Clinical Pharmacology, ASPHO Flashcards by Natalie Mathews

Gray =?

amount of radiation depositining 1 joule of energy into 1 kg

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benefit of proton radiation?

Plateau dose distribution‐ deposit 90‐100% of dose at the point they
stop in tissue (Bragg peak); avoids exit dose

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dose of TBI? waht does it do? (2)

12‐15Gy in 8‐12 fractions
• Eliminate residual cancer
cells
• Make space in bone
marrow compartment
• Immune suppression

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what is teh gross tumour volume?

volume occpied by tumor at diagnosis

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what is the clincial target volume?

• Includes gross tumor volume (GTV) and sites of suspected occult disease and involved adjacent lymph nodes

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what is the planning target volume?

Planning Target Volume (PTV)
• Includes CTV including surrounding geometric area accounting for variability in set up,
breathing and motion during treatment
• PTV is not the same as photons for protons
• PTV is same as CTV for brachytherapy

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3 sources of radiation for therapy?

photons, protons, gamma rays

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3 types of IV radiotherpay?

Systemic Delivery (IV) Radiotherapy (Radiopharmaceuticals)
• Radio‐Iodine (RAI, 131Iodine) Gamma and Beta particles, Thyroid cancer
• 131I‐Meta‐iodobenylguanidine (131I‐MIBG): delivers beta particles via neuroendocrine
transporter to Neuroblastoma or Pheochormocytoma
• 177Lu‐ DOTO‐TATE: Beta emitting, somatostatin receptor positive GI neuroendocrine
tumors (Peptide Receptor Radiouclotide Therapy, PRRT)

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which familiy of drug met enzymes is responseible for 70-80% of all phase drug metabolism (activate/deactivate)? which specific enzyme is most commonly used?

cytochrome p450; cyp3a

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which enzyme is mutated in people who have increased sensitivity to 6MP?

Thiopurine Methyl Transferase (TPMT), seen in 1/300

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which enzume is mutatied in gilberts disease?

• UDP‐glucuronosyl‐transferase 1A1

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3 ways to overcome blood brain barrier for CNS disease?

High‐dose chemotherapy
• Methotrexate, cytarabine
Identifying drugs which penetrate the BBB based on
lipophilicity, molecular weight, degree of ionization, plasma
concentration of free drug (protein binding)
• nitrosoureas, thiotepa, topotecan
Disruption of the blood‐brain barrier
• Osmotic, radiation, vasoactive compounds,
Regional Chemotherapy
• Intra‐carotid chemotherapy (cisplatin, methotrexate)
• Intrathecal injection (methotrexate, cytarabine)
• Intra‐tumoral (carmustine)
• Convection Enhanced Delivery

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IT chemo dosing based on? exception?

Intrathecal (IT) chemotherapy dose is based on age

* IT MTX dosing based on BSA, children < 18 months had higher rate of isolated CNS

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what is the goldie-coldman hypothesis? 3 points

• Cancer cells mutate and become resistance to therapy at a rate that
depends on the cancer’s inherent genetic instability
• Probability that a cancer contains a resistant clone is dependent on the
mutation rate and size of the tumor
• Even when tumor burden is low there is likely to be at least one drug
resistant clone

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main principle of chemo #1: give combo therapy: what does this mean? eg?

Concurrent administration of multiple anticancer drugs with non‐overlapping
mechanism of action and non‐overlapping toxicity profiles…Acute Lymphoblastic Leukemia: transient response rates of 60% with single agents
(MTX, MP, Prednisone, VCR, Dauno, or L‐ASP); 3‐4 drug combination induction
regimens produce durable response rate of 95%

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main principel of chemo #2: adjuvant therapy: what is this?

Administration of chemotherapy when disease burden is
minimal but risk of recurrence is high (Goldie‐Coldman Hypothesis)
• Continuation of system therapy after local control in localized cancer
• Osteosarcoma: Improved 3 y EFS when chemotherapy administered after complete resection of
localized tumor (20% surgery alone vs 65% surgery + chemotherapy) Eilber et al J Clin Oncol 1987;5:21‐6
• Maintenance Therapy
• ALL: Methotrexate, 6‐Mercopatopurine
• RMS: vinorelbine + cyclophosphamide.

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Regarding adjuvant therapy, what is neoadj therapy? benefits (2)

Neoadjuvant Setting: Administration of systemic chemotherapy prior to
definitive local control
• Reduce tumor burden at the primary site prior to definitive local therapy
(surgery/radiation)
• Control disease not amenable to local therapy (metastases)
• Assess the sensitivity of the tumor to chemotherapy by measuring tumor response

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chemo pirnicple #3: dose intensity: what does this pertain to? eg?

