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Yumiko Aoyama - One of the best experts on this subject based on the ideXlab platform.
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Population pharmacokinetic modeling of Sepantronium Bromide (YM155), a small molecule survivin suppressant, in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma
Investigational New Drugs, 2013Co-Authors: Yumiko Aoyama, Masataka Katashima, Atsunori Kaibara, Akitsugu Takada, Tetsuya Nishimura, Taiji SawamotoAbstract:Purpose Population pharmacokinetics (PK) of Sepantronium Bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m^2/day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma Sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CL_CR), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CL_CR was the most influential covariate on Sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CL_CR = 40 mL/min) compared to patients with normal CL_CR. Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for Sepantronium in cancer therapy.
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lack of differences in the pharmacokinetics of Sepantronium Bromide ym155 between us and japanese patients with advanced solid tumors or non hodgkin lymphoma
Biopharmaceutics & Drug Disposition, 2013Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji SawamotoAbstract:The analysis was designed to compare the pharmacokinetics (PK) of Sepantronium between US and Japanese patient populations using data obtained from two phase 1 studies being conducted in a similar design, one conducted in the USA and the other in Japan. Patients with a confirmed advanced solid tumor or non-Hodgkin lymphoma (NHL) (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these studies. Sepantronium Bromide was administered as a continuous intravenous infusion for 168 h (7 days) every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 h after termination of Sepantronium Bromide infusion. Forty-one subjects in the US study (including five patients with NHL) and 33 patients in the Japanese study were enrolled in both studies and 35 in US and 32 in Japan had adequate samples for PK evaluation. The PK parameters were calculated by non-compartment analysis method and were compared in the US and Japanese populations. The geometric mean ratios (90% confidence intervals) of area under the concentration–time curve, steady state concentration and amount excreted into urine between Japanese and US populations were 1.068 (0.932–1.224), 1.141 (0.996–1.307) and 0.981 (0.855–1.125), respectively. There appear to be no PK differences between the US and Japanese patients with solid tumors or NHL. Copyright © 2012 John Wiley & Sons, Ltd.
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Pharmacokinetics of Sepantronium Bromide (YM155), a small-molecule suppressor of survivin, in Japanese patients with advanced solid tumors: dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium. Methods Sepantronium was administered as a continuous intravenous infusion of 1.8–10.6 mg/m^2/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose. Results The PK of Sepantronium was dose proportional in the dose range of 1.8–10.6 mg/m^2/day. Age and sex did not significantly affect the PK of Sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of Sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function. Conclusions While age and sex did not significantly affect the PK of Sepantronium, moderate renal impairment increased exposure of Sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.
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pharmacokinetics of Sepantronium Bromide ym155 a small molecule suppressor of survivin in japanese patients with advanced solid tumors dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium.
Taiji Sawamoto - One of the best experts on this subject based on the ideXlab platform.
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Population pharmacokinetic modeling of Sepantronium Bromide (YM155), a small molecule survivin suppressant, in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma
Investigational New Drugs, 2013Co-Authors: Yumiko Aoyama, Masataka Katashima, Atsunori Kaibara, Akitsugu Takada, Tetsuya Nishimura, Taiji SawamotoAbstract:Purpose Population pharmacokinetics (PK) of Sepantronium Bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m^2/day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma Sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CL_CR), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CL_CR was the most influential covariate on Sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CL_CR = 40 mL/min) compared to patients with normal CL_CR. Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for Sepantronium in cancer therapy.
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lack of differences in the pharmacokinetics of Sepantronium Bromide ym155 between us and japanese patients with advanced solid tumors or non hodgkin lymphoma
Biopharmaceutics & Drug Disposition, 2013Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji SawamotoAbstract:The analysis was designed to compare the pharmacokinetics (PK) of Sepantronium between US and Japanese patient populations using data obtained from two phase 1 studies being conducted in a similar design, one conducted in the USA and the other in Japan. Patients with a confirmed advanced solid tumor or non-Hodgkin lymphoma (NHL) (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these studies. Sepantronium Bromide was administered as a continuous intravenous infusion for 168 h (7 days) every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 h after termination of Sepantronium Bromide infusion. Forty-one subjects in the US study (including five patients with NHL) and 33 patients in the Japanese study were enrolled in both studies and 35 in US and 32 in Japan had adequate samples for PK evaluation. The PK parameters were calculated by non-compartment analysis method and were compared in the US and Japanese populations. The geometric mean ratios (90% confidence intervals) of area under the concentration–time curve, steady state concentration and amount excreted into urine between Japanese and US populations were 1.068 (0.932–1.224), 1.141 (0.996–1.307) and 0.981 (0.855–1.125), respectively. There appear to be no PK differences between the US and Japanese patients with solid tumors or NHL. Copyright © 2012 John Wiley & Sons, Ltd.
