Author Archives: Abdul Wadud

General pharmacology of cyclophosphamide

CHEMICAL NAME:

Cyclophosphamide is a synthetic anticancer drug. Its chemical name is 2-[Bis (2-chloroethyl) amino] tetrahydro-2H-1, 3, 2-oxazaphosphorine 2-oxide monohydrate.

MOLECULAR FORMULA AND MOLECULAR WEIGHT:

Its molecular formula is  C7H15Cl2N2O2P and molecular weight is 261.1

STRUCTURE:

The structural formula of cyclophosphamide is:

Structural formula of cyclophosphamide

ABSORPTION:

After oral administration, it is rapidly absorbed by the gastrointestinal tract with a bioavailability of nearly 90% that means nearly 90% of cyclophosphamide reach in the systemic circulation. Peak concentrations of cyclophosphamide in blood occurred at 1 hour and peak concentrations of its metabolites occurred at 2-3 hours. Onset of action is 2-3 hours.

DISTRIBUTION:

Cyclophosphamide is distributed throughout the body including brain, cerebrospinal fluid (CSF), breast milk and saliva. Approximately 20% of cyclophosphamide is bound to plasma proteins; however, about 60% of its metabolites are bound to plasma proteins. Volume of distribution is approximately 0.5-0.7 Liter/kg.

METABOLISM:

Cyclophosphamide requires metabolic activation before it can act as an anticancer agent.  Liver is the major site for metabolic activation of this drug, although activation may occur in other tissues. In the liver, it is metabolized by the cytochrome P450 system into phosphoramide mustard, and acrolein. These metabolites mainly phosphoramide mustard interfere with the growth of susceptible rapidly proliferating cancer cells.

EXCRETION:

Cyclophosphamide is excreted exclusively in urine primarily in the form of metabolites, but from 10 to 20% of drug is excreted in urine as unchanged form. The excretion half-life ranges from 4-6 hours.

Dosage of cyclophosphamide in different diseases

Non Hodgkin lymphoma:

Intravenous cyclophosphamide 400 to 600 mg per square body surface area given on day 1 every 21 days, as part of CVP (cyclophosphamide,  vincristine and prednisolone) regimen, and 750 mg per square body surface area given on day 1 every 21 days, as part of CHOP [cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin) and prednisolone] regimen.

Burkitt’s lymphoma:

Usually higher doses of intravenous  cyclophosphamide (1-4 gm per square body surface area) is used in Burkitt’s lymphoma in combination with other chemotherapeutic agents such as vincristine, methotrexate, doxorubicin and cytarabine.

Chronic lymphocytic leukemia (CLL):

Usual dose is intravenous cyclophosphamide 250 mg per square body surface area on days 2-4 on cycle 1 and on days 1-3 in subsequent cycles, as part of cyclophosphamide, rituximab and fludarabine regimen.

Breast cancer:

Tablet cyclophosphamide 100 mg per square body surface area on days 1-14 given every 28 days, or intravenous cyclophosphamide 600 mg per square body surface area given every 21 days as part of CMF (cyclophosphamide, methotrexate and fluorouracil) regimen.

Malignant pheochromocytoma:

Usual dose is intravenous cyclophosphamide 750 mg per square body surface area on day 1 every 21 days for 3 to 6 cycles, as part of Averbuch’s chemoyherapy protocol includes cyclophosphamide, vincristine and dacarbazine.

Systemic lupus erythematosus (SLE):

When given intravenously, the usual dose is 7 to 25 mg per kg body weight every month for 6 cycles. When given orally, the usual dose is 1.5 to 3 mg per kg body weight per day.

Multiple sclerosis:

Intravenous cyclophosphamide 700 mg per square body surface area monthly.

Mononeuritis multiplex:

Oral cyclophosphamide 2 mg per kg body weight per day.

Pemphigus vulgaris:

Tablet cyclophosphamide 1-2 mg per kg body weight per day.

Bullous pemphigoid:

Tablet cyclophosphamide 1-2 mg per kg body weight per day.

Wegener’s granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis:

All are small vessel vasculitis. Cyclophosphamide is an effective therapy for the treatment of these vasculitis. It is given in doses of 2 mg per kg body weight per day orally together with glucocorticoids. After the induction of complete remission (complete disappearance of detectable disease), patients are maintained on cyclophosphamide therapy for up to a year to minimize the risk of relapse and gradually tapered and discontinued thereafter.

Goodpasture’s syndrome:

Usual dose is oral cyclophosphamide 2 mg per kg body weight per day together with prednisolone for two weeks.

