The bioavailability in man of ICRF-159 a new oral antineoplastic agent

Abstract

The bioavailability of the antineoplastic agent, ICRF-159, has been examined in 12 patients receiving the drug in single and subdivided dose schedules in an attempt to account for the differences in toxicity found with the different schedules clinically. Recovery of radioactivity in the urine after single large doses (13.3-19.4 g) was 8.5 +/- 3.0% of the administered dose. After doses of 3.8-5.55 g recovery was 22.7 +/- 10.5% and after the same dose subdivided into 3 equal aliquots it was 52 +/- 8.7%. Unrecovered radioactivity was largely accounted for in the faeces. Plasma radioactivity levels in 2 patients after high and low dose were equivalent. Toxicity of the drug paralleled urinary recovery of radioactivity. It is concluded that schedule dependence of toxicity of ICRF-159 is at least partly due to bioavailability factors.

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

“…Racemic razoxane is poorly soluble in water, which precluded preparation of intravenous formulation, and therefore this drug was available only for oral administration. Unfortunately, dose-dependent fluctuations in razoxane bioavailability complicated its therapeutic use (38). Nevertheless, Repta et al have observed nearly five-times higher solubility of DEX, which enabled intravenous formulation of the drug and resolved the pharmacokinetic issues (214).…”

Phase I clinical trial and pharmacokinetics of weekly ICRF-187 (NSC 169780) infusion in patients with solid tumors

“…Although there are no clinical data on weekly doses of ICRF-187, Creaven et al [42] studied ICRF-159 on both a single dose, weekly schedule and a weekly schedule using three divided oral doses, in which the latter approach was more myelotoxic at a total dose of 3 g/m 2 in each schedule. The difference between toxicity on these two weekly dose schedules was related to greater drug absorption from the GI tract on the divided dose schedule [43,44].…”

“…The difference between toxicity on these two weekly dose schedules was related to greater drug absorption from the GI tract on the divided dose schedule [43,44]. O'Connell et al [45] for the Eastern Cooperative Oncology Group (ECOG) also used a divided-dose weekly schedule (1 g/m 2 in three divided doses given one day each week) similar to that used by Creaven [43] and compared it with a loading course regimen (750 mg/m 2 in three divided doses daily for 3 consecutive days with courses repeated at 28 day intervals).…”

Metal binding by pharmaceuticals. Part 5. Interaction of Cd(II), Ni(II) and Pb(II) with the intracellular hydrolysis products of the anti-tumour agent ICRF 159 and its inactive homologue ICRF 192

“…Toxicity studies by WITTING [10], using the bisdioxopiperazine ICRF 158, discovered a marked reduction in lethality towards rats in comparison to EDTA. Pharmacological studies using ICRF 159 showed good oral acceptance with only limited side effects [34].…”