研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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Effect of everolimus on the glucose metabolic pathway in mouse skeletal muscle cells (C2C12)

Kayoko Yoshida, Chiyo K. Imamura, Kanako Hara, Mayumi Mochizuki, Yusuke Tanigawara

Metabolomics 13 （ 98 ） 2017年07月

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The effects of advanced age and serum alpha1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients

H. Kenmotsu, C.K. Imamura, A. Ono, S. Omori, K. Nakashima, K. Wakuda, T. Taira, T. Naito, H. Murakami, T. Takahashi, Y. Tanigawara

Br. J. Clin. Pharmacol 83 （ 11 ） 2416 - 2425 2017年07月

共著

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Population Pharmacokinetic and Exposure-Response Analysis of Weekly Teriparatide in Osteoporosis Patients

A. Ose, M. Serada, K. Yamashita, K. Tsurui, Y. Tanigawara

J. Clin. Pharmacol 57 （ 12 ） 1545 - 1553 2017年06月

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Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole

Imamura Chiyo K., Furihata Kenichi, Okamoto Shinichiro, Tanigawara Yusuke

Journal of Clinical Pharmacology 56 （ 4 ） 408 - 413 2016年04月

ISSN 0091-2700

This study evaluated the effects of cytochrome P450 (CYP) 2C19 polymorphisms on tacrolimus pharmacokinetics when coadministered with voriconazole. Eighteen healthy volunteers, including 6 individuals in each CYP2C19 genotype (extensive metabolizers [EMs], intermediate metabolizers [IMs], and poor metabolizers [PMs]), received a single oral dose of 3 mg tacrolimus alone or in combination with 200 mg voriconazole twice daily at steady state. When tacrolimus was coadministered with voriconazole, a significant increase in area under its concentration-time curve (AUC_0-24) was observed for all genotypes. AUC_0-12 of voriconazole in IMs and PMs were significantly higher than that in EMs (P 0-24 of tacrolimus in combination with voriconazole in IMs and PMs were also significantly higher than that in EMs (P

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Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study

Booka Eisuke, Imamura Chiyo K., Takeuchi Hiroya, Hamamoto Yasuo, Gomi Daisuke, Mizukami Takuro, Ichiyama Takashi, Tateishi Kazunari, Takahashi Tsunehiro, Kawakubo Hirofumi, Soejima Kenzo, Boku Narikazu, Tanigawara Yusuke, Kitagawa Yuko

Gastric Cancer 19 （ 3 ） 876 - 886 2015年08月

ISSN 1436-3291

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m2. A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9–108.8 mL/min as estimated by the Cockcroft–Gault equation. The S-1 dosage formula was derived as follows:(Formula presented.)where AUC is the area under the concentration–time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration–time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

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カルボプラチン投与量算出におけるCalvert式利用に関する実態調査

今村知世，加藤有紀子，下方智也，安藤雄一，谷川原祐介

医療薬学 41 （ 11 ） 759 - 767 2015年

Sunitinib-induced severe toxicities in a japanese patient with the ABCG2 421 AA genotype

Miura Yuji, Imamura Chiyo K., Fukunaga Koya, Katsuyama Yoshihiko, Suyama Koichi, Okaneya Toshikazu, Mushiroda Taisei, Ando Yuichi, Takano Toshimi, Tanigawara Yusuke

BMC Cancer 14 （ 964 ） 2014年12月

Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. Case presentation: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. Conclusion: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

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Forced expression of S100A10 reduces sensitivity to oxaliplatin in colorectal cancer cells

