Pharmacokinetics of a novel anticancer ruthenium complex (KP1019, FFC14A) in a phase I dose-escalation study

Abstract

A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration-time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.

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

“…Ruthenium compounds are currently considered the most likely candidates for the next generation of metal-based anticancer drugs [2,3]. 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].…”

“…Although the pharmacological target for antitumor ruthenium compounds has not been unequivocally identified, it is unlikely that their modes of action are similar to that of cisplatin [7]. The limitation in the application of KP1019 in the clinics was the low solubility and therefore, the maximum tolerated dose was not reachable in clinical trials [8].…”

Therapeutic Organometallic Compounds

“…Ruthenium compounds ONCO4417 and DW1/2 have been demonstrated to show Pim-1 kinase inhibition in preclinical systems (Sekhon, 2010). A phase I and pharmacokinetic study was also carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A) (Lentz et al, 2009). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks.…”

Ruthenium polypyridyl squalene derivative: A novel self-assembling lipophilic probe for cellular imaging

“…Luminescent ruthenium complexes have been studied as oxygen sensors (Gerritsen et al, 1997) and as DNA intercalators (Zeglis and Barton, 2008). Other studies have addressed the use of Ru (II) complexes as anticancer agents (Lentz et al, 2009;Levina et al, 2009;Scolaro et al, 2005) and, more recently, as cellimaging probes. For this latter application, ruthenium complexes offer several advantages:low background emission, and other characteristic photophysical properties including a long-lived excited metal-to-ligand charge transfer state, and red-shifted emission.…”