Comparative pharmacokinetics of cisplatin and three analogues in mice and humans

Pharmacokinetics of cisplatin, spiroplatin, ethylenediaminemalonatoplatinum(II) (JM-40), and carboplatin was studied in BALB/c x DBA/2 F1 mice receiving 10% lethal doses of 15.5, 6.8, 100, and 165 mg/kg, respectively. Blood samples were collected for up to 5 days after a single i.v. bolus injection. Total platinum in plasma and non-protein-bound free platinum in plasma ultrafiltrate were determined by flameless atomic absorption spectrometry. Parent JM-40 and carboplatin were determined by high performance liquid chromatography. Calculated pharmacokinetic parameters (peak concentrations, half-lives, areas under the curve) were compared with the corresponding values in patients at the maximal tolerated dose. Peak plasma concentrations were 2.4- to 20-fold higher in mice than in humans. Initial and terminal half-lives in mice were up to 6 times shorter than in patients. However, the areas under the plasma concentration versus time curves (AUCs) were found to agree. The ratios of the AUCs of free platinum in patients (AUCp) and mice (AUCm) measured over the first part of the plasma concentration versus time curve were 1.2, 0.3, 1.1, and 0.9 for cisplatin, spiroplatin, JM-40, and carboplatin, respectively. These values changed to 1.3, 0.3, 2.5, and 1.0 when the time interval was extended to free platinum levels just above the detection limit. Ratios of the AUCs of total platinum in patients and mice measured over 5 days were 2.7, 2.6, 4.2, and 1.8, respectively. Using a ratio of 1 for free platinum originating from JM-40, the retrospectively calculated maximal tolerated dose from AUCp at low dosages was 1021 mg/m2 (n = 7; range, 836-1282), compared to 1200 mg/m2 as found in the phase I trial. This suggests that the AUCp/AUCm ratio of free platinum over the first part of the concentration versus time curve can possibly be used to predict the maximal tolerated dose of platinum analogues in humans, during the early stage of phase I studies.