Download - Alkylating agents by Dr.Neenu Thomas
Alkylating Agents
Dr.Neenu Thomas1st Yr PG, Dept. Of Radiotherapy
HISTORY• Mechlorethamine-
first alkylating agent-1942
• Analogue of Sulphur mustard gas
• Weapon in first world war-1917
Alkylating Agents
Nitrogen Mustards
CarmustineLomustineStreptozotocin
BusulfanCyclophosphamideIfosfamideMelphalanChlorambucilMechlorethamine
AziridinesAlkyl
Sulfonates
Nitrosoureas Triazenes
DacarbazineTemozolomide
Thio TEPA
Mechanism of DNA alkylation by a reactive nitrogen mustard molecule and formation of
interstrand cross-link
MOA
Monofunctional adducts and 1,2- and 1,3-interstrand and intrastrand cross-links induced
by DNA interactive agents. X = antitumour agent.
MOA
CYCLOPHOSPHAMIDE
• Inactive in parent form • Activated by liver cyt-
p450 to cytotoxic metabolites PM & acrolein
• DNA adduct
MOA
Mechanism of Action
PHARMACOKINETICS• ROA- iv in Dextrose 5% or
NaCl 0.9 %, Oral• Absorption bioavailability
90%• Vol of Dist-0.6L/Kg• Distribution-including brain
& csf,also in milk & saliva• Protein binding- <20%
Cyclophosphamide & Ifosfamide
PHARMACOKINETICS• Metabolism- Prodrug
activation by Cyt-p450 active forms are 4 hydroxycyclophosphamide phosphoramide mustard & acrolein
• Elimination-t1/2- 4-6 hours parent drug & metabolites exclusively in urine
Cyclophosphamide & Ifosfamide
Indications• Breast Cancer• Ovarian Cancer• Sarcoma• NHL• High dose regimen-in bone
marrow transplantation and for other autoimmune disorders
Dosage range• Breast cancer 100mg/m2 po
days 1-14 every 28 days,iv 600mg/m2 every 21 days AC or CMF
• NHL 400-600 mg/m2 iv every 21 days CVP,750mg/m2 every 21 days CHOP
• High dose BMT 60mg/kg iv for 2 days
DRUG INTERACTION • Inhibit Activation of CP
– Antifungal Agents– Allopurinol– Chlorpromazine– Thiotepa
• Enzyme inducers– Steroids– Anticonvulsants
• Cp increase the effect Anticoagulants • Dec. the plasma levels of digoxin• Inc. the risk of doxorubicin induced cardiotoxicity
• Caution in patients with abnl renal fuction
• Encourage fluid intake 2-3l/day
• Empty bladder several times daily
Special consideration
• Myelosuppression- dose limiting mainly leukopenia 7-14 days
• Nausea & vomiting 2-4 hrs• Alopecia 2-3 wks • Amenorrhoea with ovarian failure • Cardiotoxicity• Sec malig AML & bladder cancer• SIADH
Toxicity
TOXICITY
• Hemorrhagic cystitis- Excretion of Acrolein– Rx
• Adequate hydration• Continuous irrigation of bladder with
MESNA (2mercaptoethanesulfonate)• Frequent bladder emptying
– MESNA• Free sulfhydryl• Divided doses every 4 hrs- 60% of
alkylating agents
TOXICITY
IFOSFAMIDE
• ROA- oral or iv • Absorption- bioavailability
100%• Distribution- Widely
distributed• Protein binding 20%• Metabolism in liver • Elimination- 50-70% excreted
in urine • T1/2- 3 -10hrs
PHARMACOKINETICS
Indication • Osteogenic sarcoma • Ewing sarcoma• HL &NHL • Non small cell & small cell lung
cancer• Bladder cancer • Recurrent germ cell tumors
Drug Interaction • Anticonvulsants, cimetidine &
allopurinol increase the metabolism –enhanced toxicity
• Cisplatin increases renal toxicity • Enhances anticoagulant effects
of warfarin
• Caution in patients with abnl renal function
• Uroprotection with mesna & hydration
• Monitor coagulation parameters
Special consideration
Toxicity• Myelosuppression• Bladder toxicity dose limiting • Alopecia >80 %• Amenorrhoea oligospermia
• High dose ifosfamide– Neurotoxicity
• Seizures, altered mental status,CN palsies, coma
• Painful and acute exacerbation of peripheral sensory neuropathies and motor dysfunction of distal extremities
• N-linked Chloroethyl Chloro Acetaldehyde
TOXICITY
OxidationN-Deethylation
Recommendations High risk - S.Cr>1.5mg or S.Albumin <3g/dl or both Multiple day regimens reduce risk Monitor-early signs(irritability,anxiety,hallucinations) Terminate ifosfamide Palliative therapy
Mechlorethamine
• Absorption- not orally bioavailable
• Metabolism- rapid hydrolysis in plasma
• Elimination- >50% in urine
• T ½- 15-20 min
PHARMACOKINETICS
