Phase I trial and clinical pharmacology of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea.
1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (NSC 95466) is a lipid-soluble nitrosourea that is presently undergoing clinical evaluation. In this Phase I study, the toxicity of this drug was examined after administration of the drug to cancer patients on 3 successive days every 6 to 8 weeks. Clinical pharmacology was studied using 1-[chloroethyl-14C](2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea. The dose-limiting toxicity was myelosuppression. The maximal tolerated dose was 105 mg/sq m, which produced a median platelet nadir of 40,000/microliter on Day 32 and a median white blood cell count nadir of 2200/microliter on Day 42. Progressive anemia was also observed. There was no evidence of acute or chronic hepatic, renal, or pulmonary damage. One patient with a metastatic hypernephroma exhibited a partial clinical remission. Plasma disappearance of the drug following bolus administration was biphasic, with an initial half-life of 18 to 25 min and a second half-life of 9 hr. Clearance of intact drug coincided largely with the initial disappearance phase of total radioactivity. Entry of radioactivity into the cerebrospinal fluid was observed. Approximately 35% of plasma radioactivity was protein bound, the major binder being albumin. Drug excretion was predominantly renal, and biliary elimination was only minor.
D000740:Anemia / Q000139:chemically induced; D004341:Drug Evaluation; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D007970:Leukopenia / Q000139:chemically induced; D008875:Middle Aged; D009150:Mustard Compounds / Q000009:adverse effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D009607:Nitrosourea Compounds / Q000009:adverse effects* / Q000378:metabolism; D011485:Protein Binding; D013921:Thrombocytopenia / Q000139:chemically induced
D009150:Mustard Compounds; D009607:Nitrosourea Compounds; C018627:1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidinyl)-1-nitrosourea