Cyclophosphamide

(CTX: Cytoxan)

Alkylating agent

MOA:Bifunctional alkylation of DNA producing cross links immunosuppressant

PK: parent drug not active, hydroxylated by P450 sys

Imp Toxicity: myelosuppression,immuns,n/v,alopecia cardiac, SIADH will react w/ bladder (avoid toxicity hydrate & use IFOS)

 Drug Interaction: Caution with metabolic inhibitors or inducers

Cisplatin

(CDDP,Cis-platinum)

DNA Binding Agent

MOA:Covalent (mostly intrastrand)

PK: inactivated by avid binding proteins (T1/2~45 min)

Imp Toxicity: RENAL: w/ Mg wasting and ↓ GFR,severe n/v,pheripheral neuropathy, auditory// Nephrotoxicity

Drug Interaction: C/I w/ probenecid cause nephrotoxicity

Clinical activity:testicular/ovarian, H & N,lung,lymphoma,metablastic bladder, mesothelioma

Carboplatin

(CBDCA, Paraplatin)

MOA: Covalent (mostly intrastrand binding to DNA)

PK: 70% urine (T1/2~3hr)

Imp Toxicity: myelosuppression, severe n/v,

Drug Interaction:

Clincal activity:

testicular/ovaria, H & N,bladder,lung,endometrial, brain

Cytarabine

(Ara-C, cytosine arabinoside)

Anti-metabolites

MOA: Inhibits DNA polymerase,incorporated into DNA & terminates chain elongation

PK:Inactivated in plasma by ccytidine deaminase (T1/2~10 min), carrier mediated intracellular transport; (higher w/ MTX on board)

Imp Toxicity: myelosuppression, mucositis, ↑ LFTs, CNS, Chest pain, conjuctivitis

Drug Interaction:

Clinical activity:

luekemia & lymphoma

Methotrexate

(MTX, amethopterin)

Antifolate

MOA: inhibition of dihydrofolate reductase (partially depletes reduced(activated) folates needed for DNA synthesis; metabolites inhibit purine & thymidylate biosynthesis

PK: dose dependent -bioavailability,RENAL & HEPATIC elimination,active intracellular transport, sequestration & delayed elimination from effusions/ascites

Imp Toxicity: myelosuppression, mucositis, pneumonitis, renal obstruction, neurotoxicity

Drug Interaction:NSAIDs,or probenecid

Clinical activity:

leukemia,lymphoma,peds,ovarian

5-Fluorouracil

(5-FU)

Antimetabolite

MOA: inhibition of thymidylate synthease

PK: complex conversion to activated nucleotide forms; systemic inactivation by dihydropyrimidine dehydrogenase (T1/2~10 min)

Imp Toxicity: mucositis/diarrhea (continuous infusion),myelosuppression(daily bolus), "hand & foot"

Drug Interaction: leucovorin (stabilizes/prolongs binding of 5-FU to t..synthase, MTX caution,levamisole

Clinical activity

colorectal,stomach,pancreatic,breast,head & neck,renal cell.esophageal,prostate,skin

Doxorubicin

(DOX,Adriamycin)

DNA intercalators-Topoisomerase Inhibitors

MOA: free radical formation, topo..II interaction,DNA intercalation; S phase cells most sensitive

PK: Lg Vd(25L),parent & alcohol metabolites active, elination viable (T1/2~1-2 days) w/ Doxil (3 days)

Imp Toxicity: cardiac (acute arrhy & chronic CHF dose related),myelosuppression,micositis,vesicant;radiosenstizer (make fluid/tissues red)

Drug Interaction: cyclosporine or paclitaxel (inhibits DOX clearance)

Clinical activity

danunorubicin-leukemia,doxorubicin breast,luekemia,lymphoma

Irinotecan

(CPT-11,Camptosar)

Topoisomerase I Inhibitor

MOA: stabilization of ternary complex between topo..I & double stranded DNA inducing single strand breaks & thus prevent cells from entering mitosis (G2 arrest)

PK: converted by carboxyesterases to SN-38 which is 100-1000 fold more active, several other inactivated Me via CYP3A4 glucur../bilary excretion of SN-38

Imp Toxicity: myelosuppression,diarrhea (early vs late) Hepatic

Drug Interaction: CYP 3A4 inducer/inhibitors

Clinical activity

lung, colo-rectal, ovarian

Vincristine

(VCR, Oncovin)

Miotic Inhibitor

MOA: bind tubulin,inhibit midrotubule formation(M phase spec.)

