alkylating agents

Alkylating Agents

Presented by :

Clinical Pharmacist: Heba Sabry,Reem Ahmed,Dina redda,Dalia El-Magraby and Heba Othman.

Pharm-D 4 (2009) Group 1.

Alkylating Agents Contain an alkyl group (highly reactive

chemical group which allow them to form irreversible covalent bond with other molecules specially at the cross link of DNA).

In DNA, the N-7 position of guanine is especially susceptible to alkylation, it interferes with separation of the strands and prevent mitosis.

COMMON STRUCTURE R N

CH2CH2Cl

CH2CH2Cl

Ar NCH2CH2Cl

CH2CH2Cl

Ar NCH2CH2Cl

CH2CH2Cl

or

Ar NCH2CH2

CH2CH2Cl

Nu

Enzyme, proteins DNA, RNA

Nu--

-

Ar N

CH2CH2

CH2CH2Cl

+

Alkylating Mechanism of Mechlorethamine With Guanine Base

1HN

N

O

NH2N

N

DNA Strand A

CH2CH2

N

CH2CH2

6

23 4

5 7 NHN

N

DNA Strand B

NH2

O

Cl Cl

e.g. R NCH2CH2Cl

CH2CH2Cl

Alkylation bischloroethyl groupHN

N

O

NH2N

N

DNA Strand B

HN

N

O

NH2N

N

DNA Strand A

N7-N7 Biguanyl DNA cross link

+

1. Attachment of the alkyl groups to DNA bases.

2-Formation of cross bridges, bonds between atoms in the DNA.

3-Induction of mispairing of the nucleotides leading to mutations.

Classification of alkylating agents

Nitrogen Mustard Nitrosourea Ethylenamines Alkylsulfonate Triazine Metal salts

Melphalan Carmustine Thiotepa Busulfan DTIC Cisplatin

Chlorambucil Lomustine CarboplatinIfosfamide Oxatiplatin

Cyclophosphamide

Nitrogen MustardCyclophosphamide Ifosfamide

Trade name Endoxan® cytoxan® Holoxane®

Structure

AbsorptionWell absorped orally.No oral form

DistributionWidely distributed.BBB Cross.(brain tumour)Vd 0.35-1.2 L/Kg. PPB 10% - 56% minimal.

Widely distributed.BBB Cross.Vd 0.35-0.85 L /Kg.PPB Negligible.

Metabolism Prodrugs metabolised by Cytochrome p450 to active metabolites in the liver (acrolein and phosphoramide mustard which is a potent alkylator) .

(4-OH cyclophosphamide and aldophosphamide)

Elemination Unchanged 25% of oral and IV, active metabolite 62% in the

urine for 48 hours .

Renally: 70-86%, 61% unchanged after high dose (5 gm/m2), 18% unchanged after low dose (1-2.4 gm/m2 )

P

N O

N

CH2CH2Cl

CH2CH2Cl N

P

O O

N

CH2CH2Cl

CH2CH2Cl

H

Metabolism of Ifosfamide

Generation of CAA may explain differing antitumoral activities of IFO and cyclophosphamide and Suppression of CAA metabolic pathway , although it may be beneficial as a means of reducing neurotoxic responses, may also be associated

with a reduction in antitumor effect.

Ifosfamide has been shown to require metabolic activation by microsomal liver enzymes to produce biologically active metabolites. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. Opening of the ring results in formation of the stable urinary metabolite, 4-carboxyifosfamide. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation produces the major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide. The alkylated metabolites of ifosfamide

have been shown to interact with DNA.

Cyclophosphamide Ifosfamide

Dialysis Dialyzable.Administer the dose post hemodialysis.

Not dialysable.

Administration

•PO. 1 hour before meal . •IV Push over 3 to 5 min.•Bolus infusion over 15-30 min, slow infusion 1-24 hours.

