Pharmacokinetics Of (+)-1,2-Di(3,5-Dioxopiperazin-1-Yl)Propane Intravenous Infusions In Adult Cancer Patients

(+)-1,2-Di(3,5-dioxopiperazin-1-yl)propane (ICRF-187), the D-enantiomer of the racemic antitumor agent (±)-1,2-di(3,5-dioxopiperazin-1-yl)propane, displays schedule-dependent toxicity in humans and animals. Pharmacokinetic factors which might produce schedule-dependent toxicity were studied in patients during a Phase I trial. The intact drug was assayed by high-performance liquid chromatography in simple aqueous solutions by direct injection or in urine, bile, pleural fluid, or serum after extraction and concentration. Ultraviolet absorbance was monitored at 208 nm. ICRF-187 and an internal standard of ICRF-192 were eluted as separate peaks. Peak height and peak area ratios of ICRF-187 to ICRF-192 were linear over serum ICRF-187 concentrations from 0.05 to 100 µg/ml. The detection limit for ICRF-187 was 2 ng by direct injection, and the quantitation limit in serum was 0.05 µg/ml. Using equilibrium dialysis, there was no evidence for significant protein binding of ICRF-187. Urine and serum specimens were collected during and following i.v. infusions of 1.0 g/sq m ICRF-187 by three different schedules (30-min, 8-hr, and 48-hr infusions) to five adult patients. Total urinary drug recovery was schedule independent, averaging 48%. Serum drug kinetics followed a two-compartment open model (r² > 0.98 for all infusions). Mean peak serum levels for the three schedules were 75.3, 22.8, and 2.9 αg/ml, respectively. Mean central compartment volume of distribution was 0.193 liter/kg, or slightly greater than the expected inulin space. Mean f_1/2α values were not significantly different among the schedules (9.9, 10.6, and 19.5 min, respectively), nor were mean f_1/2 β values (121.4, 143.6, and 173.0 min, respectively). Integrals of the concentration-time curves did not differ with schedule. Intact ICRF-187 distributed into pleural effusions and was cleared at rates reflecting rapid equilibration with serum in one patient and slower equilibration in a second patient. Biliary drug concentration equaled serum drug concentration in the terminal phase in one patient. Infusion of ICRF-187 over periods >8 hr was necessary for achievement of true steady-state conditions. The greater biological effect of prolonged infusions is probably based upon drug action rather than upon pharmacokinetic factors and thus might be associated with improved antitumor activity.