研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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S100A10 protein expression is associated with oxaliplatin sensitivity in human colorectal cancer cells

Suzuki Sayo, Yamayoshi Yasuko, Nishimuta Akito, Tanigawara Yusuke

Proteome Science 9 2011年12月

Background: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. The objective of our study was to find candidate protein markers for tumor sensitivity to L-OHP from intracellular proteins of human colorectal cancer (CRC) cell lines. We performed expression difference mapping (EDM) analysis of whole cell lysates from 11 human CRC cell lines with different sensitivities to L-OHP by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), and identified a candidate protein by liquid chromatography/mass spectrometry ion trap time-of-flight (LCMS-IT-TOF).Results: Of the qualified mass peaks obtained by EDM analysis, 41 proteins were differentially expressed in 11 human colorectal cancer cell lines. Among these proteins, the peak intensity of 11.1 kDa protein was strongly correlated with the L-OHP sensitivity (50% inhibitory concentrations) (P < 0.001, R ²= 0.80). We identified this protein as Protein S100-A10 (S100A10) by MS/MS ion search using LCMS-IT-TOF. We verified its differential expression and the correlation between S100A10 protein expression levels in drug-untreated CRC cells and their L-OHP sensitivities by Western blot analyses. In addition, S100A10 protein expression levels were not correlated with sensitivity to 5-fluorouracil, suggesting that S100A10 is more specific to L-OHP than to 5-fluorouracil in CRC cells. S100A10 was detected in cell culture supernatant, suggesting secretion out of cells.Conclusions: By proteomic approaches including SELDI technology, we have demonstrated that intracellular S100A10 protein expression levels in drug-untreated CRC cells differ according to cell lines and are significantly correlated with sensitivity of CRC cells to L-OHP exposure. Our findings provide a new clue to searching predictive markers of the response to L-OHP, suggesting that S100A10 is expected to be one of the candidate protein markers. © 2011 Suzuki et al; licensee BioMed Central Ltd.

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Optimal treatment schedule of meropenem for adult patients with febrile neutropenia based on pharmacokinetic-pharmacodynamic analysis

Ohata Yuka, Tomita Yoshiko, Nakayama Mitsunobu, Tamura Kazuo, Tanigawara Yusuke

Journal of Infection and Chemotherapy 17 （ 6 ） 831 - 841 2011年12月

ISSN 1341-321X

The objectives of this study were to develop a population pharmacokinetic (PK) model of meropenem, to simulate the percent time above minimum inhibitory concentration (%T > MIC) at various MICs, and to estimate effective dosage regimens by calculating the target attainment rates against various strains of bacteria. A total of 209 plasma samples (1-3 concentrations per patient) were obtained from 98 adult Japanese patients with febrile neutropenia in an open-labeled Phase 3 study. The final population PK model was fit to a two-compartment model with zero-order input. Creatinine clearance had a positive significant correlation with CL. Gender had a significant effect on Vc; however, this effect was small, and the PK profile in male patients was similar to that in female patients. The population PK parameters developed in this study are useful in simulating PK profiles of meropenem at various dosage regimens precisely for calculation of %T > MIC. The PK-PD analysis indicated that 0.5 g every 6 h (q6h) was more effective than 1 g q12h, although provided 2 g per day in total. A meropenem dosage regimen of 1 g q8h and/or longer infusion duration was better against a pathogen of comparatively low sensitivity, Pseudomonas aeruginosa (for MIC ≥2 μg/ml). Although causative bacteria were identified in a small number of patients, the target attainment rates at 75%T > MIC (89%) were comparable to microbiological response (89%). The present PK-PD analyses under various conditions are useful in the treatment of febrile neutropenia. © 2011 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

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A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures - A randomized, active comparator, double-blind study

Matsumoto Toshio, Ito Masako, Hayashi Yasufumi, Hirota Takako, Tanigawara Yusuke, Sone Teruki, Fukunaga Masao, Shiraki Masataka, Nakamura Toshitaka

Bone 49 （ 4 ） 605 - 612 2011年10月

ISSN 8756-3282

Background: Eldecalcitol is an analog of 1,25-dihydroxyvitamin D ₃ that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456. Methods and results: This 3year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75μg eldecalcitol versus 1.0μg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92years old were randomly assigned 1:1 to receive eldecalcitol (n=528) or alfacalcidol (n=526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (<50nmol/L) were Supplemented with 400IU/day vitamin D ₃. Primary end point was incident vertebral fractures. Secondary end points included any non-vertebral fractures and change in bone mineral density and bone turnover markers. Compared with the alfacalcidol group, the incidence of vertebral fractures was lower in eldecalcitol group after 36months of treatment (13.4 vs. 17.5%; hazard ratio, 0.74; predefined 90% confidence interval [CI], 0.56-0.97). Eldecalcitol reduced turnover markers and increased bone mineral density more strongly than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, which was due to a marked reduction in wrist fractures by a post-hoc analysis (1.1 vs. 3.6%; hazard ratio, 0.29; 95% CI, 0.11-0.77). Among the adverse events, the incidence of increase in serum and urinary calcium was higher in the eldecalcitol group, without any difference in glomerular filtration rate between the two groups. Conclusions: Eldecalcitol is more efficacious than alfacalcidol in preventing vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency, with a safety profile similar to alfacalcidol. © 2011 Elsevier Inc.

