Rudolf B. Schilcher

Clinical pharmacokinetics of high-dose mitomycin C

SummaryThe 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.

High-dose mitomycin-C with autologous bone marrow transplantation in patients with refractory malignancies. Influence of dose schedule on pharmacokinetics and nonhematopoietic toxicities

Thirteen courses of high-dose mitomycin-C with autologous bone marrow transplantation (ABMT) were administered to 12 patients. Four dose schedules were evaluated: A) 60 mg/ M2 × 1, 60-min infusion; B) 30 mg/M2/day × 2, 15-min infusion; C) 30 mg/M2/day × 2, 60-min infusion; D) 15 mg/M2/day × 4, 60-min infusion. Pharmacokinetic studies using HPLC technique were done in nine patients. All patients have since died and autopsies were performed in nine patients. Two major nonhematopoietic toxicities were encountered and were dose-schedule dependent: hemorrhagic colitis (six of six courses in Schedules A and B; two of seven in Schedules C and D), and hepatic dysfunction (five of six in Schedules A and B; two of seven in Schedules C and D). Histopathologic evidence of venocclusive disease of the liver was present in four of five autopsies in Schedules A and B; and two of four in Schedules C and D. One patient died as a result of liver failure associated with submassive hepatic necrosis. Saturation kinetics described by other investigators cannot be confirmed by our pharmacokinetic analyses in nine patients. Severe nonhematopoietic toxicities of mitomycin-C were found at three times the conventional dose; thus, this drug is assessed as not being clinically useful as a single agent in ABMT.

SEQUENTIAL COMBINATION CHEMOTHERAPY WITH VINBLASTINE-BLEOMYCIN AND ADRIAMYCIN-CISPLATIN IN EARLY AND LATE TESTICULAR CANCER

Publisher Summary Sequential combination chemotherapy with velban–bleomycin and adriamycin–cisplatin has produced 54% complete remission rate in disseminated testicular cancer, and the median survival of complete responders has not been reached in 30 months. With regard to the comparatively unfavorable patient selection, this result appears to match well with response rates reported. Thischapter discusses the results for the sequential combinations in disseminated disease, which is improved by an individualized leukocyte-nadir-related dose adaptation and by a closer spacing of the induction courses in good risk patients. In patients with stage IIA and stage IIB disease, the sequential chemotherapy program—together with or without radiotherapy—has shown effectiveness with respect to long-term survival, again at a low toxicity risk. An analysis of relapse patterns in a larger series are helpful to define as to which of measures, the local or the systemic one, will have to be intensified in this condition.

High-dose 1,2,4-triglycidylurazol given in regimens preparatory to bone marrow transplantation

SummaryTo elucidate its potential role in the framework of bone marrow transplantation, we studied the toxicologic and pharmacologic properties of high doses of the triepoxide derivate 1,2,4-triglycidylurazol (TGU) in a preclinical dog model. Dose-dependent and dose-limiting gastrointestinal toxicity occurred in a dose range between 40 and 75 mg/kg, with the lethal dose for 50% of animals (LD50) being estimated at 60 mg/kg. Severe and life-threatening hematologic toxicity developed at all dose levels examined but was generally reversible. The combination of TGU and total-body irradiation produced synergistic gastrointestinal toxicity, necessitating reductions of the TGU dose by 50% as compared with the single-agent dose. In contrast, the combination of TGU and high-dose busulfan resulted in no apparent nonhematologic synergistic toxicities. The immunosuppressive properties of TGU given in this combination enabled sustained histocompatible allogeneic marrow engraftment in three of four animals. The pharmacokinetics of TGU were not influenced by prior total-body irradiation or high-dose busulfan. We conclude that the myelotoxic, pharmacologic and immunosuppressive properties of high-dose TGU observed in this preclinical model seem to render the drug particularly suitable for use in regimens preparatory to bone marrow transplantation.