A Phase I and Pharmacological Study with Imidazolium- trans- DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent

Abstract

Purpose: NAMI-A {H 2 Im[trans-RuCl 4 (DMSO)HIm] or imidazolium-trans-DMSO-imidazole-tetrachlororuthenate} is a novel ruthenium-containing compound that has demonstrated antimetastatic activity in preclinical studies. This Phase I study was designed to determine the maximum-tolerated dose (MTD), profile of adverse events, and dose-limiting toxicity of NAMI-A in patients with solid tumors. Furthermore, the ruthenium pharmacokinetics (PK) after NAMI-A administration and preliminary antitumor activity were evaluated.Patients and Methods: Adult patients with solid tumors received NAMI-A as an i.v. infusion over 3 h daily for 5 days every 3 weeks. PK of total and unbound ruthenium was determined during the first and second treatment using noncompartmental pharmacokinetic analysis. The total accumulation of ruthenium in WBCs was also quantified.Results: Twenty-four patients were treated at 12 dose levels (2.4 -500 mg/m 2 /day). At 400 mg/m 2 /day, blisters developed on the hands, fingers, and toes. At 500 mg/m 2 /day, blisters persisted from weeks to months and slowly regressed. Although no formal common toxicity criteria (CTC) grade 3 developed, painful blister formation was considered dose limiting. Because the first signs developed at 400 mg/ m 2 /day, the advised dose for further testing of NAMI-A was determined to be 300 mg/m 2 /day on this schedule. PK analysis revealed a linear relationship between dose and area under the concentration-time curve (AUC) of total and unbound ruthenium (R 2 ‫؍‬ 0.75 and 0.96, respectively) over the whole dose range. Plasma clearance of total ruthenium was 0.17 ؎ 0.09 liter/h, and terminal half-life was 50 ؎ 19 h. The volume of distribution at steady state of total ruthenium was 10.1 ؎ 2.8 liters. The accumulation of ruthenium in WBC was not directly proportional to the increasing total exposure to ruthenium. One patient with pretreated and progressive nonsmall cell lung cancer had stable disease for 21 weeks.Conclusion: NAMI-A can be administered safely as a 3-h i.v. infusion at a dose of 300 mg/m 2 /day for 5 days, every 3 weeks.

Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

“…Two N-C-N ligands are orthogonal, and the angle between the N-C-N planes is 89.21°. The Fe-C and Fe-N bond lengths in 1·PF 6 and [Fe(CO) 2 (NCN)Br] [28] are similar.…”

Solution equilibria of anticancer ruthenium(II)-(η6-p-cymene)-hydroxy(thio)pyr(id)one complexes: Impact of sulfur vs. oxygen donor systems on the speciation and bioactivity

“…(NAMI-A) and sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1339) are currently undergoing clinical trials with promising results [1][2][3]; however, antitumor properties of Ru complexes were already reported in the 1950s [4]. In the last decade, numerous organometallic ruthenium(II)- 6 -arene complexes mainly with piano-stool structure were synthesized and tested in in vitro assays regarding their bioactivity.…”

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

“…Two representatives of this class of compounds have entered clinical trials so far: imidazolium trans-[tetrachlorido(dimethylsulfoxide)(1H-imidazole)ruthenate(III)] (NAMI-A) [4,5] and indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) [6][7][8] (see Chart 1 for structures). Only very moderate toxicities were observed in the case of KP1019 [6,7,9] whereas NAMI-A treatment was accompanied by painful blister formation at higher dosage, however that is actually higher than the advised dosage [10].…”