IV over 30-60 min, continuous IV infusion

Adverse effects (Dose related)

•Heamorrhagic cyctitis, Hematuria. .•Myelosuppression.•Hyperurecemia.•Gastrointestinal side effects.•Pulmonary toxicity (interstitial pneumonitis).•Nervous system toxicity , and nephrotoxicity with ifosfamide.(Somnolence, confusion to sever encephalopathy).

Drug interaction

•Microsomal enzyme inducer (phenobarbital , phenytoin)•Microsomal enzyme inhibitor ( chloramphenicol, chloroquin.)•Inc. sedative effect of succynylcholine .•Nephrotoxic drugs eg. Cisplatin•Cyclophosphamide potentiate cardiac toxicity of anthracyclines.

CyclophosphamideIfosfamide

IndicationCancer of the bladder, bones, cervix, endometrium, breast, lungs, prostate, adrenal cortex, ovaries Soft tissue sarcomas . Thymoma, brain tumour Wilms' tumour

Recurrent testicular cancer and germ cell tumors Sarcomas (soft-tissue, osteogenic sarcoma, Ewing's sarcoma) Non-Hodgkin's lymphoma Hodgkin's disease Non-small cell and small cell lung cancer Bladder cancer Head and neck cancer Cervix cancer

Doses40-50mg/Kg in divided doses over 2-5 day.CAF : 500mg/m2

FEC: 600mg/m2

1.2-2.5g/m2 for 3-5 days.

DrugReconstitution

Final concentration

Dilution

Cyclophosphamide 1000 mg

2000 mg)BMS()RT(53

no preservative

SWI1000 mg: 50 mL

2000 mg: 100 mLSigns of melting is yellowish viscous liquid.

20 mg/mL48 h F, 24 h RT

<1 g: 100 NS* >1 g: 250 NS*

high dose in BMT: may need 500 NS*

NS,10 D5W, D5NS, D5-Ringer’s, Lactated Ringer’s, Sodium Chloride 0.45%, Sodium Lactate.6d in ref, 24h at Rt.

Ifosfamide1000 m g3000 mg

)Baxter()RT(

no preservative

1000 mg: 20 mL SWI109

3000 mg: 60 mL SWIshake well

50 mg/mL48 h F

0.6–20 mg/mL500–1000 mL*NS,

D5W, D5-NS,D5-1/2NS, Lactated Ringer’s72h. In ref.

24 h F, RT when mixed with mesna10D5W or Lactated Ringer’s when mixed

Prophylaxis against hemorrhagic cystitis Against hemorrhagic cystitis, hyperhydration and mesna given. IV

dose of mesna is 20% given at 0, 4, 8 hours or (1mg/mg drug). May be given orally at 4, 8 hours at 40% of the drug dose diluted in water or juice.

Patients are encouraged to: - drink plenty of water ( fluids) during therapy( most adults

will require at least 2L/day ) . -Void frequently . - Avoid taking the drug at night . Mesna react with acrolein and urotoxic metabolites to form nontoxic

metabolites . Oral absorption of mesna is 50% bioavailability so oral dose should be

double that of IV dose.

Mesna

Upon entering the bloodstream mesna is immediately converted to an inactive disulfide form, dimesna (dithiodiethanesulfate) which issubsequently filtered and secreted by the kidneys, where the enzymes thiol transferase and glutathione reductase reduce dimesna back to mesna. The free sulfhydryl (thiol) groups of mesna combine directly with a double bond of acrolein and with other urotoxic 4-droxyoxazaphosphorine metabolites (4-hydroxycyclophosphamide and 4-hydroxyifosfamide) to form stable nontoxic compounds. The metabolite acrolein has been implicated as the majorcausative agent in oxazaphosphorine-induced urothelial toxicity

ChlorambucilMelphalan

Trade nameLeukeran®

2 mg tab.

Alkeran® either 2 mg tab . or 50 mg vial

UsesCLL , Hodgkin and non Hodgkin lymphomas

,other uses as Behcet syndrome ,nephrotic syndrom and autoimmune haemolytic anemia.