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Pharmacokinetics of Sepantronium Bromide (YM155), a small-molecule suppressor of survivin, in Japanese patients with advanced solid tumors: dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium. Methods Sepantronium was administered as a continuous intravenous infusion of 1.8–10.6 mg/m^2/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose. Results The PK of Sepantronium was dose proportional in the dose range of 1.8–10.6 mg/m^2/day. Age and sex did not significantly affect the PK of Sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of Sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function. Conclusions While age and sex did not significantly affect the PK of Sepantronium, moderate renal impairment increased exposure of Sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.
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pharmacokinetics of Sepantronium Bromide ym155 a small molecule suppressor of survivin in japanese patients with advanced solid tumors dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium.
Kazuhiko Nakagawa - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of Sepantronium Bromide (YM155), a small-molecule suppressor of survivin, in Japanese patients with advanced solid tumors: dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium. Methods Sepantronium was administered as a continuous intravenous infusion of 1.8–10.6 mg/m^2/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose. Results The PK of Sepantronium was dose proportional in the dose range of 1.8–10.6 mg/m^2/day. Age and sex did not significantly affect the PK of Sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of Sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function. Conclusions While age and sex did not significantly affect the PK of Sepantronium, moderate renal impairment increased exposure of Sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.
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pharmacokinetics of Sepantronium Bromide ym155 a small molecule suppressor of survivin in japanese patients with advanced solid tumors dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium.
Masataka Katashima - One of the best experts on this subject based on the ideXlab platform.
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Population pharmacokinetic modeling of Sepantronium Bromide (YM155), a small molecule survivin suppressant, in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma
Investigational New Drugs, 2013Co-Authors: Yumiko Aoyama, Masataka Katashima, Atsunori Kaibara, Akitsugu Takada, Tetsuya Nishimura, Taiji SawamotoAbstract:Purpose Population pharmacokinetics (PK) of Sepantronium Bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m^2/day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma Sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CL_CR), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CL_CR was the most influential covariate on Sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CL_CR = 40 mL/min) compared to patients with normal CL_CR. Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for Sepantronium in cancer therapy.
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lack of differences in the pharmacokinetics of Sepantronium Bromide ym155 between us and japanese patients with advanced solid tumors or non hodgkin lymphoma
Biopharmaceutics & Drug Disposition, 2013Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji SawamotoAbstract:The analysis was designed to compare the pharmacokinetics (PK) of Sepantronium between US and Japanese patient populations using data obtained from two phase 1 studies being conducted in a similar design, one conducted in the USA and the other in Japan. Patients with a confirmed advanced solid tumor or non-Hodgkin lymphoma (NHL) (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these studies. Sepantronium Bromide was administered as a continuous intravenous infusion for 168 h (7 days) every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 h after termination of Sepantronium Bromide infusion. Forty-one subjects in the US study (including five patients with NHL) and 33 patients in the Japanese study were enrolled in both studies and 35 in US and 32 in Japan had adequate samples for PK evaluation. The PK parameters were calculated by non-compartment analysis method and were compared in the US and Japanese populations. The geometric mean ratios (90% confidence intervals) of area under the concentration–time curve, steady state concentration and amount excreted into urine between Japanese and US populations were 1.068 (0.932–1.224), 1.141 (0.996–1.307) and 0.981 (0.855–1.125), respectively. There appear to be no PK differences between the US and Japanese patients with solid tumors or NHL. Copyright © 2012 John Wiley & Sons, Ltd.