PK: Hepatic metabolism,biliary elimination, NO CNS penetration

Imp Toxicity: neuropathy, myelosuppression,mucositis, photosensitivity, vesicants

Drug Interaction: CYP3A4 inhibitors or cyclosporine

Paclitaxel

(Taxol)

Miotic Inhibitor

MOA: promotes microtubule assembly but inhibits depolymerization(stabilizes in non functionslo state),inhibits Go→S, XRT sensitizer

PK: saturable distribution & clearance,metabolism CYP2C8 & 3A4 llimited CNS

Imp Toxicity: acute anaphylaxis, myelosuppression, total body alopecia,sensory neuropathy

Drug Interaction: CYP 3A4 &2C8 inducer/inhibitors; cisplatin (↓ taxol clearance)

Docetaxel

(Taxotere)

Miotic Inhibitor

MOA: promotes microtuble assembly but inhibits depolymerization, inhibits Go→S; XRT sensitizer

PK: metabolized by CYP3A4

Imp Toxicity: myelosuppression, hypersensitivity, rash,peripheral neuropathy, fluid retention(edema,pleural effusion,ascites) attenuated by pre/post medication w/ steriods, total body alopecia

Drug Interaction: CYP 3A4 inducer/inhibitors

Clinical activity

breast,lung,ovariion,head & neck

Erlotinib

(Tarceva)

Signal Transduction Inhibitor

MOA: competitive inhibitor of ATP on tyrosine associsted w/ epidermal growth factor activation (EGFR;ErB1;HER1)

PK: inactivated by CYP3A4

Imp Toxicity: diarrhea,rash,fatigue,n/v,pulmonary

Drug Interaction: CYP3A4 inducer/inhibitors

Clinical activity

NSCLC,pancreatic cancer, head & neck

Imatinib

(STI-571,Gleevec)

Signal Transduction Inhibitors

MOA: competitive inhibitor of ATP on several tyrosine kinases (Bcr-Abl,PDGF,SCF,c-kit) → inhibition of proliferation & induction of apoptosis

PK: metabolized by CYP3A4 to another active Me

Imp Toxicity: n/v (T,w/F)diarrhea,muscle cramps,rash fatigue

Drug Interaction: CYP3A4 inducer/inhibitors (may inhibit mutiple P450 isoenzymes)

Clinical activity

Ph+CML or ALL,GI stromal tumors

Sunitinib

(Sutent)

Signal Transduction Inhibitors

MOA: inhibits >80 tyrosine kinases(eg.PDGF) casuing anti-proliferation & antiangio

PK: metabolized by CYP3A→active Me

Imp Toxicity: ↓ LVEF,bleeding HTN,rash,mucositis,hand foot syndrome

Drug Interaction: CYP3A4 inducer/inhibitors,inhibits

UGT 1A1

Temsirolimus

(Torisel)

mTOR Inhibitor

MOA: binds to an intracellular protein (FKBP-12)& this complex inhibits mTOR (downstream of VEGF,EGF)→growth arrest

PK: metabolized CYP3A4 to active Me (sirolimus)

Imp Toxicity: immunosupression,hypersensitivity,hyperglycemia,

hyperlipidemia, n/v

Drug Interaction: invitro inhibitor of CYP3A4 & 2D6; reduced [ ] w/ enzyme inducers

Clinical activity

Renal cell carcinoma

Anastrole

(Arimidex)

Competitive Aromatase Inhibitors

MOA:blocks aromatase conversion of androgen to estrogens in peripheral tissue

PK: metabolic elimination

Imp Toxicity:menopausal sx,vaginal dryness/bleeding, GI effects osteorosis 

 Drug Interaction: tamoxifen ↓ clearance of anastrozole

Clinical activity

post menopausal breast cancer

Bicalutamide

(Casodex)

Androgen Receptor Antagonist

MOA:bind to cytosol androgen rp in prostraste

PK: extensive metabolism & glucuronidation

Imp Toxicity: gynecomastia,hot flashes,liver,diarrhea

Drug Interaction:

Clinical activity

prostate cancer w/ LHRH analog

Bicalutamide

(Casodex)

Androgen Receptor Antagonist

MOA: binds to cytosol androgen rp prostrate

PK: extensive metabolism & gluconoration

TOX: gynocomastia, hot flashes, LIVER toxic, diarrhea

DRUG INTERACTION:

Leuprolide

(Leupron)

GnRH Agonists

MOA: initial surge of LH & FSH from pituitary gland

PK: avid metabolism

TOX: hot flashes reduced libdo, GI,

Dosing can implant to stimulate upregulation

Bevacizumab

(Avastin)

Monoclonal Antibody

Humanized unconjugated

MOA: binds to vascular endothelial growth factor

(VEGF) →inhibits tumor related angiogenesis

PK: clearance dependent on tumor vol. (T1/2~20 days)

TOX: bleeding,GI perforation, reduced wound healing

Dosing wait 28 days after major surgery

Cetuximab

Murine/human chimeric unconjugated

MOA: binds to epidermal growth factor rp (EGFR) on the surface of tumor cells & competitively inhibits the ability of EGF & TGF-α to rp thus blocking signaling for tumor cell growth

PK: T1/2~ 4 days

TOX: Acenform rash,diarrhea

Rituximab

(Rituxan)

Murine/human chimeric unconjugated

MOA: binds CD on B lymphocytes mechanism cell lysis

PK: T1/2~ 3-7 days

TOX: infusion related

 thrombocytopenia risk of death

Very $$$$$$$

Trastuzmab

(Herceptin)

Humanized, unconjugated

MOA: bindsd to HER2 rp → cyclin dependent kinase inhibitor p27 accumulates & cell arrest occurs

PK: dose related ↑ in T1/2~6 days & ↓in drug clearance

TOX: CHF, diarrhea,

 hypersensitivity can be fatal

Erythropoietin

(EPO)