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Model-based analysis of covariate effects on population pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation and normal subjects

Tsuruta Kazuhisa, Yamada Yoshinobu, Serada Masashi, Tanigawara Yusuke

Journal of Clinical Pharmacology 51 （ 9 ） 1276 - 1285 2011年09月

ISSN 0091-2700

Thrombomodulin alfa is the recombinant extracellular domain of human thrombomodulin, which shows anticoagulation activity. To elucidate the pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation (DIC), population pharmacokinetic (PPK) analysis was performed using plasma concentration data obtained in phase 1 (20 patients, 348 time points) and phase 2 (116 patients, 305 time points) clinical trials. The actual and predicted plasma concentrations of thrombomodulin alfa based on the final PPK model showed a good linear correlation (R = 0.9504), and the pharmacokinetics of thrombomodulin alfa in DIC patients were affected by body weight, age, renal dysfunction, and hematocrit value. The distribution volume and clearance (CL) were proportional to body weight and were significantly increased in patients with lower hematocrit value (male <40%, female <35%). Furthermore, CL was decreased in patients with renal dysfunction and in elderly patients. Based on these results, the standard dose of thrombomodulin alfa is adjusted according to body weight. However, further dose adjustment is not needed based on age and hematocrit value, since these factors did not cause the large changes in plasma concentration that can affect the efficacy or safety. © 2011 The Author(s).

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Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure

Watanabe Mitsuhiro, Horai Yasushi, Houten Sander M., Morimoto Kohkichi, Sugizaki Taichi, Arita Eri, Mataki Chikage, Sato Hiroyuki, Tanigawara Yusuke, Schoonjans Kristina, Itoh Hiroshi, Auwerx Johan

Journal of Biological Chemistry 286 （ 30 ） 26913 - 26920 2011年07月

ISSN 0021-9258

We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

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Overview of the clinical pharmacokinetics of eldecalcitol, a new active vitamin D₃ derivative

Abe Masaichi, Tsuji Naoki, Takahashi Fumiaki, Tanigawara Yusuke

Japanese Pharmacology and Therapeutics 39 （ 3 ） 261 - 274 2011年03月

ISSN 0386-3603

Eldecalcitol, which was developed by Chugai Pharmaceutical Co., Ltd. as a treatment with the potential of becoming the drug of first choice for osteoporosis, is a new derivative of active vitamin D₃ (1,25(OH) ₂D₃) with a hydroxypropyloxy group introduced at the 2β position. The clinical development of this product has included a Phase I multiple dose study, early and late Phase II studies, a Phase III study, a clinical pharmacology study to investigate pharmacokinetics in postmenopausal women, a drug interaction study, a bioequivalence formulation study and a clinical pharmacology study to investigate pharmacokinetics in patients with impaired liver function. Using data from all these studies, we sought to characterize the pharmacokinetic profile of eldecalcitol.

Pharmacokinetics of eldecalcitol in primary osteoporosis patients - Randomized, double-blind, multicentre, long-term phase III clinical study

Miyata Kumiko, Abe Masaichi, Terao Kimio, Kawanishi Takehiko, Tsuji Naoki, Shiraki Masataka, Nakamura Toshitaka, Matsumoto Toshio, Tanigawara Yusuke

Japanese Pharmacology and Therapeutics 39 （ 3 ） 299 - 307 2011年03月

ISSN 0386-3603

Background: Eldecalcitol, which was developed by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan) as a treatment for osteoporosis, is a new derivative of active vitamin D₃(1,25 (OH)₂D₃) with a hydroxypropyloxy group introduced at the 2β position. A Phase III, alfacalcidol-controlled clinical study of eldecalcitol was conducted in primary osteoporosis patients, with the incidence of new, non-traumatic vertebral fractures designated as the primary endpoint. Objectives: The objective of this study was to characterize the pharmacokinetic profile of eldecalcitol, using data obtained from this Phase III clinical study in primary osteoporosis patients. Methods: Patients were randomly assigned to an oral eldecalcitol or alfacalcidol group. Patients in the eldecalcitol group took one capsule each of eldecalcitol 0.75 μg and alfacalcidol placebo, while those in the alfacalcidol group took one capsule each of eldecalcitol placebo and alfacalcidol 1.0 μg, once daily for 144 weeks. Efficacy and safety in patients on eldecalcitol were compared with those in patients on alfacalcidol. For the pharmacokinetic analysis, the serum eldecalcitol concentration was measured at 48, 72, 96 and 144 weeks. Results: In the eldecalcitol group, the mean trough serum eldecalcitol concentrations obtained from patients without dose reduction at the time of blood collection were 286.9, 320.1, 387.3 and 344.0 pg/mL at 48, 72, 96 and 144 weeks, respectively. At all times, the trough serum eldecalcitol concentration remained within the range of values at 72 weeks. It was concluded from these results that the serum eldecalcitol concentration had reached steady state by 48 weeks. Calculation of the trough serum eldecalcitol concentration by baseline characteristic showed that the concentration was in a similar range in all categories of age, renal function and vitamin D supplementation. Conclusions: The trough serum eldecalcitol concentration in patients receiving eldecalcitol 0.75 μg did not change substantially from 48 to 144 weeks after starting treatment, suggesting that the pharmacokinetics of eldecalcitol do not vary with long-term treatment. Analysis using trough serum eldecalcitol concentrations revealed that age, renal function and vitamin D supplementation had no substantial effect on pharmacokinetics.