Suzuki Sayo, Tanigawara Yusuke

Proteome Science 12 （ 26 ） 2014年05月

Background: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. Our recent proteomics studies have demonstrated that intracellular protein expression levels of S100A10 are significantly correlated with the sensitivity of colorectal cancer (CRC) cells to L-OHP, but not 5-FU, suggesting that S100A10 is a candidate predictive marker for the response to L-OHP. In this study, we investigated whether S100A10 is involved in L-OHP sensitivity or not.Results: Forced expression of S100A10 in COLO-320 CRC cells significantly increased the 50% inhibitory concentration (IC₅₀) for L-OHP (P = 0.003), but did not change that for 5-FU, indicating that S100A10 is more specific to L-OHP than 5-FU. Silencing of the S100A10 gene showed no apparent effect on sensitivity to L-OHP in HT29 cells. Silencing of the annexin A2 (a binding partner of S100A10) gene alone downregulated both annexin A2 and S100A10 protein levels, with no change in S100A10 gene expression. However, original levels of intact S100A10 protein in CRC cells positively correlated with S100A10 mRNA levels (P = 0.002, R = 0.91).Conclusions: The present results have shown that protein expression of S100A10 was associated with resistance to L-OHP, but not 5-FU, supporting the hypothesis that S100A10 expression may predict L-OHP sensitivity. Thus, our present study provides basic findings to support that S100A10 expression can be used as a predictive marker for tumor sensitivity to L-OHP. © 2014 Suzuki and Tanigawara; licensee BioMed Central Ltd.

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Population PK modeling and simulation based on fluoxetine and norfluoxetine concentrations in milk : a milk concentration-based prediction model

124. R. Tanoshima, F. G. Bournissen, Y. Tanigawara, J. H. Kristensen, A. Taddio, K. F. Ilett, E. J. Begg, I. Wallach, S. Ito

British Journal of Clinical Pharmacology 78 （ 4 ） 918 - 928 2014年04月

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients

Hirasawa Akira, Zama Takeru, Akahane Tomoko, Nomura Hiroyuki, Kataoka Fumio, Saito Koichiro, Okubo Keisuke, Tominaga Eiichiro, Makita Kazuya, Susumu Nobuyuki, Kosaki Kenjiro, Tanigawara Yusuke, Aoki Daisuke

Journal of Human Genetics 58 （ 12 ） 794 - 798 2013年12月

ISSN 1434-5161

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients. © 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13.

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Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections

Tanigawara Yusuke, Kaku Mitsuo, Totsuka Kyoichi, Tsuge Hiroyuki, Saito Atsushi

Journal of Infection and Chemotherapy 19 （ 5 ） 858 - 866 2013年10月

ISSN 1341-321X

An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK-PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK-PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK-PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC_0-24h/MIC and the fC _max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC_0-24h/MIC or fC _max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC_0-24h/MIC ≥ 30 and for fC _max/MIC ≥ 2 were 96.4 % and 96.3 %, respectively. The PK-PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC_0-24h/MIC ≥ 30 and fC _max/MIC ≥ 2. The PK-PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations. © 2013 The Author(s).

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Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients

Kim Hye Ryun, Park Hyung Soon, Kwon Woo Sun, Lee Ji Hyun, Tanigawara Yusuke, Lim Sun Min, Kim Hyo Song, Shin Sang Jun, Ahn Jung Bae, Rha Sun Young

Cancer Chemotherapy and Pharmacology 72 （ 4 ） 825 - 835 2013年10月

ISSN 0344-5704

Purpose: The aim of this study was to investigate the pharmacogenetic determinants of sunitinib-related toxicity and ethnic difference in metastatic renal cell carcinoma (mRCC) among Korean patients. Methods: A pharmacogenetic study was performed in 65 patients with mRCC treated with the standard schedule of sunitinib (50 mg orally once daily for 4 weeks-on/2 weeks-off). Detailed data regarding the toxicity of sunitinib, including thrombocytopenia, neutropenia, anemia, and hand-foot syndrome (HFS), were prospectively collected in a clinical trial program (n = 38) or standard oncology practice (n = 27). Total of 12 genetic polymorphisms in 8 candidate genes (CYP1A1, CYP3A5, ABCB1, ABCG2, PDGFRα, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity from sunitinib using Pearson χ ² test. Results: Common grade 3 or grade 4 treatment-related toxicities were thrombocytopenia (36.9 %, 24/65), neutropenia (18.4 %, 12/65), anemia (7.7 %, 5/65), and HFS (12.3 %, 8/65). Patients carrying an ABCG2 421 AA genotype developed significantly more grade 3 or grade 4 thrombocytopenia, neutropenia, and HFS adjusted for age, sex, and Eastern Cooperative Oncology Group performance status, and body surface area (odds ratio compared with AC/CC genotypes [OR] 9.90, P = 0.04, thrombocytopenia; OR 18.20, P = 0.02, neutropenia; and OR 28.46, P = 0.01, HFS). In addition, total and surface protein ABCG2 protein expression was decreased in ABCG2 421 AA mutant cells compared to wild type. Conclusion: Among 12 genetic polymorphisms, polymorphism in the ABCG2 421C>A gene may be mostly associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of 421C>A SNP in Asian, this may be related to differential toxicities among ethnic groups. © 2013 Springer-Verlag Berlin Heidelberg.