Multiple myeloma,ovarian cancer,

breast cancer,melanoma, certain

sarcomas,preperative BMT regimens and other uses as amyloidosis.

Doses0.1-0.2 mg/kg /day.Oral: 0.1-0.5 mg/kg/day (duration and interval according to the indication).

IV: 10-140 mg /m2:

AbsorptionRapid and complete . Oral: Incomplete and variable

food reduces the absorption

(spacing).

DistributionWidely distributed.

Vd 0.14-0.24L/Kg

PPB 99%

Widely distributed.

Vd 0.5-0.6L/Kg ,

PPB 60- 90%

MetabolismHepatic microsomal enzyme oxidation.

Active metabolite : phenylacetic acid mustard.

In plasma through hydrolysis to mono,dihydroxy products

ChlorambucilMelphalan

EliminationRenally excreted.

Urinary excretion is low.

If BUN = 30 mg/dl or more :50 %reduction

AdministrationOne time with food.On an empty stomach .

Reconstitute with 10 ml diluent and dilute in NS ,IV infusion over 15 min.May intraarterial,intraperitoneal or by regional isolation perfusion (melanoma)

Adverse reactions Seizures.(high risk in children and with high doses)

Bronchopulmonary dysplasia.

Mutagenic,carcinogenic and teratogenic infertility .

Haematologic: anemia,leukopenia and thrombocytopenia may need dose reduction.

May arterial or venous thrombus.

Local:extravasation and phlebitis.Dermatologic: :rash,dermatitis and allergy.Mutagenic,carcinogenic and teratogenicinfertility .

Drug interactionNSAID,anticoagulant : risk of bleeding ↑

Cyclosporine:nephrotoxicity ↑Carmustine :pulmonary toxicity NSAID,anticoagulant : risk of bleeding ↑

ETHYLENAMINE DERIVATIVES

Thiotepa 15 and 30 mg vials

Uses Bladder,breast and ovarian cancer

Carcinomatous meningitis, soft tissue sarcoma, Hodgkin , NHL and in preperative BMT regimens.

Polyfunctional alkylating agent. (cytotoxic effect of Thiotepa and its metabolite Tepa).

Absorption Poorly absorbed, unstable in acidic medium ( no oral form )

DistributionRapid and extensive to tissues.

Vd 0.25-1.6L/Kg.

BBB crossing and reaches CSF.

PPB About 40% .

Thiotepa MetabolismIn liver by oxidative desulfuration to

triethylenephophoramide(TEPA).

Elimination 60% of IV dose excreted in urine within 72 hours .

Administration and doses

Reconstitute with sterile water to reach 10 mg/ml, and further dilution with NS (1 mg/ml).

IV push (the doses range from 20 mg/m2 to 1000 mg/m2)

Intrathecal (carcinomatous meningitis)

Intravesical (bladder irrigation) 60 mg in 60 ml NS and retained for 2 hrs.

Adverse reactions

Haematologic.Intravesicular injection may cause abdominal pain and hematuria.

Drug interaction Decreases pseudocholinesterase activity, prolonged apnea when administered with succinylcholine.

- With mivacurium : risk of respiratory deppression.

Metals saltsCisplatinCarboplatinOxaliplatin

Trade NamePlatinol®Paraplatin®Eloxatin®

Structure

•Cyclic rings increase chemical stability so they have less side effects and less reactivity. •Ring structure hydroxylated in water to form active moeity ,this reaction is slower in carboplatin than in cisplatin so carboplatin dose is 4-6 times that of cisplatin to produce the same cytotoxic effect.