Maximize the Dose Rate of chemotherapy
• Highest possible dose at the shortest tolerable interval
• Calculated by normalizing the dose rate (mg/m2/week) for a drug and
comparing to the dose rate of a reference drug or prior regimen.
• Examples:
• Interval Compression improved EFS in localized EWS
• Dose intensity of 4 drug induction in NBL correlates with response and survival
• Children with ALL have improved survival with standard dose vs half dose MTX and MP in
maintenance.

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give 4 alkylating agnets

cyclophos
ifofos
cisplatin
busulfan
melphalan
temozolamide

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give 2antimetabolities

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give 7 common toxicities of chemo

SHAM MAN
skin reactions
hepatotox
alopecia
mucositis
myelosupp
allergic rxn
n/v

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unique tox of anthras?

cardiotox

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unique tox fo cyclo, ifos?

hemorrhagic cystitis

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unqiue tox of alkaloids, cisplatin?

peirpheral neuropathy

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unique tox of aparaginse?

coagulopathy

unique tox of cisplatin?

ototox

unique tox of cisplatingand mtx?

nephrotox

unique tox of mtx?

leucoencephalopahty

how to attenuate myelosupp? (3)

G-CSF stem cell re-infusion individualized dosing

how to attenuate n/v

antiemetics

how to attenuate heomrrhagic cysitis?

mesna

how to attenuate nephrotox from cisplatin?

hyperteonic saline

how to attenuate cardiotox from anthras?

dexrazoxane

how to attenuate myelosupp/mucositis from mtx? (2)

Leucovorin | Carboxypeptidase

vesicant= compound that causes severe skin/eye mucosal pain and irritaiton...give 5 high chemos with high vesicant potential

think DMV= super irritating | Dauno, doxo, dactino....mitotoxin c...VBL, VCR, vinorelbine

how do alkylating agents work?

• Damage to the DNA template (alkyl adducts) induces apoptosis • For bifunctional alkylators (nitrogen mustards), damage results from the formation of crosslinks (inter‐strand, intra‐strand, DNA‐ protein)

are alkylators dependent on cell cycle?

give 5 alkylating agents

``` ifos cyclophos cisplatin carboplatin busulfan temozolamide thiotepa melphalan lomustine ```

give 3 alkylating agents that are pro-drugs

Cyclophosphamide Ifosfamide Dacarbazine Temozolomide

in what 4 ways in cisplatin worse than carbo?

periopheral neuropathy, n/v, nephrotox, ototox

in what 2 ways is carboplatin worse than cisplatin?

myelosupp, hypersens

what do audiograms show in cisplatin-related ototox?

Bilateral High Frequency (Hz > 4000) hearing loss (dB) plateau then decreases high in the x-axis

what compound can help with ototox in some groups?

Sodium Thiosulfate

how does cyclophos --> nephrotox?

- Direct tubular effect--> water retention | - hemorrhagic cystitis due to acrolein= metabolite

how does ifos--> GU tox?

- prox tubular damage, ricketts in younger children - decreased GFR - distal tubular damage with RTA - hemorrahgic cystitis due to acrolein= metabolite

how does mesna work?

chelates acrolein metabolite in the bladder

other than GU tox, another organ tox secondary to ifosfamide? how can you tx this?

neurotox (esp with aprepritant)...tx iwth methylene blue

list 4 alkylating agents

``` busulfan carmustine= BCNU cisplatin ifosfamide cyclophosphamide ```

late effects of alkylators? 4

- gonadal atrophy (high dose busulfan) - pulmonary fibrosis (busulfan, carmustine) - renal dysfunction(cisplatin, ifosfamide) - ototox (cisplatin) - secondayr cancers

mtx mech?

inhibits dihydrofolate reductase

antimetabolites are cell cycle specific?

yes, specific to S phase

folate analog?

mtx

purine analog?

6MP, 6TG, fludarabine, clofarabine, cladribine, melarabine=Ara-G

pyrimidine analogs?

Ara-C, gemcitabine, fluorouracil

all anti-metabolites are ___

pro-drugs

4 frequent toxicities of antimetabolities?

myelosupp, hepatotox, mucositis, nausea, vomiting, neurotox, rash, dermatitis, pulm tox

specfici tox of HD mtx?

nephrotox

specific tox of gemcitabine?

radiation recall

specific tox of 6TG?

