Clinical Pharmacokinetics of Carboplatin

Abstract

Carboplatin [diammine(1,1-cyclobutanedicarboxylato)platinum(II)] is one of the most promising second generation platinum compounds. Its greater chemical stability in comparison with cisplatin accounts for its lower reactivity with nucleophilic sites of DNA, and may therefore be related to the higher dose necessary to obtain an antitumour effect similar to that of cisplatin. The lower reactivity with proteins may be related to the observed reduction in nephrotoxicity. Its dose-limiting toxicity is myelosuppression, especially thrombocytopenia. Total and ultrafilterable platinum are detected by flameless atomic absorption spectrophotometry, and high performance liquid chromatography with either UV or electrochemical detection is used for the quantification of carboplatin. These 3 species have been measured as a function of time in biological fluids and tissues to determine their pharmacokinetics. Carboplatin has high stability in infusion fluids in the absence of chloride, but it is less stable in plasma and urine. Protein binding is limited, while the low uptake in red blood cells appears to be species dependent. Commonly, carboplatin is administered intravenously, and its pharmacokinetics are linear up to a dose of 2400 mg/m². In comparison with cisplatin, carboplatin has longer half-lives of ultrafilterable platinum (23 and 120 min versus 6 and 36 min for distribution and initial elimination half-lives, respectively) and a higher cumulative urinary platinum excretion (77 versus 28% of the dose in 24h), both due to the lower protein binding of carboplatin. The terminal half-life of total platinum is comparable between the 2 compounds (5.8 versus 5.4 days). This value most probably represents the breakdown of proteins to which both compounds are irreversibly bound. Relationships between pharmacokinetics (area under the curve) and pharmacodynamics (extent of myelosuppression or extent of existing kidney failure) have allowed the development of equations for rational dosage reduction. Intraperitoneal administration has been used in cases of residual ovarian cancer: as a result of its higher hydrophilicity and higher molecular weight, carboplatin is cleared more slowly from the peritoneal cavity than cisplatin (6 vs 15 ml/min). The low bioavailability (4 to 12%) and the gastrointestinal side effects observed did not warrant further studies with oral administration. In contrast to results from animal studies, the modulation of carboplatin-induced myelo-suppression by diethyldithiocarbamate (DDTC) was not clinically successful. Valuable alternatives may be the combination with WR2721 or colony-stimulating factors.