Bleomycin Dry-powder injectables

Although the exact mechanism of action of bleomycin is unknown, available evidence indicates that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis.

Bleomycin is known to cause single, and to a lesser extent, double-stranded breaks in DNA. In in vitro and in vivo experiments, bleomycin has been shown to cause cell cycle arrest in G2 and in mitosis.

When administered into the pleural cavity in the treatment of malignant pleural effusion, bleomycin acts as a sclerosing agent.

Bleomycin is rapidly absorbed following either intramuscular, subcutaneous, intraperitoneal, or intrapleural administration reaching peak plasma concentrations in 30 to 60 minutes. Systemic bioavailability of bleomycin is 100% and 70% following intramuscular and subcutaneous administrations, respectively, and 45% following both intraperitoneal and intrapleural administrations, compared to intravenous and bolus administration.

Following intramuscular doses of 1 to 10 units/m2, both peak plasma concentration and AUC increased in proportion with the increase of dose.

Following intravenous bolus administration of 30 units of bleomycin to one patient with a primary germ cell tumor of the brain, a peak CSF level was 40% of the simultaneously-obtained plasma level and was attained in 2 hours after drug administration. The area under the bleomycin CSF concentration x time curve was 25% of the area of the bleomycin plasma concentration x time curve.

Bleomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 L/m2 in patients following a 15 units/m2 intravenous bolus dose. Protein binding of bleomycin has not been studied.

Bleomycin is inactivated by a cytosolic cysteine proteinase enzyme, bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity. Systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function.

The primary route of elimination is via the kidneys. About 65% of the administered intravenous dose is excreted in urine within 24 hours. In patients with normal renal function, plasma concentrations of bleomycin decline biexponentially with a mean terminal half-life of 2 hours following intravenous bolus administration. Total body clearance and renal clearance averaged 51 mL/min/m2 and 23 mL/min/m2, respectively.

Following intrapleural administration to patients with normal renal function, a lower percentage of drug (40%) is recovered in the urine, as compared to that found in the urine after intravenous administration.