Cytoxan® (cyclophosphamide) is an alkylating agent. It is a potent immunosuppressant, as it depletes regulatory T cells. The 2% solution of cyclophosphamide has a pH varying from 4 to 6. It can be used medically as an antineoplastic agent. It appears as a fine, white, crystalline powder. It is associated with rare cases of acute liver injury and minor transient serum enzyme elevations. When used in myeloablative therapy, high doses of cyclophosphamide can cause acute sinusoidal obstruction syndrome. The anhydrous form of cyclophosphamide acts as a synthetic nitrogen mustard alkylating agent with immunosuppressive and antineoplastic activities. It is converted to the active metabolite, phosphoramide mustard, in the liver. Phosphoramide mustard inhibits protein synthesis and DNA replication by binding and crosslinking with RNA and DNA. Cyclophosphamide has a melting point that varies between 41 and 45 °C.1 Various research studies have been conducted to investigate the efficacy of cyclophosphamide in patients with idiopathic pulmonary fibrosis (IPF).
The elimination half-life (t ½) of intravenously administered cyclophosphamide ranges from 3 to 12 hours; the total body clearance is 4 to 5.6 L/h. The pharmacokinetic dose range used is clinically linear. It is administered at 4.0 g/m2 over a 90-minute infusion period. The kinetics of the drug are described by first-order renal elimination. The peak concentration of cyclophosphamide occurs 1 hour after oral administration. After intravenous and oral administration, the area under the curve ratio ranges from 0.87 to 0.96. There are no dose-dependent changes, as 20% of cyclophosphamide is protein-bound. More than 60% of its metabolites are protein-bound, and the volume of distribution varies from 30 to 50 L for total body water. The liver is the main site of activation for cyclophosphamide as 75% of the administered dose is activated by liver microsomal cytochrome P450s, including CYP2A6, CYP3A4, CYP3A5, CYP2C9, CYP2C18, and CYP2C19. The highest 4-hydroxylase activity is displayed by CYP2B6. The drug is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its open-ring tautomer, aldophosphamide.2
Mechanism of Action
Cyclophosphamide exerts its effects through the alkylation of DNA. It inhibits protein synthesis through DNA and RNA crosslinking. It is not cell cycle phase-specific. It metabolizes to an active form and has antineoplastic effects due to phosphoramide mustard, which is formed following metabolism of the drug by liver enzymes such as cytochrome P450. Hepatic enzymes form hydroxycyclophosphamide from cyclophosphamide, which is subsequently metabolized to aldophosphamide. Alkylating agents like acrolein and phosphoramide mustard are cleaved from aldophosphamide. Crosslinkages within and between DNA strands are formed at the N-7 guanine position by the phosphoramide metabolite. The manifestation of hemorrhagic cystitis is due to acrolein. Cyclophosphamide has selectivity for T cells and immunosuppressive effects in addition to antineoplastic and antimitotic effects. A lower dose of cyclophosphamide is used selectively for the immunomodulation of regulatory T cells. The drug decreases the secretion of interleukin (IL)-12 and interferon-gamma and increases the secretion of Th2 cytokines such as IL-10 and IL-4 in the peripheral blood and CSF.3
Cytoxan can have a wide range of side effects. Patients should inform their physician if they experience abdominal pain, weight loss, appetite loss, nausea, vomiting, diarrhea, hair loss, changes in skin color, or sores in the mouth or on the tongue. Other adverse effects include sore throat, fever, chills, slow wound healing, unusual bruising or bleeding, changes in the growth of the fingernails or toenails, shortness of breath, difficulty breathing or swallowing, painful urination or red urine, rash, hives, swelling in the legs or ankles, chest pain, and jaundice. Some of the side effects can be serious, and the patient should immediately inform their doctor if they develop any of these symptoms. According to the studies conducted, cyclophosphamide may increase the risk of developing cancer. If a patient experiences a serious side effect, their physician can send a detailed report to the US Food and Drug Administration (FDA) MedWatch adverse event reporting program.4
Get detailed prescribing information on the Cytoxan monograph page at MPR.
IPF and Cyclophosphamide
Cyclophosphamide is commonly used to treat idiopathic pulmonary fibrosis (IPF) when patients do not respond to steroids. Immunosuppressive therapy has limited efficacy in treating IPF. Corticosteroids are considered the mainstay of therapy, but only 30% of patients show an objective response. Cyclophosphamide can be used in patients with a high risk of complications or serious adverse effects following corticosteroid administration. Few research studies have analyzed the efficacy of cyclophosphamide in treating IPF. A hypothesis was tested stating that cyclophosphamide may be efficacious in patients with usual interstitial pneumonia (UIP) who are refractory or intolerant to corticosteroids. A worse prognosis is seen in patients with severe and increased lung fibrosis; these patients are unlikely to benefit from cyclophosphamide therapy. Patients with UIP who fail to respond to corticosteroids have shown improved pulmonary function with marginal efficacy with cyclophosphamide. After corticosteroids have been discontinued and cyclophosphamide has been initiated, most patients have shown long-term stability. There are frequent side effects associated with cyclophosphamide. A study conducted on patients with UIP showed that those who took cyclophosphamide therapy either developed adverse conditions, remained stable, or did not respond to the medication. Sustained response of cyclophosphamide therapy is witnessed in only a few patients, with some remaining stable and others deteriorating.5
- Cyclophosphamide. PubChem. Accessed August 12, 2021.
- Cyclophosphamide. Package insert. Baxter Healthcare Corp. Accessed August 12, 2021.
- Ogino MH, Tadi P. Cyclophosphamide. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2021. Accessed August 12, 2021.
- Cyclophosphamide. MedlinePlus. Updated July 27, 2021. Accessed on August 12, 2021.
- Zisman DA, Lynch JP III, Toews GB, Kazerooni EA, Flint A, Martinez FJ. Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids. Chest. 2000;117(6):1619-1626. doi:10.1378/chest.117.6.1619
Reviewed by Harshi Dhingra, MD, on 8/12/2021.