Introduction
Cisplatin, cisplatinum or cis-diamminedichloroplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin.
Uses
Cisplatin is a platinum based chemotherapy agent used to treat various sarcomas, carcinomas, lymphomas, and germ cell tumors.
For the treatment of metastatic testicular tumors, metastatic ovarian tumors and advanced bladder cancer.
Associated Conditions
Pharmacodynamics
Cisplatin is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.
Mechanism of Action
Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.
Absorption
Following cisplatin doses of 20 to 120 mg/m^2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration.
Volume of Distribution
Volume of distribution at steady state = 11-12 L/m^2
Protein Binding
Cisplatin does not undergo instantaneous and reversible binding to plasma protein that is characteristic of normal drug-protein binding. However, the platinum itself is capable of binding to plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound.
Route of Elimination
The parent compound, cisplatin, is excreted in the urine. Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.
Half Life
Cisplatin decays monoexponentially with a half life of 20 to 30 minutes following administrations of 50 or 100 mg/m^2. Cisplatin has a plasma half-life of 30 minutes. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more.
Clearance
- 15-16 L/h/m^2 [total body clearance, 7-hour infusion of 100 mg/m^2]
- 62 mL/min/m^2 [renal clearance, 2-hour infusion of 100 mg/m^2]
- 50 mL/min/m^2 [renal clearance, 6- to 7-hour infusion of 100 mg/m^2] The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption.
Food Interactions
- Avoid echinacea. Echinacea should be used with caution, if at all, in patients receiving therapeutic immunosuppressants. Monitor for reduced efficacy of the immunosuppressant during concomitant use.
Dosage
Metastatic Testicular Tumors: The usual Cisplatin Injection dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.
Metastatic Ovarian Tumors: The usual Cisplatin Injection dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1). The dose of cycloposphamide when used in combination with cisplatin is 600 mg/m2 IV once every four weeks (DAY 1). In combination therapy, Cisplatin Injection and cyclophosphamide are administered sequentially. As a single agent, Cisplatin Injection should be administered at a dose of 100 mg/m2 IV per cycle once every four weeks.
Advanced Bladder Cancer: Cisplatin Injection should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended.
Non Small Cell Lung Carcinoma: Cisplatin Injection (75 mg/m2) should be administered in combination with Paclitaxel (135 mg/m2) in every three weeks. Or, as directed by the registered physicians.
