This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rademaker-Lakhai, J. M. Articles by Schellens, J. H. M. Search for Related Content PubMed PubMed Citation Articles by Rademaker-Lakhai, J. M. Articles by Schellens, J. H. M.

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

¹ The Netherlands Cancer Institute, Amsterdam, the Netherlands; ² Slotervaart Hospital, Amsterdam, the Netherlands; ³ Faculty of Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands

Purpose: NAMI-A {H₂Im[trans-RuCl₄(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/m²/day). At 400 mg/m²/day, blisters developed on the hands, fingers, and toes. At 500 mg/m²/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/m²/day, the advised dose for further testing of NAMI-A was determined to be 300 mg/m²/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 (R² = 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/m²/day for 5 days, every 3 weeks.

This article has been cited by other articles:

				B. Gava, S. Zorzet, P. Spessotto, M. Cocchietto, and G. Sava Inhibition of B16 Melanoma Metastases with the Ruthenium Complex Imidazolium trans-Imidazoledimethylsulfoxide-tetrachlororuthenate and Down-Regulation of Tumor Cell Invasion J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 284 - 291. [Abstract] [Full Text] [PDF]

				F. Frausin, V. Scarcia, M. Cocchietto, A. Furlani, B. Serli, E. Alessio, and G. Sava Free Exchange across Cells, and Echistatin-Sensitive Membrane Target for the Metastasis Inhibitor NAMI-A (Imidazolium trans-Imidazole Dimethyl Sulfoxide Tetrachlororuthenate) on KB Tumor Cells J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 227 - 233. [Abstract] [Full Text] [PDF]