Pharmacokinetics in mice implanted with xenografted tumors after intravenous administration of tasidotin (ILX651) or its carboxylate metabolite

Abstract

The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tasidotin and its metabolites were characterized after singledose administration of tasidotin (20 and 120 mg/kg), tasidotin-C-carboxylate (150 mg/kg), or tasidotin (53 mg/kg) in the presence and absence of Z-prolyl prolinal (5 mg/kg administered 1 hour prior to tasidotin administration), a competitive antagonist of prolyl oligopeptidase, the enzyme responsible for the metabolism of tasidotin to tasidotin-Ccarboxylate. A secondary study was done comparing tumor growth in tasidotin-treated mice with implanted LOX tumors in the presence and absence of Z-prolyl-prolinal. After tasidotin administration, the pharmacokinetics of tasidotin and tasidotin-C-carboxylate were similar in plasma and tumors in LOX-and H460-implanted mice, indicating the resistance was not due to pharmacokinetic factors. Tumor carboxylate concentrations were much higher than in plasma after tasidotin administration. The metabolite appeared to contribute ~17% to 33% to the total exposure in LOX tumors and 20% to 49% in H460 tumors but <5% in plasma. Less than 5% of the administered tasidotin dose was converted to tasidotin-C-carboxylate, with no apparent differences between LOX-and H460-treated animals. The presence of Z-prolyl-prolinal decreased the amount of tasidotin converted to tasidotin-C-carboxylate from 5.5% to 0.90%, a reduction of almost 80%. After tasidotin-Ccarboxylate administration, the half-life was on the order of minutes compared with hours when observed after tasidotin administration. Tasidotin-C-carboxylate elimination was not dependent on tasidotin pharmacokinetics, suggesting that the rate of efÀ ux from cells into plasma was the ratelimiting step in its elimination. Tasidotin-C-carboxylate was also further metabolized to desprolyl-tasidotin-C-carboxylate, although the metabolite ratios were <10%. Pretreatment with Z-prolyl-prolinal completely abolished the antitumor activity of tasidotin, indicating that the metabolite is the main moiety responsible for activity and that, despite tasidotin itself having activity in vitro, tasidotin is acting mainly as a prodrug.

Pharmacokinetics of venlafaxine and its major metabolite o-desmethylvenlafaxine in freely moving mice using automated dosing/sampling system

“…Common problems include catheter occluded with blood clots, trauma, and infections associated with catheter surgery or retrieval, and positional errors caused by shifting or realignment of the catheter tip within the vein or artery. [ 18 19 ] Encountering any of these difficulties may result in loss of a timed-sample or loss of life. Overcoming these difficulties, the current study is approaching to establish automated systems for pharmacokinetic studies in mice.…”

Depsipeptides Targeting Tumor Cells: Milestones from In Vitro to Clinical Trials

“…Tasidotin is a third-generation analog of dolastatin 15 that is metabolically stable due to its resistance to hydrolysis [ 149 ]. It showed in vivo anticancer activity in preclinical models of pediatric sarcomas [ 216 ], LOX melanoma xenografts [ 217 ], and xenograft models of breast, ovarian, prostate, and colon cancer [ 216 ].…”

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

“…Tasidotin, which is orally active, reduces the shortening rate, the switching frequency from growth to shortening (catastrophe frequency), and the fraction of time the microtubules grow . Tasidotin is a proapoptotic cytotoxic compound and it is also a P‐gp substrate as all the other dolastatins. It showed promising in vivo anticancer activity in preclinical models of pediatric sarcomas, LOX melanoma xenografts, and xenograft models of breast cancer, ovarian cancer, prostate cancer, and colon cancer as reported in the ILX‐651 investigators brochure (Genzyme Corp., 2004) cited by Garg et al., but not in H460 NSCLC xenografts .…”

“…Tasidotin is a proapoptotic cytotoxic compound and it is also a P‐gp substrate as all the other dolastatins. It showed promising in vivo anticancer activity in preclinical models of pediatric sarcomas, LOX melanoma xenografts, and xenograft models of breast cancer, ovarian cancer, prostate cancer, and colon cancer as reported in the ILX‐651 investigators brochure (Genzyme Corp., 2004) cited by Garg et al., but not in H460 NSCLC xenografts . Tasidotin was also efficient in vivo in murine P388 leukemia model .…”