Pt

NH3

NH3

Cl

Cl

Pt

O

O

NH3

NH3

CisplatinCarboplatinOxaliplatin

Indications•Seminoma cancer•Ovarian cancer•Testicular cancer•Bladder cancer•Head and neck cancer•Cervical cancer•NSCLC•SCLC•Eesophageal cancer•Brain cancer•Melanoma•Neuroblastoma

•Seminoma cancer•Ovarian cancer•Testicular cancer•Bladder cancer•Head and neck cancer•Cervical cancer•NSCLC•SCLC•Brain cancer•Neuroblastoma•Wilm’s tumor•retinoblastoma

•Colorectal cancer

Doses50-100 mg/m2 as a single IV infusion every 3-4 weeks or 15-20 mg/m2 as a daili inf. For 5 days every 3-4 weeks

CALVERT FORMULA= Total dose(mg)=

Target AUC×(GFR+25)

85 mg/m2 in a combination therapy


Side effect•Nephrotoxicity•Ototoxicity•Neurotoxicity•Ematogenesis•Anaphylaxsis•Hypomanesemia and hypocalcemia

•Hematological toxicity(thrombocytopenia,leukopenia)•Anaphylaxsis

•Anaphylaxsis•neuropathy

StabilityFurther diluted in dextrose 5% or sodium chloride and protected from light

Further diluted in dextrose 5% or sodium chloride but dextrose is preferable as after 24 hrs in saline there is 4-5% loss of carboplatin

Further diluted in dextrose 5% only


AdministrationI.V within 2-6 h (1 mg/min) or 24 h infusion . It has been proposed that a longer infusion time of 6-8 hours may decrease gastrointestinal and

renal toxicities.

I.V within 15' (short infusion). I.V within 2 h.

Hydration• Only required for cisplatinPretreatment hydration: Patients should be adequately hydrated before and for 24 hours after administration of cisplatin to ensure good urinary output and minimise nephrotoxicity. Hydration may be achieved by IV infusion of 2 litres of either sodium chloride IV infusion 0.9% or glucose-saline (eg glucose 4% in one-fifth sodium chloride IV infusion 0.9%) over a 2 hour period. During the last 30 minutes of the pretreatment hydration or after the hydration, 375 mL of 10%

mannitol injection may be administered via a side-arm drip .

Post-treatment hydration: Adequate hydration and urinary output must be maintained during the 24 hours following infusion. It has been suggested that IV hydration continue after treatment with the aim to administer 2 litres of sodium chloride IV

infusion 0.9% or glucose-saline over a period of 6-12 hours.

Radiation and Platinum Drug Interaction

Platinum drugs have chemical as well as biochemical and biological effects on cells, all of which may interact with radiation effects.

The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues.

The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or morbidity, depending upon such dose and time relationships.

Recommendations for minimizing Nephrotoxicity include:

Prepare cisplatin in saline containing vehicles. Infusion rate of cisplatin. Vigorous hydration(2 L glucose and normal saline) +

KCl + MgSO4 before cisplatin administrarion. Simultaneous administration of either mannitol or

furosemide. Maintaining urine output 100-150 ml/hr for 24 hours

after cisplatin administration. Avoid other nephrotoxic agents

(aminoglycosides,amphotericin…etc.).

Dacarbazine(DTIC)

Structure•Acts as an antimetaboliteinhibiting purine bases.•Dimethyl triazinoimidazoleCarboxamide.

DistributionLocalized in liver.BBB minimal.Vd 0.63L/KgPPB minimal .

MetabolismThrough liver enzyme.

Elimination•Renal 50% unchanged, 10 – 20% as its metabolite.

Administration Infused within 30-120 mins. with light protection as this compound unstable under light .

TriazineN

N

CONH2

N N N CH3

CH3

Dacarbazine(DTIC)

Adverse effects•Extravasation(irritant not vesicant).•Photosensitivity.•Hepatotoxicity.•Myelosuppression.

Drug interaction•Microsomal enzyme inducer Phenobarbitane ,carbamazepine.•Microsomal enzyme inhibitor amiodarone, ciprofloxacin ,ketoconazole…etc.•Inc. effect of allopurinol due to inhibition of xanthine oxidase.

