Pharmacokinetics of ethylenediaminemalonatoplatinum(II) (JM-40) during phase i trial

Pharmacokinetics of the cis-platin analog ethylenediaminemalonatoplatinum(II) (JM-40) was studied in 28 cycles of 19 patients during the phase I study of this drug. The drug was administered intravenously by short-term (10-60min) infusion. Doses ranged from 20 to 1, 200 mg m^‑2. JM-40 was determined in plasma ultrafiltrate and urine by HPLC. Platinum (Pt) concentrations were determined in plasma, plasma ultrafiltrate, urine and red blood cells by atomic absorption spectrometry up to 5 days after administration of the drug. Ultrafilterable Pt could be determined up to 45 days after the infusion in one patient sampled over such a long period. Pharmacokinetics of JM-40 showed a linear behaviour. The final half-life of total Pt in plasma was 4.1 +0.9 days. The disposition of JM-40 was similar to that of ultrafilterable Pt in respect to t_{½ α}, (10 and 13 min), t_{½ β} (44 and 57 min), volumes of distribution V_c (11 and 121) and V_ss (17 and 201), systemic clearance (256 and 223ml min^‑1), renal clearance (69 and 73 ml min^‑1) and metabolic clearance (183 and 154ml min^-1). During the first 6h 27±9% of the administered dose was excreted as JM-40. Cumulative platinum excretion in the urine amounted to 29±13%, 42±14% and 60±13% over the first 6h, 24h and 5 days, respectively. The uptake of platinum in red blood cells was limited, comprising only 0.24±0.12% of the administered dose. Although JM-40 and carboplatin are structurally closely related, pharmocokinetics and toxicity of JM-40 were more similar to cis-platin than to carboplatin.