John D. Young

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.

Chemotherapy in a pregnant rat model: 2.5-Fluorouracil: Nonlinear kinetics and placental transfer

As more women postpone childbearing into their later reproductive years (M. A. Adams, G. P. Oakley, and J. S. Marks, J. Amer. Med. Assoc. 247, 493, 1982), the incidence of cancer in pregnancy is likely to increase. Information regarding the placental transfer and pharmacokinetics of antineoplastic agents is limited. The purpose of this study was to determine the kinetics of 5-fluorouracil, a fluorinated pyrimidine with known nonlinear kinetics (J. M. Collins, R. L. Dedrick, F. G. King, et al., Clin. Pharmacol. Ther. 28, 235, 1980) in a pregnant rat model and compare maternal and fetal disposition. A significant amount of 5-fluorouracil crosses the placenta and the relative fetal exposure increases in a dose-dependent fashion. In the pregnant rat model, 5-FU exhibited nonlinear pharmacokinetics as reflected by an increasing half-life, and a greater than proportional increase in the area under the concentration-time curve (AUC) with increasing dose. Fetal saturation of elimination occurred at a lower dose than in the maternal compartment. The significance of these findings to observed embryotoxicity is discussed in a pharmacodynamic model relating the pharmacokinetic behavior of a drug to its embryotoxic effects.

Chemotherapy in a pregnant rat model: 1. Mitomycin-C: Pregnancy-specific kinetics and placental transfer

Although cancer complicates pregnancy infrequently, its occurrence jeopardizes maternal and fetal well-being. Treatment with chemotherapeutic agents may adversely affect rapidly dividing fetal tissue, while physiologic changes in pregnancy may alter maternal drug disposition. Previous work on placental transfer and pregnancy-specific kinetics of antineoplastic agents is limited, making the establishment of treatment guidelines for the pregnant cancer patient difficult. Using a pregnant rat model and sensitive HPLC methodology we quantitated the placental transfer and resulting fetal exposure of mitomycin-C (MMC), an alkylating agent. Following maternal dosing, the relative fetal exposure was 6.4%, indicating that MMC does cross the placenta, although to a limited degree. Significant pregnancy-specific alterations in drug disposition, including higher plasma concentrations and decreased clearances in pregnant animals, highlight the need for drug-level monitoring and possible dosage modification when these agents are used in pregnancy.

Phase I trial of aclacinomycin-A - A clinical and pharmacokinetic study

SummaryAclacinomycin-A is a new anthracycline antibiotic with a broad spectrum of antitumor activity in animals. Compared to doxorubicin, it was found to produce less cardiotoxicity and alopecia. A Phase I trial of aclacinomycin-A given as a weekly 15 min IV infusion was conducted in 20 previously treated patients with advanced solid tumors. Four dose levels ranging from 40 to 100 mg/m2 were studied; myelotoxicity was dose-limiting at 85 and 100 mg/m2. Other toxicities were moderate to severe nausea and vomiting in 9 patients, mild phlebitis in 2 patients, and mild abnormality of liver function tests in 3 patients. No cardiac or renal toxicities were seen, but two partial responses were observed. The pharmacokinetic profile of aclacinomycin-A in plasma and urine was studied in 3 patients given 65 mg/m2 using a high performance liquid chromatography assay. The data obtained were consistent with a two compartment model of drug disposition with initial and terminal half-life values of 6.6 min and 13.3 h, respectively. The major fluorescent metabolite was eliminated with a terminal half-life of 25 h. Two metabolites as well as the parent drug were excreted in the urine as less than 10% of the doses given. This pharmacokinetic profile is similar to that of other anthracyclines, although aclacinomycin-A appears to have lower blood levels than doxorubicin given at equivalent doses. On this weekly schedule, the recommended dose is 65 mg/m2 for Phase II trials.

Pharmacokinetics of mitomycin-C in plasma and tumor tissue of cervical cancer patients and in selected tissues of female rats.

Mitomycin-C (MMC) is an alkylating agent which has shown significant activity in gynecologic cancers, both in vivo and in vitro. We determined the delivery of MMC to target tissue by comparing plasma and tumor tissue concentrations of MMC as measured by high-performance liquid chromatography (HPLC) in five patients with cervical cancer. In a companion study, we measured MMC concentrations in plasma and selected tumors of female rats given an equivalent dose. In patients, the mean terminal half-life and total body clearance rates of MMC were 40 min and 275 ml/min/m2, respectively. The mean cervical tumor to plasma concentration of MMC was 1.26 +/- 0.34 (mean +/- SE, n = 4). In female rats, the terminal half-life and total body clearance rates of MMC were 28.4 min and 270 ml/min/m2, respectively. Tissue concentrations of MMC in rats were lower than plasma concentrations measured at corresponding times. The highest concentrations were found in lung and uterus (including cervix) with lower concentrations in ovary and liver. The mean half-life for elimination of MMC from tissues of rats was 20.3 +/- 2.8 min (mean +/- SE, n = 6). Based on similar pharmacokinetic parameters in rats and patients, the rat appears to be a suitable model for the disposition of MMC in human patients. The near equivalent drug concentrations found in tumor and plasma of patients suggests that the in vitro tests conducted at concentrations based on plasma level may be relevant to cervical tumor tissue, as well.

Pharmacokinetics of intraperitoneal doxorubicin in combination with systemic cyclophosphamide and cis-platinum in the treatment of stage III ovarian cancer

The pharmacokinetics of intraperitoneal doxorubicin in three previously untreated patients with ovarian cancer are described. All patients were maximally cytoreduced (largest residual tumor less than or equal to 2 cm). The average total body clearance (TBC) was 16.3 ml/kg/min (range 10.6-20.4 ml/kg/min) and the mean volume of distribution (VD) was 42.4 liter/kg (range 27.6-46.9 liter/kg). Half-life of elimination (t 1/2 beta) was 2.6 hr. In spite of a therapeutic advantage of 60 when administered intraperitoneally, prohibitive local toxicity limited the use of doxorubicin via the intraperitoneal route in patients with ovarian cancer.

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.

High-performance liquid chromatographic determination of nafazatrom in human plasma using fluorescence detection

A rapid, sensitive, and selective high-performance liquid chromatographic assay was developed for determination of the pyrazole derivative nafazatrom (Bay g 6575, NFZ) in human plasma. Separation was obtained using a normal-phase Si-60 column and a mobile phase of methylene chloride--methanol (90:10, v/v) containing 0.25% water. The fluorescence of NFZ was monitored at excitation and emission wavelengths of 232 and 362 nm, respectively. The recovery of NFZ extracted from plasma with methylene chloride was 109 +/- 5% (mean +/- S.D.) in the concentration range from 5.0 to 500 ng/ml. The assay was applied to the determination of plasma concentrations of NFZ following administration of the compound to patients in a Phase I clinical trial.