Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing

Sessa, Cristiana; Viganò, Lucia; Grasselli, Giacomo; Trigo, José; Marimón, Irene; Lladó, Anna; Locatelli, Alberta; Ielmini, Nicoletta; Marsoni, Silvia; Gianni, Luca

doi:10.1016/j.ejca.2005.09.033

Cited by 35 publications

(21 citation statements)

References 10 publications

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“…First, the prior oral administration shortened the t 1/2 of intravenously administered TSU-68, whereas the t 1/2 was unchanged in the case of the oral administration twice a day. The lowered exposure by oral administration observed in humans is also achieved with little change in t 1/2 (Xiong et al, 2004;Sessa et al, 2006). A possible explanation for the unchanged t 1/2 is that the observed t 1/2 after the second dose reflects the absorption rate rather than the elimination rate (i.e., flip-flop kinetics; Toutain and Bousquet-Mélou, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…In clinical pharmacokinetic studies, repeated oral administration of TSU-68 twice daily for 28 days resulted in an approximately 50% decrease in the AUC seen after the first administration (Brahmer et al, 2002;Murakami et al, 2003;Sessa et al, 2006). Clarifying the cause of this phenomenon would lead not only to a better understanding of the pharmacokinetic characteristics but also to a prediction of drugdrug interactions.…”

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confidence: 99%

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Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats

Kitamura

Yamamoto²,

Nagayama³

et al. 2007

Drug Metab Dispos

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ABSTRACT:TSU-68 ((Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) is a new drug under investigation that inhibits receptor tyrosine kinases involved in tumor angiogenesis. In clinical pharmacokinetic studies, lower plasma concentrations of orally administered TSU-68 are observed after the second dose given within 12 h after the first dose. We examined the cause of this observation through in vivo and ex vivo approaches using rats in which a rapid decrease in the exposure was shown as in humans. In rats, the area under the concentration-time curve after the second dose was decreased to 26% of that after the first dose during administration of TSU-68 (200 mg/kg) twice a day. Plasma clearance of TSU-68 intravenously administered 12 h after oral administration was 1.5-fold higher and the half-life was 2-fold shorter compared with those after the single intravenous administration. The amount of absorbed TSU-68, as indicated by the radioactivity totally excreted in the bile and urine following oral administration of [ 14 C]TSU-68, was unchanged by the prior oral administration. These results demonstrate that administered TSU-68 causes an increase in its elimination but not a decrease in its absorption after the subsequent administration. Furthermore, rat liver taken 12 h after administration of TSU-68 exhibited 6-fold higher activity of its microsomal oxidase than untreated liver. This result suggests that TSU-68 induced its own oxidative metabolism (i.e., autoinduction). In conclusion, the decrease in plasma concentrations of TSU-68 during the administration twice a day to rats was due to the rapid autoinduction. The same mechanism is probably at work in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats

Kitamura

Yamamoto²,

Nagayama³

et al. 2007

Drug Metab Dispos

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“…Dose-limiting toxicities included abdominal pain, anorexia, nausea/vomiting, pericardial effusion and thrombocytopenia (22,23). According to Kuenen et al, the maximum tolerated dose was 100 mg/m 2 t.i.d., and no objective response was achieved in any patient.…”

Section: Discussionmentioning

confidence: 99%

“…Phase I clinical studies of TSU-68 in patients with solid tumors have been conducted (22,23). Dose-limiting toxicities included abdominal pain, anorexia, nausea/vomiting, pericardial effusion and thrombocytopenia (22,23).…”

Section: Discussionmentioning

confidence: 99%

Combination therapy of tyrosine kinase receptor inhibitor TSU-68 (SU6668) and paclitaxel inhibits subcutaneous xenografts of endometrial cancer

Сузуки¹

2008

Mol Med Rep

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Abstract. TSU-68 is a small-molecular-weight synthetic inhibitor of the tyrosine kinase receptors Flk-1/KDR, PDGFRß and FGFR1, which are involved in angiogenesis. Using a mouse model in which endometrial cancer was subcutaneously implanted, we investigated the effects of TSU-68 alone or in combination with paclitaxel. We subcutaneously implanted a cell strain of endometrial cancer, HEC1A, into BALB/c nude mice. TSU-68 was orally administered every day, while paclitaxel was intraperitoneally injected once a week, and the rates of subcutaneous tumor proliferation were compared. In a group treated with high-dose (200 mg/kg/day) TSU-68 alone, subcutaneous tumor proliferation was significantly inhibited in comparison with a vehicle-treated control group (p<0.05). In groups treated with low-dose TSU-68 or paclitaxel alone (100 and 10 mg/kg/day, respectively), tumor proliferation was not significantly inhibited. In a low-dose combination therapy group (100 mg/kg/day of TSU-68 + 10 mg/kg/day of paclitaxel), tumor proliferation was significantly inhibited in comparison with the control and low-dose TSU-68 or paclitaxel therapy groups (p<0.01). High-dose monotherapy with TSU-68 inhibited the proliferation of the subcutaneously implanted tumor. Furthermore, a combination of TSU-68 and paclitaxel at a low dose, one at which respective monotherapy was not effective, inhibited tumor proliferation. Combination therapy with the two agents may therefore be useful for treating endometrial cancer.

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“…There are, however, other examples where induction of DMEs in rats is also observed in humans. For example, TSU-68, an experimental receptor tyrosine kinase inhibitor, showed autoinduction of CYP1A in rats (Kitamura et al 2007;Kitamura, Matsuoka et al 2008) and humans (Kitamura, Asanoma et al 2008;Sessa et al 2006).…”

Section: Animal Modelsmentioning

confidence: 99%

Hepatic Drug-Metabolizing Enzyme Induction and Implications for Preclinical and Clinical Risk Assessment

Mohutsky

Romeike²,

Meador

et al. 2010

Toxicol Pathol

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Hepatic drug metabolizing enzyme (DME) induction complicates the development of new drugs owing to altered efficacy of concomitant treatments, reduction in exposure resulting from autoinduction, and potential generation of toxic metabolites. Risk assessment of DME induction during clinical evaluation is confounded by several uncertainties pertaining to hazard identification and dose response analysis. Hepatic DME induction rarely leads to clinical evidence of altered metabolism and toxicity in the patient, which typically occur only if the DME induction is relatively severe. High drug doses are associated with a greater likelihood of hepatic DME induction and downstream effects; therefore, drugs of low potency requiring higher dosing tend to lead to a greater risk of drug-drug interactions. Vigilance in clinical trials for increased or diminished drug effect and, specifically, pharmacokinetic studies in the presence of other drugs and concomitant diseases are necessary for a drug risk assessment profile.Efforts to remove hepatic DME-inducing drugs from development can be facilitated with current in vitro and in vivo assessments and will improve with the development of newer technologies. A carefully tailored case-by-case approach will lead to the development of efficacious drugs with an acceptable risk/benefit profile available to patients.

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Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing

Cited by 35 publications

References 10 publications

Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats

Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats

Combination therapy of tyrosine kinase receptor inhibitor TSU-68 (SU6668) and paclitaxel inhibits subcutaneous xenografts of endometrial cancer

Hepatic Drug-Metabolizing Enzyme Induction and Implications for Preclinical and Clinical Risk Assessment

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