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Pharmacokinetics of Sepantronium Bromide (YM155), a small-molecule suppressor of survivin, in Japanese patients with advanced solid tumors: dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium. Methods Sepantronium was administered as a continuous intravenous infusion of 1.8–10.6 mg/m^2/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose. Results The PK of Sepantronium was dose proportional in the dose range of 1.8–10.6 mg/m^2/day. Age and sex did not significantly affect the PK of Sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of Sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function. Conclusions While age and sex did not significantly affect the PK of Sepantronium, moderate renal impairment increased exposure of Sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.
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pharmacokinetics of Sepantronium Bromide ym155 a small molecule suppressor of survivin in japanese patients with advanced solid tumors dose proportionality and influence of renal impairment
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Yumiko Aoyama, Masataka Katashima, Taiji Sawamoto, Tetsuya Nishimura, Taroh Satoh, Kazuhiko NakagawaAbstract:Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of Sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of Sepantronium.
Aya Kita - One of the best experts on this subject based on the ideXlab platform.
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predicting response to Sepantronium Bromide ym155 a survivin suppressant by pet imaging with 11c ym155
Nuclear Medicine and Biology, 2018Co-Authors: Keisuke Mitsuoka, Aya Kita, Yoshihiro Murakami, Kenna Shirasuna, Akihiro Noda, Kentaro Yamanaka, Naoki Kaneko, Sosuke MiyoshiAbstract:Abstract Introduction Sepantronium Bromide (YM155) is a survivin suppressant that induces apoptosis in tumor cells. Although YM155 induces tumor regression in various tumor types in vivo , phase I and II studies demonstrated responding and non-responding patient populations. We investigated 11 C-labeled YM155 ([ 11 C]YM155) used as a positron emission tomography (PET) tracer to assess whether tumor uptake of [ 11 C]YM155 correlated with its anti-tumor effect, thereby allowing identification of patients who would respond to YM155 treatment. Methods (1) Uptake of YM155 was measured in 39 human cancer cell lines in vitro using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). (2) In vivo tumor uptake was assessed in xenografted mice and total body distribution was evaluated in a cynomolgus monkey using [ 11 C]YM155 with PET/computed tomography (CT) (mice) and PET (monkey) imaging. Results Intracellular uptake of YM155 in human cancer cell lines correlated well with its in vitro efficacy measured by GI 50 (Pearson's r = −0.5709). Similarly, in vivo studies using tumor xenografted mice showed that tumors sensitive to YM155 demonstrated robust uptake of [ 11 C]YM155, whereas insensitive tumors demonstrated low uptake. In the monkey, the biodistribution of [ 11 C]YM155 indicated low accumulation in lung, breast, head, and neck and was only significant in organs involved with drug clearance: i.e. liver, kidneys, and bladder. Conclusions Robust uptake of [ 11 C]YM155 by a tumor appears to be a positive predictive marker for a good response to YM155. The findings suggest the potential utility of PET/CT imaging with [ 11 C]YM155 for selection of patients whose tumors are likely to respond to YM155. Advances in knowledge YM155 efficacy correlated closely with its in vitro intracellular uptake and uptake on [ 11 C]YM155 PET imaging. [ 11 C]YM155 PET may predict tumor sensitivity to YM155. Implications for patient care The concept that tumor response can be accurately predicted prior to chemotherapy should be exploited to improve cancer treatment outcomes through judicious patient selection. The small molecule Sepantronium Bromide (YM155), a survivin suppressant, has been developed for the treatment of several cancers, including non-Hodgkin lymphoma, lung cancer, and breast cancer. The preferentially high in vitro uptake of YM155 by YM155-sensitive cancer cells and the high in vivo uptake of [ 11 C]YM155 in YM155-sensitive tumors demonstrated by PET imaging suggest the potential utility of performing [ 11 C]YM155 PET to allow the identification of patients with YM155-sensitive tumors.