Ewing’s sarcoma:

It is one type of malignant bone tumor. Intravenous cyclophosphamide 500 -1200 mg per square body surface area is used as chemotherapy in Ewing’s sarcoma in combination with other chemotherapeutic agents such as doxorubicin, etoposide, vincristine and dactinomycin.

Autoimmune hemolytic anemia:

Usually prednosolone is used to prevent hemolysis (breakdown of red boold cell) in autoimmune hemolytic anemia. If the hemolysis fails to respond to prednosolone, repeated cycles of cyclophosphamide at a dose of 50 mg per kg body weight per day for 4 days may be considered.

Bone marrow transplantation:

Usual dose is 60 mg per kg body weight intravenously for 2 days.

Side effects of cyclophopsphamide

Cyclophosphamide may cause any of the following side effects –

1. Nausea and vomiting:

The common side effect of cyclophosphamide is nausea with or without vomiting. These are dose-related and occur within 2-4 hours of therapy. These can be controlled by taking anti-emetic medications such as ondansetron, granisetron, dolasetron, palonosetron etc.

2. Diarrhea:

Cyclophosphamide can also cause diarrhea. If diarrhea occurs, appropriate amount of electrolytes containing fluids should be taken orally. Sometimes, intravenous (IV) fluids along with antidiarrheal agents such as loperamide, octreotide or opiate-based medications may be needed if severe diarrhea developed.

3. Urinary bladder toxicity:

The presentations of urinary bladder toxicity are dysuria (painful urination), hemorrhagic cystitis (blood in the urine with painful voiding due to diffuse inflammation of the urinary bladder) and increased urinary frequency. It occurs in 5% to 10% of patients and may starts within 24 hours of drug therapy or may be delayed for up to several weeks. Bladder toxicity can occur both in oral and intravenous therapy but less with intravenous therapy. After intake of cyclophosphamide, it is broken down into the phosphoramide mustard and acrolein. The byproduct acrolein causes urinary bladder injury and produces toxicity. Among bladder toxicity, hemorrhagic cystitis is the more dangerous side effect. When this drug is taken for one to several years in doses of 2 mg/kg/day, the incidence of hemorrhagic cystitis is at least 30%. To reduce the risk of bladder toxicity, all patients should intake cyclophosphamide in the morning with a large amount of liquid throughout the day and void every 2 hours. It can reduce the risk of urinary bladder injury by diluting urine. If severe hemorrhagic cystitis developed, mesna (2-mercaptoethanesulfonate) can be used that binds urotoxic metabolites of cyclophosphamide and reduce the risk of bleeding from urinary bladder.

4. Urinary bladder cancer:

The incidence of development of urinary bladder cancer is at least 6% after long term use of cyclophosphamide in doses of 2 mg/kg/day. Bladder cancer can appear several years after the discontinuation of this drug. Therefore, follow up of patients for urinary bladder cancer should continue indefinitely who have taken prolonged period of daily cyclophosphamide.

5. Bone marrow suppression:

Bone marrow suppression is an important side effect of cyclophosphamide therapy. Bone marrow is the source of all blood cells in our body. If cyclophosphamide causes bone marrow suppression, the number of blood cells can be reduced. As a result, (i) body’s defense mechanism becomes declined due to insufficient white blood cells and patient is prone to infection, (ii) anemia may develop due to insufficient red blood cells, and (iii) bleeding from different sites of body such as from nose, gum, skin, mucus membrane may occur due to reduced number of platelets (prevention and arrest of bleeding is an important function of platelet). Therefore, monitoring of blood cells count every 1-2 weeks is necessary during therapy.

6. Gonadal suppression:

Gonad means testis (in case of male) or ovary (in case of female). Cyclophosphamide can suppress the gonad that causes azoospermia (absence of sperm in semen) or anovulation (no production and discharge of an ovum), which may be permanent. Therefore, permanent infertility (inability to produce offspring) can occur in cyclophosphamide therapy that can be minimized by collection and storage of pre-treatment sperm or ova.

7. Myelodysplasia:

Myelodysplasia is a hematopoietic stem cell disorder leading to ineffective blood cell production. Myelodysplasia occur in 2% cases with chronic use of cyclophosphamide.

8. Pulmonary fibrosis:

Cyclophosphamide can cause sporadic interstitial pneumonitis that leads to fibrosis in the lung.

9. Hypogammaglobulinemia:

Rarely, cyclophosphamide causes hypogammaglobulinemia that means it lowers the level of gamamaglobulin. Gamamaglobulin is one type of antibody that plays an important role in body’s defense mechanism. When a patient with cyclophosphamide therapy develops hypogammaglobulinemia, he or she affected by frequent infections.

