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Similar to Alkylating agents by Dr.Neenu Thomas
Alkylating agents by Dr.Neenu Thomas
- 1. Alkylating Agents Dr.Neenu Thomas 1st YrPG, Dept. Of Radiotherapy
- 2. HISTORY • Mechlorethamine- first alkylating agent-1942 •Analogue of Sulphur mustard gas • Weapon in first world war-1917
- 3.
- 5. Mechanism of DNAalkylation by a reactive nitrogen mustard molecule and formation of interstrand cross-link M O A
- 6. Monofunctional adducts and1,2- and 1,3- interstrand and intrastrand cross-links induced by DNA interactive agents. X = antitumour agent. M O A
- 7.
- 8. • Inactive inparent form • Activated by liver cyt- p450 to cytotoxic metabolites PM & acrolein • DNA adduct M O A Mechanism of Action
- 9. PHARMACOKINETICS • ROA- ivin 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
- 10. PHARMACOKINETICS • Metabolism- Prodrug activationby Cyt-p450 active forms are 4 hydroxycyclophospham ide phosphoramide mustard & acrolein • Elimination-t1/2- 4-6 hours parent drug & metabolites exclusively in urine Cyclophosphamide & Ifosfamide
- 11. Indications • Breast Cancer •Ovarian Cancer • Sarcoma • NHL • High dose regimen-in bone marrow transplantation and for other autoimmune disorders
- 12. Dosage range • Breastcancer 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
- 13. DRUG INTERACTION • InhibitActivation 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
- 14. • Caution inpatients with abnl renal fuction • Encourage fluid intake 2-3l/day • Empty bladder several times daily Special consideration
- 15. • Myelosuppression- doselimiting 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
- 16.
- 17. • 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 T O X I C I T Y
- 18.
- 19. • ROA- oralor iv • Absorption- bioavailability 100% • Distribution- Widely distributed • Protein binding 20% • Metabolism in liver • Elimination- 50-70% excreted in urine • T1/2- 3 -10hrs PHARMACOKINETICS
- 20. Indication • Osteogenic sarcoma •Ewing sarcoma • HL &NHL • Non small cell & small cell lung cancer • Bladder cancer • Recurrent germ cell tumors
- 21. Drug Interaction • Anticonvulsants,cimetidine & allopurinol increase the metabolism –enhanced toxicity • Cisplatin increases renal toxicity • Enhances anticoagulant effects of warfarin
- 22. • Caution inpatients with abnl renal function • Uroprotection with mesna & hydration • Monitor coagulation parameters Special consideration
- 23. Toxicity • Myelosuppression • Bladdertoxicity dose limiting • Alopecia >80 % • Amenorrhoea oligospermia
- 24. • High doseifosfamide –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 T O X I C I T Y Oxidation N-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
- 25.
- 26. • Absorption- not orallybioavailable • Metabolism- rapid hydrolysis in plasma • Elimination- >50% in urine • T ½- 15-20 min PHARMACOKINETICS
- 27. Indication • HL • NHL •Cutaneous T cell lymphoma • Intrapleural intrapericardial intraperitoneal treatment of metastatic disease
- 28. • HL 6mg/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
- 29. • Sod thiosulfateinactivates Drug Interaction
- 30. • Potent vesicant •Inflammation & necrosis pvt by instillation of 2.6 % sod thiosulfate solution Special consideration
- 31.
- 32. Mono & Bifunctional DNA Adduct Mechanismof Action Melphalan
- 33. PHARMACOKINETICS • ROA- Oral& iv • Absorption-oral absorption poor Bioavail 60% Food Reduces • Vol of Dist- 0.5L/Kg • Distribution-Protein binding >50 % Melphalan
- 34. PHARMACOKINETICS • Elimination –via Hydrolysis of chloro ethyl sidechains to mono and dihydroxy forms • 25-30% in urine • 13-40 min (iv) Melphalan
- 35. • Multiple Myeloma •Ovarian cancer • Myeloablative therapy –Bone marrow transplant CLINICAL USE Melphalan
- 36. • Multiple myeloma- 9mg/m2 iv D1-D4 every 4 weeks melphalan prednisone regimen • Transplant 140mg/m2 single agent Dosage range
- 37. DRUG INTERACTION • Cimetidine –30% reduction in Melphalan Absorption – Steroids enhance antitumor activity – Cyclosporine enhance renal toxicity Melphalan
- 38.
- 39. PHARMACOKINETICS • ROA- Oral bioavailability75% • Absorption- Food Reduces • Distribution-Protein binding >98 % • CNS Penetration- low con in CSF Chlorambucil
- 40. PHARMACOKINETICS • Metabolism-liver cyt p450Phenyl acetic acid • Elimination – 60% of drug metabolites eliminated in urine • T1/2 1.5-2.5 hrs Chlorambucil
- 41.
- 42. • CLL 0.1 0.2mg/kgPo daily 3-6 wks- initiation • 2-4mg po daily maintenance Dosage range
- 43. • Anticonvuslants increased formationof toxic metabolites Drug Interaction
- 44. Special consideration • Cautionwhen combined with allopurinol –drug induced hyperuricemia • Closely monitor CBCs • Discontinued if generalised skin rash develops-EM,TEN,SJS
- 45. • Myelosupression • Nausea& vomiting • Hyperuricemia • Pulmonary fibrosis & pneumonitis • Skin rash urticaria • Amenorrhoea ,oligospermia • Sec malig Toxicity
- 46.
