Ultrafilterable platinum (UP) disposition was studied in 22 cancer patients receiving their first course of cisplatin (50 to 140 mg/m2) by two-hour infusion. UP plasma and urinary platinum levels were quantitated using a high-performance liquid chromatographic (HPLC) assay, which was selective for cisplatin and active platinum metabolites. Creatinine clearance was determined in all patients at the time of the pharmacokinetic studies and ranged from 58 to 214 mL/min. Creatinine clearance was a poor predictor of UP disposition in patients, probably as a consequence of the complex renal clearance mechanism for UP in the human kidney, which involves both tubular secretion and reabsorption. However, the peak plasma level of UP was closely related to the area under curve (AUC) of UP (r2 = .831), P less than .0001) and was significantly correlated with the decline in creatinine clearance observed after four courses of cisplatin therapy to 12 of the patients (r2 = .727, P less than .005). Cisplatin dose and the AUC of UP were less satisfactory predictors of the change in creatinine clearance with four courses of therapy (r2 = .488, P less than .025 and r2 = .623, P less than .005). The large interpatient variability in all the parameters of cisplatin disposition measured in this study suggested that there may be a role for individualization of cisplatin dosage based on a peak level obtained in the first course of therapy. Longer term infusion of cisplatin could also be justified.

Objectives: The investigational objectives of this open, noncomparative phase I study were to determine the pharmacokinetic profile of a single dose of 11.25 mg leuprorelin acetate, the effective duration of the chemical castration (serum testosterone ≤1.73 nmol/l) and safety in patients with locally advanced and/or metastatic carcinoma of the prostate foreseen for chemical castration, in the hope that such a dose of leuprorelin acetate may be suitable as a depot formulation to be administered 3-monthly to these patients. Methods: A total of 24 males up to 85 years old with histologically proven advanced carcinoma of the prostate were enrolled in the study to obtain 18 eligible patients. Each patient was given 11.25 mg of leuprorelin acetate in a depot formulation subcutaneously after reconstitution in 2 ml of a special suspension vehicle. The study period lasted 24 weeks. Patients whose serum testosterone levels reincreased prior to the end of the observation period of 24 weeks were withdrawn from the study and received the monthly depot formulation of 3.75 mg of leuprorelin acetate. Results: The 3M-depot formulation of leuprorelin acetate ensured continuous and constant drug release and effective suppression of testosterone serum levels to castration range for at least 13 weeks. After an initial rise, 5α-dihydrotestosterone as well as the gonadotropin serum levels of luteinizing hormone and follicular stimulating hormone reflected the testosterone serum pattern. Conclusion: The results of this study show that the 3M-depot preparation of leuprorelin acetate is effective in suppressing the serum testosterone levels to the castration range for a targeted period of at least 13 weeks.

A model incorporating recent information regarding the specificity of a high-performance liquid chromatographic assay for "active" platinum in plasma ultrafiltrate, and the concept of mobile and fixed metabolites, was developed for cancer patients treated with cisplatin. Model parameters were determined using plasma and urinary platinum data obtained in 20 patients. It was assumed in the model that parent drug accounted for essentially all the platinum measured in plasma ultrafiltrate in the 2 h period immediately post infusion. At times greater than 4 h post infusion, platinum concentrations in plasma ultrafiltrate were assumed to be due entirely to reactive, mobile metabolites with possible cytotoxicity. The model accurately simulated platinum concentrations in plasma ultrafiltrate over a 24-h period following a 2-h infusion of 80 mg/m2 of cisplatin to seven patients, 100 mg/m2 to ten patients and 120 mg/m2 to three patients.