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formulation design and evaluation of liposomal Sepantronium Bromide ym155 a small molecule survivin suppressant based on pharmacokinetic modeling and simulation
Pharmaceutical Research, 2015Co-Authors: Kohsuke Shakushiro, Hiroki Kawano, Mari Nakata, Aya Kita, Atsushi Maeda, Shunsuke Watanabe, Kazuhiro SakoAbstract:Purpose Sepantronium Bromide (YM155) is administered by 168-hour continuous infusions in clinical studies due to its time-dependent pharmacological efficacy and rapid elimination from plasma. To enable more convenient administration, i.e., bolus injections with low frequency, we prepared liposomal formulations of YM155 and evaluated their antitumor activities.
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Formulation Design and Evaluation of Liposomal Sepantronium Bromide (YM155), a Small-Molecule Survivin Suppressant, Based on Pharmacokinetic Modeling and Simulation
Pharmaceutical Research, 2015Co-Authors: Kohsuke Shakushiro, Hiroki Kawano, Mari Nakata, Aya Kita, Atsushi Maeda, Shunsuke Watanabe, Kazuhiro SakoAbstract:Purpose Sepantronium Bromide (YM155) is administered by 168-hour continuous infusions in clinical studies due to its time-dependent pharmacological efficacy and rapid elimination from plasma. To enable more convenient administration, i.e., bolus injections with low frequency, we prepared liposomal formulations of YM155 and evaluated their antitumor activities. Methods A kinetic simulation model of liposomal YM155 to predict the free drug concentration in both tumor and plasma was developed. A liposomal formulation with the target drug release rate was prepared based on the simulation. Antitumor activities of the formulation were examined in various tumor xenograft mouse models. In addition, antitumor activities of liposomal formulations with different drug release rates were compared in order to confirm the validity of the simulation-based prediction. Results Liposomal YM155 with the release half-life of 48 h was prepared as a promising formulation. This formulation showed significantly potent antitumor activities in tumor xenograft models by weekly bolus injections. Further studies demonstrated that this release rate was optimal for YM155 in terms of both efficacy and safety. Conclusions We successfully developed a liposomal formulation of YM155 that could substitute for long-term continuous infusion of the drug solution in clinical settings by being given as weekly bolus injections.
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antitumor efficacy and biodistribution of liposomal Sepantronium Bromide ym155 a novel small molecule survivin suppressant
European Journal of Pharmaceutics and Biopharmaceutics, 2014Co-Authors: Kohsuke Shakushiro, Hiroki Kawano, Mari Nakata, Aya Kita, Atsushi Maeda, Shunsuke Watanabe, Kazuhiro SakoAbstract:Abstract Sepantronium Bromide (YM155) exhibits time-dependent antitumor activity, although the plasma half-life of YM155 after a bolus intravenous (i.v.) administration is very short. Therefore, greater antitumor efficacy is obtained by continuous infusion than by bolus i.v. administration. In the present study, we attempted to liposomalize YM155 to obtain a longer circulation time than that achieved by bolus i.v. administration and yet retain sufficient antitumor activity. Encapsulation of YM155 in polyethylene glycol-coated liposomes extended the half-life of the drug, and high tumor accumulation of the drug was observed. Bolus i.v. administration of liposomal YM155 by a weekly administration regimen showed antitumor activity comparable to that obtained by the continuous infusion without severe toxicity in a murine xenograft model. Therefore, this liposomal formulation can be a new dosage form of YM155 that achieves sufficient efficacy and safety and is a more convenient administration regimen for users. It should be noted that liposomal YM155 showed unexpectedly high accumulation in the kidneys. This is a specific finding for liposomal YM155, offering important information for the consideration of the potential toxicity of liposomal YM155.
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Combination of YM155, a Survivin Suppressant, with Bendamustine and Rituximab: A New Combination Therapy to Treat Relapsed/Refractory Diffuse Large B-cell Lymphoma
Clinical Cancer Research, 2014Co-Authors: Naoki Kaneko, Aya Kita, Keisuke Mitsuoka, Kentaro Yamanaka, Sosuke Miyoshi, Masamichi Mori, Nobuaki Amino, Sadao KuromitsuAbstract:Purpose: There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of Sepantronium Bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models. Experimental Design: Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts. Results: The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G 1 population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G 2 –M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell–like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab. Conclusions: These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL. Clin Cancer Res; 20(7); 1814–22. ©2014 AACR .