10. Opportunistic infection:

Opportunistic Infection is caused by opportunistic microorganisms that usually do not cause harm but do so when lowered body’s immune system. The incidence of development of life threatening opportunistic infections in cyclophosphamide therapy is low if the white blood cell count is maintained at more than 3000/µl and the patient is not taking daily glucocorticoids. However, Pneumocystis jiroveci infection and certain fungal infections can be seen with normal white blood cell count, particularly in patients taking glucocorticoids.

11. Alopecia:

Alopecia means loss of hair from head. It starts 2-3 weeks after drug therapy. Significant alopecia is unusual in chronic use of low dose cyclophosphamide. It affect the hair follicles and produces diffuse non-scarring alopecia. Most of the cases alopecia is reversible after the discontinuation of drug.

12. Hyperpigmentation:

Cyclophosphamide induces melanin pigment production that causes diffuse hyperpigmentation of skin.

 

Precautions should be taken during cyclophosphamide therapy

Drug and fluid intake:

Cyclophosphamide should be administered in the morning and encourage the patients to intake plenty of fluid at least 2-3 liter per day to reduce the risk of urinary bladder toxicity. Intravenous fluid may be required for hydration in case of high dose cyclophosphamide.

Kidney impairment:

Cyclophosphamide should be used cautiously in patient with abnormal kidney function. Dose should be reduced in this setting and creatinine clearance level should be maintained at baseline.

Hepatic impairment:

If liver function abnormality present, the dose of cyclophosphamide should be reduced and the transaminase levels should be maintained at less than 3 times of upper limit of normal value.

P-450 system stimulating drugs:

The liver cytochrome P-450 oxidase system stimulating drugs such as phenytoin, phenobarbital and so on if administered with cyclophosphamide, it can increase the rate of metabolism of cyclophosphamide to its cytotoxic metabolites. In this setting, the physician should be alert for possible desirable or undesirable effects. Sometimes, the dose may need to be adjusted or liver cytochrome P-450 oxidase system stimulating drugs should be avoided.

Doxorubicin:

Cyclophosphamide can increase the risk of doxorubicin induced cardiotoxicity. Therefore, special caution should be taken in patients who concomitantly receiving cyclophosphamide and doxorubicin.

Anticoagulant drugs:

Extreme caution should be taken when cyclophosphamide is given to patients who taking anticoagulant drugs because, cyclophosphamide can increase the effect of anticoagulant drugs. Therefore, the dose of anticoagulant drugs may need to be decreased depending on the coagulation parameters.

Digoxin:

Cyclophosphamide can decrease the plasma concentration of digoxin by activating its metabolism in liver. Therefore, the dose of digoxin may need to be adjusted in the concomitant administration of cyclophosphamide and digoxin.

Depolarizing muscle relaxant drugs:

Cyclophosphamide can cause a persistent inhibition of cholinesterase activity. Concomitant administration of cyclophosphamide and depolarizing muscle relaxant drugs (such as succinylcholine) may potentiate the effect of depolarizing muscle relaxant drugs that causes prolonged apnea. Therefore, the anesthesiologist should be alerted if a patient has been treated with cyclophosphamide within 10 days of general anesthesia.

Mechanism of resistance of cyclophosphamide

Cyclophosphamide is one of the most active chemotherapeutic drug used in the treatment of many cancerous conditions. Sometimes it may resistant and cannot act properly. As a result, treatment failure developed. Resistance to cyclophosphamide is multifactorial with a diverse spectrum of mechanisms observed in cancer treatment which includes;

► Cell may uptake reduced amount of drug and this small amount of drug fails to stop the growth of cancer cells.

► Cyclophosphamide is activated by liver cytochrome P-450 oxidase system. Sometimes, the activity of these enzymes may be reduced. Therefore, the inactive cyclophosphamide cannot convert into appropriate amount of active cytotoxic metabolites which ultimately fails to stop the growth of cancer cells.

► Within the cells, the level of sulfhydryl proteins including glutathione and glutathione associated enzymes may be increased. The high level of sulfhydryl proteins may interact with the active metabolites of cyclophosphamide and prevent its binding to target DNA. As a result, cyclophosphamide-induced DNA lesions is hampered and ultimately cancer cells damage is prevented.

► The activity of aldehyde dehydrogenase enzyme in the body may be increased. The overactive aldehyde dehydrogenase appears to be involved directly in the detoxification of cyclophosphamide and its active metabolites. As a result, detoxified cyclophosphamide cannot stop the growth of cancer cells.

► Sometimes the activity of DNA repairing enzymes increased. When cyclophosphamide produces DNA lesions, the overactive DNA repairing enzymes repair the lesions DNA, possibly through the nucleotide excision repairing process and prevent the cancer cells from dying.