Clinical and pharmacological studies with cis-diamminedichloroplatinum (II).

Abstract

cis -Diamminedichloroplatinum(II) is the first of a group of platinum coordination complexes with antineoplastic activity to be studied in humans. This Phase I investigation characterizes the toxicity and pharmacological disposition of the drug in 10 patients. Plasma levels of cis -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. Urinary excretion was incomplete, with only 27 to 45% of radioactivity excreted in the first 5 days. The initial fractions of radioactivity were largely unchanged drug, although this changed with time. The incorporation of thymidine-3H into DNA was inhibited in leukemic leukocytes only after prolonged exposure in vitro to cis -diamminedichloroplatinum(II). Acute lymphocytic cells appeared more sensitive than myelocytic cells in vitro , although the only objective antineoplastic response noted was a transient decrease 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.