Clinical and Pharmacological Studies with t / s - Diamm inedichloropl atinu m ( II ) '

ns-Diamminedichloroplatinum(II) is the first of a group of platinum coordination complexes with antineoplastic ac tivity to be studied in humans. This Phase I investigation characterizes the toxicity and pharmacological disposition of the drug in 10 patients. Plasma levels of m-diamminedichloroplatinum(II) decayed in a biphasic mode, with an initial half-life of 25 to 49 min and a secondary phase ranging from 58 to 73 hr. Protein binding exceeded 90% of radioactivity in this phase. Intracellular leukocyte levels approximated 6 to 11% of coincident plasma samples. Uri nary excretion was incomplete, with only 27 to 45% of ra dioactivity excreted in the first 5 days. The initial frac tions of radioactivity were largely unchanged drug, al though this changed with time. The incorporation of thymidine-3H into DNA was inhibited in leukemic leukocytes only after prolonged exposure in vitro to c/J-diamminedichloroplatinum(II). Acute lymphocytic cells appeared more sensitive than myelocytic cells in vitro, although the only objective antineoplastic response noted was a transient de crease in blast count in a patient with acute myelocytic leukemia. Renal impairment was the dose-limiting toxicity in the single-dose escalation scheme used. Rises in serum creatinine occurred in three of six patients who received doses of 1.95 mg or more per kg, and progressive renal failure contributed to the death of one patient.