtubule formation.
Vinca Alkaloids DLTs -4
leukopenia and thrombocytopenia (vinblastine and vinorelbine),
neurologic toxicity,
constipation,
paralytic ileus (vincristine)
Vinca Alkaloids ADRs
Neurologic toxicity,
constipation,
abdominal cramps (much less than vincristine)
vincristine ONLY -rare bone marrow suppression and SIADH
Vinca Alkaloids DAs -4
Hepatic.
50% dec if bili 1.5-3.0
75% dec if bili > 3.0
generally omitted if bilirubin > 5.0 mg/dL.
Vinca Alkaloids administration issues. How do you manage? -2
potent vesicants
#apply warm pack and administer hyaluronidase
M phase specific (3pts)
drugs that work in mitosis (vincas, taxanes, ixabepilone)
S phase specific (2pts)
DNA synthesis (antimetabolites and tecan’s)
G2 phase specific (2pts)
after mitosis, before synthesis (bleomycin, etoposide)
G1 phase specific (2pts)
after synthesis, before mitosis (steroids, asparaginase)
nonspecific cell cycle agents
cell kill proportional to dose (kill both nml and malignant cells to the same extent)
everything else (alkylating agents, anthracyclines, antitumor antibiotics, nitrosureas, misc)
cell phase/cycle specific agents -2
preferentially kill proliferating cells
admin as “continuous infusion”
targeted therapy agents -3
effect on specific “tumor cells”
prevent from entering cell cycle
target signals that trigger cell growth, metastasis, and immortality
alkylating agent DLT -1
myelosuppression (usually neutropenia)
mechlorethamine administration issues -2
potent vesicant.
extravasation= 4mL 10% sodium thiosulfate + 6mL sterile water for injection inject SQ around site
what is the cyclophos ADR that you always forget?
SIADH
bendamustine renal dosing
DO NOT USE if CrCl <40
thiotepa and excretion in sweat -3
for high dose BMT doses:
bath 3-4 times daily
no tight clothes, to prevent skin breakdown
dacarbazine unique ADRs -3
inc LFTs
flu-like sx
injection site pain
platinum MOA
form a reactive electrophile that covalently binds to DNA (alkylating-like)
crcl calculation
((140-age) x wt in kg) / (SCr x 72) (x0.85 for females)
cisplatin DLT -1
N/V (acute and delayed)
carboplatin DLT -1
myelosuppression (thrombocytopenia)
platinum ADR -6
nephrotox,
hypomag,
hypoK,
ototox,
peripheral neuropathies,
myelosuppression
carbo=less of all but myelos
oxal=minimal nephrot, otot
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
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)
taxane DLT -1
leukopenia
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)
taxane administration issues -4
P cremophor hypersensitivity rxn- premed dex 20, diphen 50, ranit 50 iv
administer prior to platinums to reduce myelosuppression
nab-albumin paclitaxel administration issues -1
does not contain cremophor->less hypersensitivity reactions
taxane DAs -3
hepatic
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
epothilones (ie. ixabepilone) DLT -2
leukopenia
PN
epothilones (ie. ixabepilone) ADR -6
anemia,
thrombocytop,
diarrhea,
fatigue,
myalgia,
alopecia
epothilones (ie. ixabepilone) admin issues -1
premed with diphen 50, ranit iv 50 (or cimet iv 300)
no steroid needed
miscellaneous tubulin agent (ie eribulin) MOA -2
marine macrolide halichondrin B, synthetic,
inhibits tubulin polymerization
miscellaneous tubulin agent (ie eribulin) ADR -2
neutropenia,
neuropathy (less than vincristine)
miscellaneous tubulin agent (ie eribulin) DA -2
both renal and hepatic dose adjustments
antimetabolite general MOA (4pts)
1 compete for binding sites on enzymes
S phase specific:
inhibit cell growth and proliferation
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
folate antagonist (methotrexate and pemetrexed) DLT -2
leukopenia
thrombocytopenia
folate antagonist (methotrexate and pemetrexed) ADR -5
watch third spacing
renal tubular necrosis (high doses),
pulmonary pneumonitis,
alopecia,
stomatitis, mucositis
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
pemetrexed premeds -3
folic acid and vitamin b12
reduce myelosuppression
methotrexate DDI (3pts)
1 highly protein bound drugs may displace MTX from albumin and inc tox (ie. sulfonamides, salicylates, phenytoin, tetracycline)
purine analogue thioguanine (6-TG) and mercaptopurine (6-MP) MOA -2
S cycle specific.
structural analogues of guanine that are incorporated into DNA.
thioguanine (6-TG) and mercaptopurine (6-MP) DLT -2
leukopenia and thrombocytopenia
thioguanine (6-TG) and mercaptopurine (6-MP) ADRs -4
liver tox and jaundice (much higher with 6-MP),
stomatitis, mucositis,
rash,
N/V
mercaptopurine (6-MP) DDI -2
metabolized by xanthine oxidase.