VOD

specific tox of fludarabine?

immunosupp

specific tox of cladribine?

immunosupp

specific tox of ara-c?

flu-like sx

other than ara-c, another drug with AE= flu-like sx?

gemcitabine

neurotox secondary to mtx? (2) resolution?

acute encephalopathy (5-14 days later) with HD-- resolution in 1-7 days; 10-50% recur....chronic encephalopathy= permanent

cytarabine neutotox?

acute cerebellar syndrome...onset 3-8 days days...resolves in 1 week, but 30% have rseidual defect

nelarabine neutotx?

somnolence, seizures, guillain-barre-like weakness, paresthesia...gradually reversible

fludarabine neurotox?

progress leukoencephalopahty, can be fatal

what is the MAX mtx infusion duration?

42 hours...must start leucovorin within this timeframe!!

4 ways to maange nephrotox from HD Mtx?

- Hydration and alkalination of urine - increase leucovorin/give more often - dialysis - glucarpidase=carboxypeptidase

how does glucarpidase work?

cleaves mtx into DAMPA and glutamic acid

allopurinol's effect on 6MP? if giving both at same time do what?

allopurinol inhibits xanthine oxidase, which is responsibilie for metabolism of PO 6mp (not iV)--> 6mp becomes more bioavailable...if giving both, decresae 6MP dose by 75%!

give 3 drugs that interact with mtx--> decreased secretion of mtx

salicylates, pencillin, NSAIDs, ciproflox

topoisomerase 1 does what? 2 does wht?

--> single strand DNA breaks? ....2--> double stand DNA breaks

3 classes of topoisomerase inhibitors?

anthracyclines, epipodophyllotoxins, camptothecins, anthracednediones, phenoxazones

give 3 anthracyclines

doxo, dauno, idarubicin

give 2 epipodophyllotoxins

etoposide, teniposide

mitxantrone= what type of chemo?

anthracenedione= topoisomerase 2 inhibitor

dactinomycin= what type of chemo?

phenoxazone= topoisomerase 2 inhibitor

topotecan and irinotecan = what type of chemo?

camptothecins...= topoisomeraise ONE inhibitors

give 2 antitumour antibiotics

anthracyclines, dactinomycin

how to tx irinotecan induced diarrhea iwthin 8 hours of starting?

atropine

how to tx irinotecan diarrhea after 8 hours?

loperimide, octreotide

how to prevent irinotecan diarreha? how does this work?

cefixime; decreases glucuronidase producing bacteria in the gut

give 4 tubulin binding agents

vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel

4 specific AEs of vcr?

- peripheral nueroptahy (loss of DTRs, numbness) - CN involvement (double vision) - SIADH - autonomic neuorpathy= constipation

3 drugs that reduce clearance of vinca alkaloids?

fluconazole, cipro, grapefruit juice

3 drugs taht increase clearance of vinca alkaloids?

st johns wort, phenobarb, rifampin

5 AEs of steroids?

AVN, htn, diabetes, immunouppression, growth failiure, centripedal obesity

tox assoicated with bleomycin

interstitial pneumonitis, alopecia, reynaud, hyperpigemntation of skin and nails

goals of phase 1 trial?

establish safe dose, establish tox profile, establish pharmacology

population used in phase 1 trials?

relapsed cancer, <25 pts

phase 2 trial goal?

determine response to a certain drug

populaiton for phase 2 trial?

relapased cancer pts

goal of phase 3 trail?

efficacy (benefit) of drug, with endpoint being survival

population in phase 3 trial?

untreated cancer pts

3 AEs of Aresnic trioxide?

prolonged QTc, leukocytosis, APL differentation syndrome

3 AEs of ATRA?

differentation syndrome, venous thrombosis, pseudotumour cerebri

3 AEs of imatinib?

increased transaminases, n/v, fatigue

2AEs of crizotinib?

hepatotox, AKI

NTRK fusion (NTRK-ETV6) seen in which tumours?

congential mesoblastic neprhoma, infantile fibrosarcoma

give an NTRK inhibitor

larotrectinib

give an inhibitor of dna methylation

azacitidine

give an immune hceckpoint inhibitor and an AE of it

nivolumab, pleural effusion

give 3 MABs used to treat cancer, the cancer they treat, mech, and AE

- avastin=bevacizumab; LGG; blocks angiogenesiss via VEGF inhibition; hypertesnion - rituximab; PTLD and b-cell lymphoma; inhibits CD20-> depletes normal b-cells--> hypogammaglobulinemia - dintuximab, NBL, anti-GD2--> antibody dependent cell mediated toxicity; neuropathic pain

AE of gemtuzumab?

infusion-related reaction, myelosupp

AE of inotuzumab?

infusion-related reaction, myelosupp, VOD

AE of brentuximab?

neutropenia, neuropathy