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Clinical dose findings of sitafloxacin treatment : pharmacokinetic-pharmacodynamic analysis of two clinical trial results for community-acquired respiratory tract infections

Kohno Shigeru, Niki Yoshihito, Kadota Jun Ichi, Yanagihara Katsunori, Kaku Mitsuo, Watanabe Akira, Aoki Nobuki, Hori Seiji, Fujita Jiro, Tanigawara Yusuke

Journal of Infection and Chemotherapy 19 （ 3 ） 486 - 494 2013年06月

ISSN 1341-321X

The adequacy of sitafloxacin clinical dose regimens was assessed by comparing the efficacy of the administration of 100 mg sitafloxacin once daily (100 mg qd group) and 50 mg sitafloxacin twice daily (50 mg bid group). Patients with respiratory tract infections caused by pneumococci were orally treated with sitafloxacin (100 mg qd or 50 mg bid) for 7 days. The clinical efficacy, pneumococci eradication rate, safety, and pharmacokinetic and pharmacodynamic indices of the two groups were then assessed. The clinical efficacy was 93.5 % in both groups. The pneumococci eradication rate was 98.2 % in the 100 mg qd group and 92.7 % in the 50 mg bid group. The mean of the free AUC _0-24h divided by the minimum inhibitory concentration (MIC) (fAUC_0-24h/MIC) did not differ significantly between the 100 mg qd (103.24) and the 50 mg bid groups (105.25). The mean of the free C _peak divided by the MIC (fC _peak/MIC) was higher in the 100 mg qd group (10.19) than in the 50 mg bid group (6.53). The pathogen eradication rate was 98.9 % (89/90) when the fAUC_0-24h/MIC was greater than 30, and the eradication rate was 98.9 % (89/90) when the fC _peak/MIC was greater than 2. The incidences of adverse drug reactions were 33.7 % in the 100 mg qd group and 40.4 % in the 50 mg bid group. No obvious differences in the efficacy and safety were observed between the dosage groups. For cases in which a sufficiently high C _peak is necessary to ensure the susceptibility of the pathogens to the drug, 100 mg sitafloxacin once daily should be administered. © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

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Clinical and bacteriological efficacies of sitafloxacin against community-acquired pneumonia caused by Streptococcus pneumonia : nested cohort within a multicenter clinical trial

Fujita Jiro, Niki Yoshihito, Kadota Jun Ichi, Yanagihara Katsunori, Kaku Mitsuo, Watanabe Akira, Aoki Nobuki, Hori Seiji, Tanigawara Yusuke, Cash Haley L., Kohno Shigeru

Journal of Infection and Chemotherapy 19 （ 3 ） 472 - 479 2013年06月

ISSN 1341-321X

We evaluated the clinical and bacteriological efficacy of oral sitafloxacin (STFX) in clinically diagnosed community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae. Additionally, we cultured these patient samples to test the minimal inhibitory concentrations (MICs) of levofloxacin (LVFX), moxifloxacin (MFLX), STFX, and penicillin G (PCG), as well as identified mutations in the quinolone resistance determinant regions (QRDRs) in LVFX-resistant strains. This study is a nested cohort from a prospective, multicenter clinical trial consisting of 139 patients with community-acquired pneumonia (CAP), from which 72 were included in this study. After diagnosis of CAP caused by S. pneumoniae, STFX (50 mg twice daily, or 100 mg once daily) was orally administered for 7 days. Sixty-five patient sputum samples were then cultured for MIC analysis. In a LVFX-resistant strain that was identified, mutations in the QRDRs of the gyrA, gyrB, parC, and parE genes were examined. Of 72 patients eligible for this study, S. pneumoniae was successfully cultured from the sputum of 65 patients, and only 7 patients were diagnosed by urinary antigen only. Clinical improvement of CAP was obtained in 65 of the 69 clinically evaluable patients (65/69, 94.2 %). Eradication of S. pneumoniae was observed in 62 patients of the 65 bacteriologically evaluable patients (62/65, 95.4 %). Additionally, STFX showed the lowest MIC distribution compared with LVFX, MFLX, and PCG, and no major adverse reactions were observed. STFX treatment in patients with CAP caused by S. pneumoniae was found to be highly effective both clinically (94.2 %) and bacteriologically (95.4 %). © 2012 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

