Clinical phase I and pharmacokinetic trial of the new titanium complex budotitane

Abstract

Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.

22 Ti Anti‐Tumor Titanium Drugs

“…Budotitane, CremophorEL and propyleneglycol are dissolved separately in water-free ethanol in the weight ratio of 1:9:1. The solutions are then mixed and evaporated at [30][31][32][33][34][35][36][37][38][39][40] C. Within the resulting co-precipitate, budotitane is enveloped between layers of the solubilizer and is protected against hydrolysis. This co-precipitate can be dissolved in water under the formation of micelles.…”

Therapeutic Organometallic Compounds

“…Dose limiting toxicities of titanium compounds include nephrotoxicity and elevation of creatinine and bilirubin levels. (Hannon, 2007) Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] (Fig 11), was the first non-platinum transition-metal anticancer agent to be tested in clinical trials (Schilling et al, 1995). It is effective against a number of tumors in animals and is well tolerated (Bharti & www.intechopen.com Singh, 2009).…”

Synthesis, solution and solid state structure of titanium–maltol complex

“…Titanocene dichloride and budotitane possess the same limitation, low hydrolytic stability at physiological pH [15,17,26]. As a result, the mechanistic aspects and hydrolysis products of these antitumor species remain mostly uncharacterized.…”

“…But titanium(IV) complexes also have a role in the bioinorganic chemistry with two classical examples: titanocene dichloride (Cp 2 TiCl 2 ) and budotitane (Ti(bza) 2 (OEt) 2 ), which exhibit anti-cancer activities [15][16][17][18][19][20][21][22][23][24][25]. With the discovery of the biological properties of these two Ti(IV) complexes, many research groups have devoted their efforts to synthesize new titanium complexes with enhanced antitumor activity.…”