Clinical pharmacokinetics of high-dose mitomycin C

Abstract

The pharmacokinetic profile of high-dose mitomycin C was determined in blood plasma and urine of twelve patients with advanced malignancies in a program including autologous bone marrow transplantation. A total dose of 60 mg/m2 was given, either as a single 60-min infusion or divided into infusions of 30 mg/m2 on each of 2 days or 15 mg/m2 on each of 4 days. One group was given 15-min infusions. Samples of blood plasma and urine were analyzed by high-performance liquid chromatography. Drug concentrations in plasma followed a biphasic pattern, with a terminal elimination half-life of 45 min. This half-life value and other parameters were unaffected by dose level, infusion time, and repeated doses. The lower peak plasma concentrations following 30 mg/m2 given as 60-min infusions compared to the same dose given over 15 min may have accounted for a dramatic drop in the incidence of a severe hemorrhagic colitis. Mitomycin C was excreted in urine at about the same rate as it was eliminated from plasma, but a larger percentage of the dose appeared in urine after 15-min infusions than after 60-min infusions. The pharmacokinetic profile, together with clinical observations, suggests that the dose-limiting toxicity of mitomycin C may be related to peak drug levels, and that both these levels and the toxicity are lessened as the infusion time is increased.

Study of the Pharmacokinetics of Mitomycin C in Humans during Intraperitoneal Chemohyperthermia with Special Mention of the Concentration in Local Tissues

“…In spite of this important uptake, only low values were simultaneously observed in serum (maximum levels at 45 min 0.4 ± 0 .1 8 mg/l) under those obtained after high-dose MMC intravenous infusion [14], These data are similar to those observed previously [9], and do not vary far from those obtained by the intraperi toneal route alone [12,13].…”

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

“…Table 1 shows the results of the chemosensitivity assays for 14 drugs tested against the three carcinoid cell lines. The IC 50 values were compared to the following individual achievable peak plasma concentrations (PPC): vinblastine 8.5 ng/ml [22], taxol 3.5±1.4 µM [23], camptothecin derivative topotecan (TPT) 65±20 nM [24], 5-FU 0.6 µM/l [25], doxorubicin 73.5±26.4 ng/ml [26], gemcitabine 50 µM [27], tamoxifen 0.4 µM [28], cisplatin 6.3 µM [29], oxaliplatin 9.1±1.25 µM [30], carboplatin 105 µM [31], mitomycin C 345±151 ng/ml [32], streptozotocin 100±10 µg/ml [33], etoposide 5.6±2.5 µg/ml [34] and dacarbazine 8.6±0.6 µg/ml [35]. UMC-11 cells exhibited marked chemoresistance against most drugs, with the exception of vinblastine, camptothecin, oxaliplatin, carboplatin, mitomycin C and dacarbazine, where IC 50 values were below PPC for the respective drugs.…”

The Akt/PKB pathway: molecular target for cancer drug discovery

“…By the early 1980s, TCN-P had been identified as an inhibitor of DNA and protein synthesis, and shown preclinical activity against leukemias and carcinomas. A number of phase I and II clinical trials of TCN/API-2 have been conducted in patients with advanced tumors, including carcinomas of the breast, colon, bladder, ovary, pancreas and lung (Cobb et al, 1983;Mittelman et al, 1983;Feun et al, 1984Feun et al, , 1993Powis et al, 1986;Schilcher et al, 1986;Hoffman et al, 1996). Owing to the fact that TCN-p was used as a cytotoxic drug, the majority of clinical trials were carried out with high doses of the drug in order to achieve maximal clinical efficacy.…”