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Blood-direct InvaderPlus® as a new method for genetic testing

Hirasawa Akira, Akahane Tomoko, Tanigawara Yusuke, Aoki Daisuke

Personalized Medicine 9 （ 6 ） 657 - 663 2012年08月

ISSN 1741-0541

Aim: This study compared the efficiency of Blood-direct InvaderPlus® with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. Materials & methods: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. Results: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A16,27,28,60, VKORC1 -1639G>A, VKORC1 1173T>C and CYP2C92 and3 much faster than the conventional methods. Conclusion: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms. © 2012 Future Medicine Ltd.

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Pharmacokinetics of mizoribine in adult living donor liver transplantation

Shinoda M., Tanabe M., Kawachi S., Ono Y., Hayakawa T., Iketani O., Kojima M., Itano O., Obara H., Kitago M., Hibi T., Matsubara K., Shimojima N., Fuchimoto Y., Hoshino K., Wakabayashi G., Shimazu M., Tanigawara Y., Kuroda T., Morikawa Y., Kitajima M., Kitagawa Y.

Transplantation Proceedings 44 （ 5 ） 1329 - 1335 2012年06月

ISSN 0041-1345

We investigated the pharmacokinetics of mizoribine in the acute phase after adult living donor liver transplantation (LDLT). Between February 2004 and October 2009, 16 recipients received immunosuppressive therapy that included mizoribine (100 to 200 mg/d) after undergoing LDLT. We determined the serum levels of mizoribine before (C0) and 3 (C3), 4 (C4), and 10 (C10) hours after administration on postoperative days 3, 7, and 21. We assessed area under the concentration time curve (AUC) (hour · μg/mL), normalized serum concentration (NSC) at C0 [concentration (μg/mL)/dose (mg/kg body weight)], and estimated glomerular filtration rate (eGFR). The mizoribine concentration showed increases at C3 and C4 followed by a decrease at C10 on all days. AUC was 4.3, 5.9, and 8.3 in the 200-mg/d dose group on days 3, 7, and 21, respectively. NSC at C0 increased for 3 weeks after LDLT. There was a significant correlation between the NSC at C0 and eGFR on day 21, but not on days 3 and 7. There were no correlations between the NSC at C0 and either aspartate aminotransferase, total bilirubin, albumin, trough cyclosporine, or trough tacrolimus on any day. The pharmacokinetics of mizoribine in the acute phase after LDLT seems to be affected by postoperative day and renal function. © 2012 Elsevier Inc.

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Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

Matsuoka Hiromichi, Arao Tokuzo, Makimura Chihiro, Takeda Masayuki, Kiyota Hidemi, Tsurutani Junji, Fujita Yoshihiko, Matsumoto Kazuko, Kimura Hideharu, Otsuka Masatomo, Koyama Atsuko, Imamura Chiyo K., Tanigawara Yusuke, Yamanaka Takeharu, Tanaka Kyoko, Nishio Kazuto, Nakagawa Kazuhiko

Oncology Reports 27 （ 5 ） 1393 - 1399 2012年05月

ISSN 1021-335X

Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naïve cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRM1, 118A→G) and catechol-O-methyltransferase (COMT, 472G→A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the mRNA expression levels of arrestin β 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRM1 and morphine treatment; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G→A genotype may be a predictive biomarker of the response to morphine treatment.