- 47.
- 48. PHARMACOKINETICS • ROA- ivintravesical Absorption oral incomplete • Protein binding- <10% • CNS penetration- CSFcon equivalent to plasma • Distribution- 0.7L/Kg Thiotepa
- 49. PHARMACOKINETICS • Metabolism –Thiotepa TEPA –inactivationby CYP2B • Elimination- 60%in urine – t1/2 < 2hr Thiotepa
- 50. • Breast cancer •Ovarian cancer • HL • NHL Indication
- 51. • 10-20mg/m2 iv every3-4 weeks • Intravesical instillation 60mg in 60ml sterile water weekly upto 4 weeks Dosage range
- 52. • Monitor cbcafter 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
- 53.
- 54. PHARMACOKINETICS • Highly variable –Age –Circadianvariation –Disease type • ROA- Oral • Absorption- excellent bioavailability Busulphan
- 55. 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
- 56. CLINICAL USE • CML •Myeloablative treatment- prior to BMT Busulphan
- 57. • CML remission induction4- 8mg/day po • Maintenance dose 1-3mg/day po • Transplant 4mg/day iv 4 days Dosage range
- 58. • Pretreatment withAnti convulsants increase rate of elimination by 20% • Concurrent treatment with CP increases clearance • Acetaminophen& itraconazole decrease metabolism enhanced toxicity Busulphan Drug Interaction
- 59. Special consideration • Monitorpatients for pulmonary symptoms • Ingestion on an empty stomach decrease the risk of nausea
- 60. Toxicity • Myelosuppression • Nauseaand vomiting >80% • Mucositis • Impotence, male sterility ,amenorrhoea • Interstitial pulmonary fibrosis busulfan lung may occur 1-10 yrs after therapy • Hepatovenoocclusive disease >16mg/day
- 61.
- 62.
- 63. By alkylation of DNAand possibly by carbamoylation of protein Mechanism of Action Nitrosourea
- 64. 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
- 65. PHARMACOKINETICS • Vol ofDist- 3-5 L/kg • Elimination-60-70% in urine – mostly as metabolites –t1/2 0.4-4.3 h Nitrosourea
- 66. CLINICAL USE • Braintumour- GBM,glioma • Multiple Myeloma • Hodgkins Lymphoma,NHL Nitrosourea
- 67. • 200mg/m2 iv every6 weeks • Implantable BCNU impregnated wafers at the surgical resection Dosage range
- 68. • Cimetidine &hotericin B enhances toxicity • decrease the plasma level of Digoxin & phenytoin Drug Interaction
- 69. • Administer slowly overa period of 1-2 hrs to avoid intense pain & burning • Pfts should be obtained at baseline Special consideration
- 70. 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
- 71.
- 72. • 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
- 73.
- 74. 130mg/m2 po every 6weeks Dosage range
- 75. • PFTs monitored periodically •Administer drug on empty stomach Special consideration
- 76. • Decreased cellularuptake 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
- 77.
- 78. • Methylates nucleic acids andinhibits DNA RNA & protein syn Mechanism of Action
- 79. Mechanism of Resistance •Increased activity of DNA repair enzymes O6alkyl guanine DNA alkyl transferase (AGAT)
- 80. • 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
- 81. • Metastatic malignant melanoma •HL • Sarcoma • Neuroblastoma Indication
- 82. • HL 375mg/m2iv D1 D15 every 28 days ABVD Dosage range
- 83. • Heparin lignocaine hydrocortisoneincompatible with dacarbazine • Anticonvulsants decrease the efficacy Drug Interaction
- 84. • Potent vesicant •Use of aggressive antiemetics • Avoid sunexposure Special consideration
- 85. Toxicity • Flu likesyndrome • CNS toxicity paresthesia neuropathies, ataxia,seizures • Photosensitivity • Teratogenic
- 86.
- 87. Temozolomide Spontaneously releases the cytotoxicspecies 3- methyl-(triazen-1-yl) imidazole-4- carboxamide(MTIC) Dacarbazine Requires metabolic activation mediated by microsomal enzymes CH 3
- 88. • 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
- 89. Mechanism of Resistance •Increased activity of DNA repair enzymes O6alkyl guanine DNA alkyl transferase (AGAT)
- 90. PHARMACOKINETICS • ROA- Oral,iv •Absorption- –oral bioavailability 100% –Food reduces • Peak con- <1 h Nitrosourea
- 91. 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- 1.8h Nitrosourea
- 92. • 150mg/m2 po dailyfor 5 days - 28 days • 75mg/m2 po daily for 42 days with RT- GBM Dosage range
- 93. CLINICAL USE • Glioma •Astrocytoma • Melanoma Busulphan
- 94. DRUG INTERACTION Toxicity increases in priorexposure to nitrosureas
- 95. • Moderately emetogenic agent. •Avoid sun exposure after Rx • Caution in elderly patients Special consideration
- 96. Toxicity • Myelosupression-Dose limiting toxicity •Photosensitivity • Teratogenic