Indication • HL• NHL • Cutaneous T cell lymphoma • Intrapleural intrapericardial
intraperitoneal treatment of metastatic disease
• HL 6 mg/m2 iv D1 &D8 every 28 days MOPP regimen
• Cutaneous 10mg in 60ml sterile water
• Intracavitary use 0.2 0.4 mg/kg
Dosage range
• Sod thiosulfate inactivates
Drug Interaction
• Potent vesicant • Inflammation &
necrosis pvt by instillation of 2.6 % sod thiosulfate solution
Special consideration
Melphalan
Phenylalanine
Mono & Bifunctional DNA Adduct
Mechanism of Action
Melphalan
PHARMACOKINETICS• ROA- Oral & iv• Absorption-oral
absorption poor Bioavail 60% Food Reduces
• Vol of Dist- 0.5L/Kg• Distribution-Protein
binding >50 %Melphalan
PHARMACOKINETICS
• Elimination – via Hydrolysis of chloro ethyl sidechains to mono and dihydroxy forms
• 25-30% in urine • 13-40 min (iv)
Melphalan
• Multiple Myeloma• Ovarian cancer• Myeloablative therapy
– Bone marrow transplant
CLINICAL USE
Melphalan
• Multiple myeloma -9mg/m2 iv D1-D4 every 4 weeks melphalan prednisone regimen
• Transplant 140mg/m2 single agent
Dosage range
DRUG INTERACTION • Cimetidine
– 30% reduction in Melphalan Absorption
– Steroids enhance antitumor activity
– Cyclosporine enhance renal toxicity
Melphalan
Chlorambucil
Aromatic Mustard
PHARMACOKINETICS• ROA- Oral bioavailability
75%• Absorption- Food
Reduces• Distribution-Protein
binding >98 %• CNS Penetration- low
con in CSFChlorambucil
PHARMACOKINETICS• Metabolism-liver cyt
p450 Phenyl acetic acid
• Elimination – 60% of drug metabolites eliminated in urine
• T1/2 1.5-2.5 hrsChlorambucil
• CLL• NHL• HL
Indication
• CLL 0.1 0.2mg/kg Po daily 3-6 wks-initiation
• 2-4mg po daily maintenance
Dosage range
• Anticonvuslants increased formation of toxic metabolites
Drug Interaction
Special consideration• Caution when
combined with allopurinol –drug induced hyperuricemia
• Closely monitor CBCs• Discontinued if
generalised skin rash develops-EM,TEN,SJS
• Myelosupression• Nausea & vomiting • Hyperuricemia• Pulmonary fibrosis & pneumonitis• Skin rash urticaria• Amenorrhoea ,oligospermia • Sec malig
Toxicity
Neurotoxicity–Phenylacetic acid–Oxidative N
dechloroethylation
TOXICITY
Chlorambucil
Thiotepa
Thiotepa
PHARMACOKINETICS• ROA- iv intravesical
Absorption oral incomplete
• Protein binding- <10%• CNS penetration-
CSFcon equivalent to plasma
• Distribution- 0.7L/KgThiotepa
PHARMACOKINETICS
• Metabolism– Thiotepa TEPA– inactivation by CYP2B
• Elimination- 60%in urine – t1/2 < 2hr
Thiotepa
• Breast cancer• Ovarian cancer• HL• NHL
Indication
• 10-20mg/m2 iv every 3-4 weeks
• Intravesical instillation 60mg in 60ml sterile water weekly upto 4 weeks
Dosage range
• Monitor cbc after intravesical adm –bone marrow depression from systemically absorbed drug
• Resuscitation equipment should be available-hypersensitivity
• Caution about the chance of skin changes urticaria, bronzing, flaking
Special consideration
Busulphan
Busulphan
PHARMACOKINETICS• Highly variable
–Age –Circadian variation–Disease type
• ROA- Oral • Absorption- excellent
bioavailabilityBusulphan
PHARMACOKINETICS• CNS Penetration- Enter
Easily• Vol of Dist- 27+/- 11L/m2
• Metabolism- By liver cyt p450
• Elimination-t1/2 2.5hrs• Higher clearance rate in
evening in young– Faster in Children– Less rapidly in leukemic
patients Busulphan
CLINICAL USE
• CML• Myeloablative
treatment- prior to BMT
Busulphan
• CML remission induction 4-8mg/day po
• Maintenance dose 1-3mg/day po
• Transplant 4mg/day iv 4 days
Dosage range
• Pretreatment with Anti convulsants increase rate of elimination by 20%
• Concurrent treatment with CP increases clearance
• Acetaminophen& itraconazole decrease metabolism enhanced toxicity
Busulphan
Drug Interaction
Special consideration• Monitor patients
for pulmonary symptoms
• Ingestion on an empty stomach decrease the risk of nausea
Toxicity• Myelosuppression• Nausea and vomiting >80%• Mucositis• Impotence, male
sterility ,amenorrhoea• Interstitial pulmonary fibrosis
busulfan lung may occur 1-10 yrs after therapy
• Hepatovenoocclusive disease >16mg/day
Nitrosourea