TriazineDacarbazine(DTIC)

StructureActs as an antimetabolite

inhibiting purine bases.Dimethyl triazinoimidazole

Carboxamide.

DistributionLocalized in liver.

BBB minimal.

Vd 0.63L/Kg

PPB minimal .

MetabolismThrough liver enzyme.

EliminationRenal 50% unchanged, 10 – 20% as its metabolite.

Administration Infused within 30-120 mins. with light protection as this compound unstable under light .

N

N

CONH2

N N N CH3

CH3

Dacarbazine(DTIC)

Adverse effectsExtravasation(irritant not vesicant).Photosensitivity.Hepatotoxicity.Myelosuppression.

Drug interactionMicrosomal enzyme inducer Phenobarbitane ,carbamazepine.Microsomal enzyme inhibitor amiodarone, ciprofloxacin ,ketoconazole…etc.Inc. effect of allopurinol due to inhibition of xanthine oxidase.

Alkyl Sulphonate

ProcarbazineTrade nameMatulane®, Natulane

Structure1-methyl-2-benzyl derivative

of hydrazine

Absorption completely absorbed from the GI tract.

Distributiondistributes widely throughout the body tissues, concentrating in the liver, intestinal wall, skin, and kidneys. Procarbazine crosses the blood-brain barrier .

Metabolismextensive metabolism by the liver. Some metabolites have cytotoxic activity.

EliminationBoth unchanged drug and its metabolites are excreted in the urine. Seventy percent of a dose can be found in the urine in the first 24 hours after a dose..

Administrationorally

Procarbazine

Adverse

Effects

principal toxic effect is bone marrow depression, resulting in leukopenia, anemia, and thrombocytopenia. In patients with preexisting renal, hepatic, or bone marrow impairment, severe toxicity may occur. Procarbazine therapy should be discontinued if the leukocyte count is reduced to 4000/mm3 or less, or if the platelet count falls to 100,000/mm3 or less

Drug interaction

CNS Depressants Concomitant administration of CNS depressants such as barbiturates, antihistamines, opiates, hypotensive agents, should be undertaken with caution as these drugs may cause potentiation of CNS depression caused by procarbazine. • Other Drugs and Food Patients receiving procarbazine should not drink alcohol since a disulfiram-like reaction may result. Since procarbazine hydrochloride possesses some monoamine oxidase inhibitory activity, sympathomimetic drugs (including those in nose drops and cough preparations), local anesthetics, tricyclic antidepressants, and other drugs and foods with known high tyramine content such as cheese, bananas, yogurt, tea, coffee, wine and cola drinks, and cigarettes should be avoided.

Busulfan

AdministartionOrally taken anytime during the day with large amount of fluids before or shortly after meal.IV infusion over 2 hours through central venous catheter.

Adverse effectsSkin hyperpigmentation.Seizures.Hepatic veno- occlusive disease.

Drug interactionPhenytoin.(induction of glutathione S-transferase).Acetaminophen.(reduction of glutathione level)Itraconazole.NSAID and anticoagulant…..etc.Succinylcholine.

NITROSOUREACarmustine Lomustine

Trade name BCNU – BiCNU CCNU -CeeNU

Structure

Absorption not absorbed orallyAbsorbed orally.

DistributionHighly lipid solubleVd 2.6-3.3L/KgBBB crossingPPB 80%

Highly lipid soluble, extensive tissue distribution.Vd no information foundBBB crosing and reaches CSFPPB moderate 50%

MetabolismHepatic microsomal enzyme oxidative system.

C

O

NHCH2CH2Cl

NON CH2CH2ClNH C N CH2CH2Cl

O NO

Alkyl SulphonateBusulfan

Trade nameMyleran®, Busulfex®

Structure

1,4-Butanediol dimethanesulfonate

AbsorptionHighly absorbed.

DistributionRapidly distributed and eliminated from the plasma.Vd 0.6-1L/KgBBB crosses.PPB minimal.

MetabolismSlowly , in the liver conjugated with glutathione.

