Clinical pharmacokinetics of oxaliplatin: A critical review

Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O'] pl atinum; Eloxatine) is a novel platinum coordination complex used for the tr eatment of metastatic colorectal carcinoma in combination with fluoropyrimi dines. The objective of this review is to integrate the key data from multi ple studies into a single, comprehensive overview of oxaliplatin dispositio n in cancer patients. The pharmacokinetics (PKs) of unbound platinum in pla sma ultrafiltrate after oxaliplatin administration was triphasic, character ized by a short initial distribution phase and a long terminal elimination phase (t(1/2) 252-273 h). No accumulation was observed in plasma ultrafiltr ate after 130 mg/m(2) every 3 weeks or 85 mg/m(2) every 2 weeks. Interpatie nt and intrapatient variability in platinum exposure (area under the curve( 0-48)) is moderate to low (33 and 5% respectively). In the blood, platinum binds irreversibly to plasma proteins (predominantly serum albumin) and ery throcytes. Accumulation of platinum in blood cells is not considered to be clinically significant. Platinum is rapidly cleared from plasma by covalent binding to tissues and renal elimination. Urinary excretion (53.8 +/- 9.1% ) was the predominant route of platinum elimination, with fecal excretion a ccounting for only 2.1 +/- 1.9% of the administered dose 5 days postadminis tration. Tissue binding and renal elimination contribute equally to the cle arance of ultrafilterable platinum from plasma. Renal clearance of platinum significantly correlated with glomerular filtration rate, indicating that glomerular filtration is the principal mechanism of platinum elimination by the kidneys. Clearance of ultrafilterable platinum is lower in patients wi th moderate renal impairment; however, no marked increase in drug toxicity was reported. The effect of severe renal impairment on platinum clearance a nd toxicity is currently unknown. Covariates such as age, sex, and hepatic impairment had no significant effect on the clearance of ultrafilterable pl atinum, and dose adjustment due to these variables is not required. Oxalipl atin undergoes rapid and extensive nonenzymatic biotransformation and is no t subjected to CYP450-mediated metabolism. Up to 17 platinum-containing pro ducts have been observed in plasma ultrafiltrate samples from patients, The se include several proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo-diaminocyclohexane platinum complexes, along with sev eral other noncytotoxic products. Oxaliplatin does not inhibit CYP450 isoen zymes in vitro, Platinum was not displaced from plasma proteins by a variet y of concomitant medications tested in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and irinothecan have been observed. T hese results indicate that the additive/synergistic antitumor activity obse rved with these agents is not due to major alterations in drug exposure, an d the enhanced efficacy is likely to be mechanistically based. Together, th ese PK, biotransformation, drug-drug interaction analyses and studies in sp ecial patient populations provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition observed in patients .