Nitrosourea
Carmustin (BiCNU)
Nitrosourea
By alkylation of DNA and
possibly by carbamoylation
of protein
Mechanism of Action
Nitrosourea
PHARMACOKINETICS• ROA- iv• Absorption- not absorbed
orally• Distribution lipid soluble
drug cross BBB >50%in plasma– Metabolism- Spontaneous
decomposition to chloroethyl carbonium ion
– Isocyanate may also form
Nitrosourea
PHARMACOKINETICS
• Vol of Dist- 3-5 L/kg• Elimination-60-70% in
urine – mostly as metabolites– t1/2 0.4-4.3 h
Nitrosourea
CLINICAL USE• Brain tumour-
GBM,glioma• Multiple
Myeloma• Hodgkins
Lymphoma,NHLNitrosourea
• 200mg/m2 iv every 6 weeks
• Implantable BCNU impregnated wafers at the surgical resection
Dosage range
• Cimetidine & amphotericin B enhances toxicity
• decrease the plasma level of Digoxin & phenytoin
Drug Interaction
• Administer slowly over a period of 1-2 hrs to avoid intense pain & burning
• Pfts should be obtained at baseline
Special consideration
Toxicity• Facial flushing & burning
sensation at the iv site• Hepatotoxicity with elevated
LFT 90% within 1 week ,hepatovenoocclusive d/s 5-20%
• Pulmonary toxicity at cumulative dose >1400
Lomustin (CCNU)
Nitrosourea
• Absorption- completely orally • Distribution- Lipid soluble
drug with broad tissue distribution
• Cross BBB and csf con 15-30 %of plasma levels
• Metabolism- in liver • Elimination- 50% in urine • T1/2- 72 hrs
PHARMACOKINETICS
•Brain tumor•HL•NHL
Indication
130mg/m2 po every 6 weeks
Dosage range
• PFTs monitored periodically
• Administer drug on empty stomach
Special consideration
• Decreased cellular uptake of drug• Decreased expression of drug
activating enzymes of the liver p450 system
• Increased expression of sulfhydryl proteins including gluthathione and asso enzymes
• Increased expression of aldehyde dehydrogenase resulting in enhanced enzymatic detoxification of drug
• Enhanced activity of dna repair enzymes
Mechanism of Resistance
Dacarbazine
Nonclassic alkylating agent
• Methylates nucleic acids and inhibits DNA RNA & protein syn
Mechanism of Action
Mechanism of Resistance• Increased
activity of DNA repair enzymes O6alkyl guanine DNA alkyl transferase (AGAT)
• ROA- iv• Absorption- slow & variable • Distribution- widely
distributed • Protein binding- 20%• Metabolism- in liver to MTIC
AIC• Elimination- 40 -60%
unchanged in urine• t1/2- 5 hrs
PHARMACOKINETICS
• Metastatic malignant melanoma
• HL • Sarcoma• Neuroblastoma
Indication
• HL 375mg/m2 iv D1 D15 every 28 days ABVD
Dosage range
• Heparin lignocaine hydrocortisone incompatible with dacarbazine
• Anticonvulsants decrease the efficacy
Drug Interaction
• Potent vesicant• Use of
aggressive antiemetics
• Avoid sunexposure
Special consideration
Toxicity• Flu like syndrome• CNS toxicity paresthesia
neuropathies, ataxia,seizures
• Photosensitivity• Teratogenic
Temozolomide
TemozolomideSpontaneously releases the cytotoxic species 3-methyl-(triazen-1-yl) imidazole-4-carboxamide(MTIC)
DacarbazineRequires metabolic activation mediated by microsomal enzymes
CH3
• Imidazotetrazine analog• Methylates guanine
residues(N7,O6) in DNA and inhibits DNA,RNA,protein syn
• Cytotoxicity-formation of O6 methyl guanine adducts
Mechanism of Action
Mechanism of Resistance• Increased
activity of DNA repair enzymes O6alkyl guanine DNA alkyl transferase (AGAT)
PHARMACOKINETICS• ROA- Oral,iv• Absorption-
–oral bioavailability 100%
–Food reduces • Peak con- <1 h
Nitrosourea
PHARMACOKINETICS• CNS Penetration- High, CSF
con 30-40% Selective distribution over tumour in brain
• Metabolism- MTIC &AIC• Vol of Dist- 3-5 L/m2
• Elimination-– Majority in urine 40-50%
• t1/2- 1.8hNitrosourea
• 150mg/m2 po daily for 5 days -28 days
• 75mg/m2 po daily for 42 days with RT- GBM
Dosage range
CLINICAL USE
• Glioma• Astrocytoma• Melanoma
Busulphan
DRUG INTERACTION Toxicity increases in prior exposure to nitrosureas
• Moderately emetogenic agent.
• Avoid sun exposure after Rx
• Caution in elderly patients
Special consideration
Toxicity• Myelosupression-Dose
limiting toxicity• Photosensitivity• Teratogenic