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A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese

Kiyotani Kazuma, Mushiroda Taisei, Tsunoda Tatsuhiko, Morizono Takashi, Hosono Naoya, Kubo Michiaki, Tanigawara Yusuke, Imamura Chiyo K., Flockhart David A., Aki Fuminori, Hirata Koichi, Takatsuka Yuichi, Okazaki Minoru, Ohsumi Shozo, Yamakawa Takashi, Sasa Mitsunori, Nakamura Yusuke, Zembutsu Hitoshi

Human Molecular Genetics 21 （ 7 ） 1665 - 1672 2012年04月

ISSN 0964-6906

Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 singlenucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P 5 2.87 3 10^-9.9.4× 10^-8). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrencefree survival in the replication study (log-rank P 5 2.02 × 10^-4) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (logrank P 5 1.26 × 10-10). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P 5 6.29 × 10^-9]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P 5 2.28 × 10^-12). © The Author 2011. Published by Oxford University Press. All rights reserved.

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Optimal dose finding of garenoxacin based on population pharmacokinetics/pharmacodynamics and Monte Carlo simulation

Tanigawara Yusuke, Nozawa Kenji, Tsuda Hisatsugu

European Journal of Clinical Pharmacology 68 （ 1 ） 39 - 53 2012年01月

ISSN 0031-6970

Purpose: Garenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens. Methods: At the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once daily by the interim PK/PD analysis using phase I and phase II clinical data. The criteria used to determine an optimal dose were (1) the target attainment of the area under the unbound concentration-time curve divided by the minimum inhibitory concentration (fAUC _0-24/MIC ratio) and (2) the maintenance of a trough concentration above the mutant prevention concentration. In a confirmatory phase III study, garenoxacin was administered 400 mg once daily to 136 patients infected with mild or moderate chronic respiratory diseases. Results: Logistic regression analysis showed that fAUC _0-24/MIC ratio was a significant variable that predicted clinical response (p∈=∈0.0164). Of all subjects, 92.4% reached the target value of fAUC _0-24/MIC ratio∈>∈30 h, and the clinical efficacy rate of this population was 91.8%. On the other hand, there was no significant relationship between exposure values (AUC _0-24 and maximum concentration) and the incidence of adverse events by the Mann-Whitney test. Conclusions: The antimicrobial efficacy of the actual phase III study was consistent with the expectation from the Monte Carlo PD simulation. We were able to show that the optimal garenoxacin dosage regimens were successfully determined using prospective population PK/PD analysis and clinical trial simulations. © 2011 The Author(s).

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Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients

Kiyotani Kazuma, Mushiroda Taisei, Imamura Chiyo K., Tanigawara Yusuke, Hosono Naoya, Kubo Michiaki, Sasa Mitsunori, Nakamura Yusuke, Zembutsu Hitoshi

Breast Cancer Research and Treatment 131 （ 1 ） 137 - 145 2012年01月

ISSN 0167-6806

CYP2D6 is a key enzyme responsible for the metabolism of tamoxifen to active metabolites, endoxifen, and 4-hydroxytamoxifen. The breast cancer patients who are heterozygous and homozygous for decreased-function and null alleles of CYP2D6 showed lower plasma concentrations of endoxifen and 4-hydroxytamoxifen compared to patients with homozygous-wild-type allele, resulting in worse clinical outcome in tamoxifen therapy. We recruited 98 Japanese breast cancer patients, who had been taking 20 mg of tamoxifen daily as adjuvant setting. For the patients who have one or no normal allele of CYP2D6, dosages of tamoxifen were increased to 30 and 40 mg/day, respectively. The plasma concentrations of tamoxifen and its metabolites were measured at 8 weeks after dose-adjustment using liquid chromatography-tandem mass spectrometry. Association between tamoxifen dose and the incidence of adverse events during the tamoxifen treatment was investigated. In the patients with CYP2D6*1/*10 and CYP2D6*10/*10, the mean plasma endoxifen levels after dose increase were 1.4- and 1.7-fold higher, respectively, than those before the increase (P < 0.001). These plasma concentrations of endoxifen achieved similar level of those in the CYP2D6*1/*1 patients receiving 20 mg/day of tamoxifen. Plasma 4-hydroxytamoxifen concentrations in the patients with CYP2D6*1/*10 and CYP2D6*10/*10 were also significantly increased to the similar levels of the CYP2D6*1/*1 patients according to the increasing tamoxifen dosages (P < 0.001). The incidence of adverse events was not significantly different between before and after dose adjustment. This study provides the evidence that dose adjustment is useful for the patients carrying CYP2D6*10 allele to maintain the effective endoxifen level. © 2011 Springer Science+Business Media, LLC.

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