Mechanismof Action

Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.

Pharmacodynamics

In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil (5-FU), oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].

Pharmacokinetics

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinumin plasma ultrafiltrate. The decline of ultrafilterable platinumlevels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t½α; 0.43 hours and t½β; 16.8 hours) and a long terminal elimination phase (t½γ ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour IV infusion of ELOXATIN at a dose of 85 mg/m² expressed as ultrafilterable platinumwere Cmax of 0.814 mcg/mL and volume of distribution of 440 L. Interpatient and intrapatient variability in ultrafilterable platinumexposure (AUC_0-48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinumultrafiltrate levels and clinical safety and effectiveness has not been established.

Distribution

At the end of a 2-hour infusion of ELOXATIN, approximately 15% of the administered platinumis present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinumis irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinumalso binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinumaccumulation was observed in plasma ultrafiltrate following 85 mg/m² every two weeks.

Metabolism

Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolismin vitro.

Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples frompatients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.

Elimination

The major route of platinumelimination is renal excretion. At five days after a single 2-hour infusion of ELOXATIN, urinary elimination accounted for about 54% of the platinumeliminated, with fecal excretion accounting for only about 2%. Platinumwas cleared fromplasma at a rate (10 – 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinumis significantly correlated with GFR.

Pharmacokinetics in Special Populations

Pediatric

[See Use In Specific Patient Populations].

Renal Impairment

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