75% dose reduction with allopurinol.
other purine analogues names (3pts) and ADR
cladribine, fludarabine, pentostatin
unique myelosuppression of t-helper cells->often requires abx px
pyrimidine analogues names (2pts) and MOA -4
S cycle specific.
cytarabine and gemcitabine.
structural analogues of nucleosides cytidine and deoxycytidine.
inhibit DNA polymerase.
pyrimidine analogues DLT -2
leukopenia and thrombocytopenia
pyrimidine analogues ADR -9
for high dose araC: excess BM depression, CNS tox, conjunctivitis (steroid eye gtts)
N/V,
mucositis,
diarrhea,
flu-like sx,
rash,
TLS (often give with allopurinol)
“false” pyrimidine analogues names (2pts) and MOA -5
1inhibit formation of base thymidine by inhibiting enzyme thymidylate synthase (rate limiting step).
S cycle specific.
5-FU and capecitabine.
“false” pyrimidine analogues DLT -5
5-FU: leukopenia and thrombocytopenia.
anemia (bolus inf),
HFS and diarrhea (continuous inf)
cape: HFS,
diarrhea
“false” pyrimidine analogues ADR -7 (3+4)
5-FU: skin discoloration,
nail changes,
photosensitivity,
neurologic tox
cape: N/V,
fatigue,
rash
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
hypomethylating pyrimidine analogues DLT -1
myelosuppression
hypomethylating pyrimidine analogues ADR -2
mild GI tox
infx’s
bleomycin MOA -2
binds to DNA producing single and double stranded DNA breaks through the generation of free radicals
indx: testicular, hodgkins, NHL
bleomycin DLT -1
fatal lung disease
MAX DOSE is 400 units!!
bleomycin ADR
hyperpigmentation,
rashes,
fever,
rare allergic rxns
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
omacetaxine ADR -10
thrombocytopenia,
inc risk of hemorrhage,
anemia, neutropenia, lymphop
diarrhea, N,
fatigue,
asthenia, inj site rxn, pyrexia, infx, hyperglycemia
antiestrogens - tamoxifen MOA -2
inhibits nuclear binding of estrogen to estrogen receptor.
antiestrogens - tamoxifen ADR -8
menopausal sx (hot flashes, N/V),
vaginal bleeding,
bone pain,
menstrual irregularities,
HA,
depression.
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
antiestrogens - nonspecific aromatase inhibitor ADRs -5
neuro - lethargy, nystagmus, dizziness
N/V,
leukopenia, thrombocytop
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
antiestrogens - nonsteroidal aromatase inhibitor ADR -5
GI disturbances,
hot flashes,
thromboembolic events,
wt gain,
edema
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
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)
luteinizing hormone-releasing hormone antagonists = gonadotropin releasing hormone antagonist (1pt) names and MOA. -6
NO tumor flare.
Degarelix
blocks GnRH receptors in anterior pituitary
- > decrease FSH and LH release
- > decrease in androgen and estrogen production
T reduced ~90% in 24hours
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
antiandrogen ADR (7pts)
gynecomastia,
hot flashes,
inc LFTs,
N/V,
diarrhea,
visual disturbances
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
abiaterone administration -3
250mgx4 daily = 1000mg WITH pred 5bid
1hr before or 2hr after meals
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
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
abiaterone DDI
CYP2D6 Inh
CYP3A4 substrate
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.
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
misc hormonal agents - enzalutamide DDI -2
CYP3A4, 2C9, 2C19 inducer (warfarin)
CYP3A4, 2C8 substrate
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
misc hormonal agents - estramustine ADR (6pts)
N/V, edema, CV tox, thromboembolic events, gynecomastia
monoclonal Ab MOA (4pts)
antibody dependent cellular cytotoxicity (ADCC)
CDCC - complement dependent
??
