Oxaliplatin: pharmacokinetics and chronopharmacological aspects

Oxaliplatin is the first clinically available diaminocyclohexane platinum coordination complex. The drug is non-cross-resistant with cisplatin or carboplatin and is one of the few active drugs against human colorectal cancer. Its cytotoxicity is synergistic with fluorouracil and folinic acid (leucovorin), the reference treatment for this disease. The main cumulative dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy. The drug can also produce diarrhoea, vomiting and haematological suppression. Unlike cisplatin, no renal failure or peripheral motor neuropathy have been reported and the sensory neuropathy is partly reversible. Unlike carboplatin, oxaliplatin produces only mild to moderate haematological toxicity. Oxaliplatin undergoes biotransformation into aquated forms in the blood, where 3 species can be found: total platinum, ultrafilterable or 'free' platinum and erythrocyte platinum. Flameless atomic absorption (FAAS) is used for assaying platinum concentration in various tissues. Inductively-coupled plasma mass spectrometry (ICP-MS), with a >10-fold lower sensitivity threshold than FAAS, was also used for the determination of oxaliplatin pharmacokinetics. The pharmacokinetics of oxaliplatin are described by a 3-compartment model. The drug rapidly crosses the cellular membrane as a result of its lipophilicity. Hence, at the end of a 2-hour infusion, approximately 40% of the blood platinum is found in erythrocytes. The distribution half-life of ultrafiltrated plasma platinum ranges from 10 to 25 minutes and its terminal elimination half-life is 26 hours (determined with FAAS) or 270 hours (ICP-MS). The elimination half-life of erythrocytic platinum is 12 to 50 days, close to that of erythrocytes. 30 to 50% of the platinum is recovered in the urine within 2 to 5 days, with renal clearance accounting for half of the total clearance of ultrafiltrated platinum. The total clearance of this species is correlated with the glomerular filtration rate. No pharmacokinetic-pharmacodynamic relationship has been established for oxaliplatin. Pharmacokinetic alterations produced by fluorouracil + folinic acid or irinotecan were minimal if any. The prolonged stability of oxaliplatin makes it suitable for continuous infusions over 4 to 5 days, with a delivery rate which can be either constant or chronomodulated (peak rate at 1600h), using programmable ambulatory pumps. Chronomodulation significantly reduces toxicity and improves antitumour activity as compared with constant rate infusion. These differences in pharmacodynamic properties were paralleled by differences in plasma concentration time courses. The different drug concentration profiles achieved with different infusional modalities may be useful tools for understanding the relationship between the pharmacokinetics and pharmacodynamics of oxaliplatin and may lead to further optimisation of its administration schedule and its combination with other drugs.