EliminationRenally ( 1% excreted unchanged ) .

O

O O

O

CH3 S OCH2CH2CH2CH2O S CH3

CarmustineLomustine EliminationRenally: 60% to 70% of a

dose is excreted in urine after 4 days as metabolites, 10% in respiration as CO2 .

Renally: slowly 60% of a dose excreted after 48 hours with 50% excreted in the 1st 12 h.

AdministrationIV administration over a period of 1-2 hours (to prevent irritation at injection site, burning with rapid infusion), reconstituted with alc.

Orally on empty stomach with much water as single dose .

Adverse reactions

Vesicant.,PhelibitisDelayed hematological toxicity.Hepatotoxicity.Pulmonary toxicity.

Delayed Hematologic ToxicityPulmonary toxicityReversible hepatotoxicityNephrotoxicityGIT toxicity,confusion…

Drug interaction Amphotericin B.

Microsomomal enzyme inducers.

Phenobarbital increase the eliminationCimetidine decrease the clearance leading to toxicity

Carmustine Lomustine The recommended dose as single agent

•150 to 200 mg/m² intravenously every 6 weeks.

•130 mg/m2 as a single oral dose every 6 weeks

repeat course of should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm³, leukocytes

above 4,000/mm³), and this is usually in 6 weeks

Doses subsequent to the initial dose should be adjusted according to the

hematologic response of the patient to the preceding dose

Uses Brain tumour,Non-Hodgkin's lymphomas,Hodgkin’sdisease,multiple myloma

CarmustineLomustine EliminationRenally: 60% to 70% of a

dose is excreted in urine after 4 days as metabolites, 10% in respiration as CO2 .

Renally: slowly 60% of a dose excreted after 48 hours with 50% excreted in the 1st 12 h.

AdministrationIV administration over a period of 1-2 hours (to prevent irritation at injection site, burning with rapid infusion), reconstituted with alc.

Orally on empty stomach with much water as single dose .

Adverse reactions

Vesicant.Delayed hematological toxicity.Hepatotoxicity.Pulmonary toxicity.

Disorientaion, ataxia.

Drug interactionAmphotericin B.Microsomomal enzyme inducers.

Other alkylating agents: Temozolomide

Trade name

Temodar®

) cap.5,10,100 and 250 mg(UsesRefractory astrocytoma.

AbsorptionCompletely absorped.

Is a prodrug and by hydrolysis in the body turn into the active molecule

MetabolismBy liver ,cytochrome P450.

EliminationRenal elimination ,dose reduction may be necessary in renal impaairment (no guidelines)


Orally, once daily.

Doses:150-200 mg/m2 for 5 days each 28 days cycle.

Side effectsHaematologic

Severe nausea and vomiting

Teratogenic.Drug interactions

Valproic acid may reduce its clearance by 5.%

Other alkylating agents: Streptozocin

Trade name

Zanosar®

) 1 gm vial(UsesPancreatic islet cell carcinoma

and carcinoid tumour.AbsorptionNot absorped from GIT.MetabolismBy liver

EliminationRenal elimination.

If crcl 10-50 ml/min:give 75 % of the dose.

If less than 10 ml/min : give 50% of the dose.


Direct IV injection or infusion..

Doses:500 mg/m2 IV /day for 5 days (every 6 weeks).

1-1.5 gm /m2 IV as a single dose (every week).

Reconstitute 1 gm with 9.5 ml NS or D5%, may further dilution with NS or D5% and administered over 15 min ti 6 hrs.

Side effectsNephrotoxicity in 25 -75 % of patients.

Haematologic

Severe nausea and vomiting.

May induce DM in animals.

Teratogenic.

Drug interactions

-Avoid using with other nephrotoxic drugs.-Doxorubicin: it prolong doxorubicin half life so dose of

doxorubicin should be reduced.--Phenytoin may diminish the cytotoxic effect.of

streptozocin.

alkylating agents

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