- zumab
- ximab
- umab
- momab
zumab= humanized ximab= chimeric umab= human momab= murine
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
alemtuzumab administration -3
3mg, then 10mg, then 30mg as tolerated
alemtuzumab ADR -3
serious, prolonged, sometimes fatal heme tox (avg neutropenia duration 28d, thrombocyto 21d),
infusion related rigors,
hypotension
brentuximab vedotin MOA -2 and indx -3
CD30 antibody linked to monomethylauristatin (MMAE) which Inh microtubule polymerization
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
brentuximab vedotin dose and administration issues -2
1.8mg/kg q3wk up to 16c
premed for infusion rxns
rituximab MOA. -3
CD20 binding and apoptosis
rituximab ADR -5
infusion rxns (fever, chills/rigors, hypot, N) (premed), TLS, mucocutaneous rxns, hepatitis B reactivation, PML
ofatumumab MOA -3 and indx -1
ADCC
ofatumumab dose and administration issues -4
300mg D1, 2000mg D8 weekly x7, then 4 wks later 2000mg q4wk x4 doses
ofatumumab ADR -6
infusion rxns (fever, chills/rigors, hypoT, N), neutrop, thrombocytop, bacterial or fungal infx, hepatitis b reactivation, PML
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
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
ibritumomab tiuxetan ADR -2
thrombocytop (61%),
neutrop
tositumomab MOA -4 indx -1
ritux refractory FL
CD20 antibody LINKED to I-131
gamma XRT->imaging purposes
beta XRT->cytotoxic
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)
tositumomab administration issues -2
premed APAP, diphen
thyro-protective regimen at least one day prior to tx
ipilimumab MOA -3
may also antagonize CTLA-4 on regulatory T cells to limit their ability to suppress the antitumor T cell effector response
CTL4, a negative regulator of T cell function
-> Inc T-cell stimulation and antitumor reaction
ipilimumab dose -1
3mg/kg over 90 min q3wk x4
ipilimumab ADR -3
skin, liver, GI, pituitary (endocrinopathy) GVHD,
neuropathy
most during tx, but also weeks to months after
trastuzumab MOA
binds to Her-2/neu oncogene (25% of breast CA)
-> antibody dependent cellular cytotoxicity (ADCC)
IHC 2-3, FISH (+)
trastuzumab dose - 1
qwk schedule: 4mg/kg week 1, then 2mg/kg q3wk schedule: ??
trastuzumab ADR -5
CHF,
infusion related sx
Others: rash,
myelosuppression,
GI tox (diarrhea)
pertuzumab MOA. -3
Her-2 receptor on extracellular domain blocking ligand dependent HER2, HER3 ligand dimerization.
pertuzumab dosing -1
840mg load then 420mg q3w flat dosing (not wt or BSA-based)
pertuzumab ADR (10pts)
diarrhea, N, alopecia, rash, neutrop, fatigue, PN, embryo-fetal tox, LV dysfunction, infusion related rxn
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.
cetuximab dose -1
400mgm2 load then weekly 250
cetuximab ADR (9pts)
infusion related rxns required dose mods, skin rash, asthenia/malaise, diarrhea, N/V, interstitial lung dz, hypoMg
panitumumab MOA -2
EGFR-1 (same as cetux)
IgG2
panitumumab dose -1
6mg/kg q2wk
panitumumab ADR (4pts)
skin rash,
infusion related rxns,
interstitial lung dz,
hypoMg
bevacizumab MOA -4
binds to VEGF ligand-> prevents binding to receptor.
bevacizumab dose and administration issues -2
usually 5mg/kg q2wk
bevacizumab DLT (3pts)
HTN,
bleeding episodes,
thrombotic events (MI, PE, DVT)
bevacizumab ADR -3
rare perforation of bowel,
proteinuria
Wound healing
VEGF diagram
SEE PG 776
erlotinib and gefitinib MOA -3
EGFR-TKI (blocks intracellular phosphorylation)
erlotinib and gefitinib indications
E 1st or 2nd line NSCLC, panc, maintenance NSCLC
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)
erlotinib and gefitinib DDI -2
CYP3A4 substrate
increased INR with warfarin
lapatinib MOA and dose -3
MBC in combo with cape
TKI of both EGFR and Her-2
lapatinib ADR (5pts)
diarrhea (common),
dec LVEF,
QT prolongation,
rash,
HFS
lapatinib DDI -2
CYP3A4 and 2C8 inhibitor
lapatinib DA -1
hepatic
imatinib, dasatinib, nilotinib, bosutinib, ponatinib MOA -5
Bcr-Abl TKI -> apoptosis of Bcr-Abl (+) cells
imatinib, dasatinib, nilotinib, bosutinib, ponatinib drug resistance -2
1 Bcr-Abl point mutation ->dec binding (dependent resistance)
imatinib, dasatinib, nilotinib, bosutinib, ponatinib DLT -1
myelosuppression (mostly leukop and thrombocytop)
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)
imatinib, dasatinib, nilotinib, bosutinib, ponatinib DA -1
hepatic (mostly)
imatinib, dasatinib, nilotinib, bosutinib, ponatinib DDI
CYP3A4 substrate and inhibitors
