Pharmacokinetics of (glycolato-0,0?)-diammine platinum (II), a new platinum derivative, in comparison with cisplatin and carboplatin

Abstract

The pharmacokinetics of (glycolato-0,0')-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m2, respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 micrograms/ml and 959 micrograms/min per ml for 254-S, 3.09 micrograms/ml and 208 micrograms/min per ml for cisplatin, and 19.90 micrograms/ml and 3446 micrograms/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.

Relationship between Cisplatin or Nedaplatin-Induced Nephrotoxicity and Renal Accumulation

“…However, in a steady state, kidney accumulation of cisplatin was higher, which may lead to renal toxicity. As nedaplatin disappears in plasma immediately after administration, the rate of kidney excretion may be higher than that of cisplatin, 24,25) contributing to a low kidney accumulation of nedaplatin. As another possibility, the renal cell level of nedaplatin may be lower than that of cisplatin, since it is speculated that cisplatin is ingested by the tubular epithelial cells via a transport system on the basolateral membrane of the kidney tubule.…”

Phase I–II study of irinotecan (CPT-11) plus nedaplatin (254-S) with recombinant human granulocyte colony-stimulating factor support in patients with advanced or recurrent cervical cancer

“…The plasma concentration profile of unbound platinum after 254-S infusion has been reported to be similar to that of total platinum, and the protein binding of 254-S to be lower than that of CDDP (Ota et al, 1994). Nedaplatin has a short elimination half-life and a phamacokinetic profile similar to that of CBDCA (Sasaki et al, 1989). Nephrotoxicity and gastrointestinal toxicity often limits the clinical use of antitumour agents such as CDDP, but 254-S causes less nephrotoxicity and gastrointestinal toxicity than CDDP, although its haematological toxicity can be a limiting factor at high dosage, as found with CBDCA (Kameyama et al, 1990;Ota et al, 1992;Suzumura et al, 1989).…”

A feasibility study of outpatient chemotherapy with S-1 + cisplatin in patients with advanced gastric cancer

“…To our knowledge, there has been no randomized controlled trial to determine an adequate infusion volume on the day of CDDP administration, and there is far less evidence for the amount of oral hydration required before or after the day of CDDP administration. A report on the pharmacokinetics of CDDP showed that the blood level of free CDDP, which causes renal toxicity, diminished below the limit of detection sensitivity on the day after CDDP administration [13], and it is thought that hydration on the day after CDDP administration may not be indispensable.…”