Nilotinib without food
CYP3A4 and general DDI -3
inducer (phenytoin)
inhibitor (cimetidine, itraconazole)
substrates (simvastatin, cyclosporine)
sunitinib MOA, indx and dose -3
refractory GIST, advanced RCC
multi-R TKI: PDGFR, EGFR, stem cell factor R, others
sunitinib ADR -12
common:
diarrhea, N/V,
stomatitis, dyspepsia,
skin discoloration
others: fatigue, HTN, bleeding, swelling, mouth pain, taste disturbance, CHF
sunitinib DDI. -1
CYP3A4 substrate
sorafinib MOA and dose -3
multi-R TKI: PDGFR, VEGFR, stem cell factor R, raf/mek pathway kinases
sorafinib ADR -4
common: diarrhea
others: rash,
HTN,
HFS
sorafinib DA -1
HFS
sorafinib DDI. -2
CYP3A4, UGT1A9 substrate (increases AUC of SN-38)
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
pazopanib ADR
common: diarrhea
others: HTN, inc LFTs, prolonged QT, arterial thrombosis, hemorrhagic events, proteinuria, hypothyroidism
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
axitinib ADR
diarrhea, rash, HFS, bleeding, thrombotic events, HTN, hepatotox, hypothyroidism, proteinuria, GI perforation, fatigue
RARE: PML
axitinib DA and DDI
hepatic - decrease for Childs-Pugh B
CYP3A4 substrate
vandetanib MOA and dose
VEGFR, EGFR, RET TK #progressive medullary thyroid CA #300mg qd
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
vandetanib DA and DDI
renal: CrCl <50 reduce to 200
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
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
cabozantinib DDI
CYP3A4 substrate
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
regorafenib ADR
black box: hepatotoxicity
others: asthenia, fatigue, dec appetite, HFS, diarrhea, mucositis, wt loss, infx, htm, dysphonia, hemorrhage
regorafenib DDI
CYP3A4 substrate
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
bortezomib DLT
thrombocytop or neuropathies (PN dec with SQ admin)
bortezomib ADR (5pts)
thrombocytop, fatigue, PN, TLS, neutrop
carfilzomib ADR (13pts)
fatigue, anemia, thrombocytop, N, diarrhea, dyspnea, pyrexia, inf related rxns
RARE: cardiac arrest, MI, CHF, hepatotox, TLS
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
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)
temsirolimus and everolimus dose and admin issues and DDI
both CYP3A4 substrates
#T 25mg iv weekly (diphen premed) #E 10mg qd
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
crizotinib MOA and dose
EML4-ALK fusion oncogene TKI (blocks activation downstream Ras pathway, which inhibits apoptosis)
crizotinib ADR
severe: pneumonitis, hepatotox, QT prolongation
crizotinib DA and DDI
HOLD or REDUCE for hepatotox, QT prolongation, or myelosuppression
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
vemurafenib ADR
24% SQUAMOUS CELL CANCER
common: arthralgia, rash, alopecia, fatigue, photosensitivity rxn, N, pruritis, skin papilloma
vemurafenib DDI
CYP3A4 substrate and inducer
CYP1A2 moderate Inh
CYP2D6 weak Inh
increases warfarin levels
thalidomide and lenalidomide MOA
#not fully understood #immune modulation (inc T-helper cells) #cytokine inhibition (TNF-alpha) #antiangiogenesis
thalidomide dose
pharmacies and prescribers need to enroll in STEPS program
lenalidomide dose
patients, pharmacies, prescribers need to enroll in RevAssist
thalidomide ADR
common: somnolence/drowsiness, constipation, dizziness/orthostatic, hypotension, rash, PN
RARE: neutrop
SERIOUS: teratogenicity (pregnancy test)
lenalidomide ADR
common: neutrop, thrombocytop, thrombotic issues
MUCH less somnolence, PN than thalidomide
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
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
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
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
vismodegib DDI and donating blood
AVOID pgp inhibitors and drugs that alter gastric pH
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
denileukin difitox admin issues
premed with pred 20 or dex iv 8 to lower hypersensitivity rxns
denileukin difitox ADR
capillary leak sx (hypotension, edema, hypoalbuminemia) occurs within 2 wks and get worse with each infusion. hypersens rxns, flu-like sx
vorinostat MOA
histone deacetylase (HDAC) inhibitor. leads to accumulation of acetylated histones which induces cell cycle arrest or apoptosis
vorinostat ADR
PE, VTE, n/v/d, dose related thrombocytop and anemia
RENAL DOSE ADJUSTMENTS
see pg 790
HEPATIC DOSE ADJUSTMENTS
see pg 791