Levofloxacin 注射剤の母集団薬物動態／薬力学解析

谷川原祐介，清水貴子，戸塚恭一

日本化学療法学会雑誌 59 （ S-1 ） 55-63 2011年

研究論文（学術雑誌）, 共著, 査読有り

Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/pharmacodynamic considerations

Ohata Yuka, Tomita Yoshiko, Nakayama Mitsunobu, Kozuki Tsuneo, Sunakawa Keisuke, Tanigawara Yusuke

Drug Metabolism and Pharmacokinetics 26 （ 5 ） 523 - 531 2011年

ISSN 1347-4367

A population pharmacokinetic (PK) model for meropenem in Japanese pediatric patients with various infectious diseases was developed based on 116 plasma concentrations from 50 pediatric patients. The population PK parameters developed in this analysis are useful for calculation of the percent time above minimum inhibitory concentration (%T>MIC) and for optimal dosing of meropenem in pediatric patients. After dosing at 20mg/kg t.i.d. by 0.5-h infusion (approved standard dose for pediatric patients in Japan), the target value of 50%T>MIC was achieved, indicating that 20mg/kg t.i.d. by 0.5-h infusion is effective for susceptible bacteria. In contrast, for bacteria with higher MICs such as Pseudomonas aeruginosa (MIC ≥ 2 μg/mL), the probability of target attainment of 50%T>MIC was 60.7% at a dose of 40mg/kg t.i.d. by 0.5-h infusion (highest dose approved for pediatric patients in Japan). The simulations described in this article indicated that 40 mg/kg t.i.d. with a longer infusion duration (e.g., 4 h) is more effective against bacteria with a MIC higher than 2 μg/mL. The predicted probability of target attainment for 50%T>MIC (97.0%) was well correlated not only to the microbiological efficacy rate (97.0%) but also to the clinical efficacy rate (95.9%) in the present phase 3 study. © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

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

Journal of Clinical Oncology 28 （ 8 ） 1287 - 1293 2010年03月

ISSN 0732-183X

Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen. © 2010 by American Society of Clinical Oncology.

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Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer

Hirose Takashi, Fujita Ken Ichi, Nishimura Kazuko, Ishida Hiroo, Yamashita Keishi, Sunakawa Yu, Mizuno Keiko, Miwa Keisuke, Nagashima Fumio, Tanigawara Yusuke, Adachi Mitsuru, Sasaki Yasutsuna

Oncology Reports 24 （ 2 ） 529 - 536 2010年

ISSN 1021-335X

We developed a population pharmacokinetic (PPK) model of S-1 including the cytochrome P450 (CYP) 2A6 genotype and then used this PPK model to assess the influence of the CYP2A6 genotype on PK parameters of S-1 and the relationship between toxicity and the individual maximum concentrations (Cmax) or the area under the concentrationtime curve (AUC) of 5-fluorouracil (5-FU) in Japanese patients with advanced cancer. Fifty-eight patients with advanced cancer were assessed. A dose of 80 mg/m²/day of S-1 was given orally. On the basis of the CYP2A6 genotypes (*1, *4, *7 and *9), all patients were classified as having the wildtype, 1 variant allele or 2 variant alleles. The PPK model was established with plasma concentration data for tegafur (FT), 5-chloro-2,4-performed dihydroxypyridine (CDHP) and 5-FU. In patients with 2 variant alleles of CYP2A6, the clearance of FT was 58% less than in patients with the wildtype or 1 variant allele. The AUC of 5-FU correlated with the AUC of CDHP, but not with the AUC of FT. Therefore, the CYP2A6 genotype did not affect the AUC of 5-FU. The individual AUC or Cmax of 5-FU did not differ significantly between patients with grade 3 or 4 toxicities and patients with grade 0-2 toxicities. In conclusion, the CYP2A6 genotype did not affect the AUC of 5-FU, although the clearance of FT was lower in patients with 2 variant alleles of CYP2A6 than in patients with the wild-type or 1 variant allele.

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抗MRSA薬のTDMに関する全国アンケート調査

小林昌宏，竹末芳生，谷川原祐介，三鴨廣繁，木村利美，平田純生，白石　正，栄田敏之，高倉俊二

日本化学療法学会雑誌 58 （ 2 ） 119-124 2010年

研究論文（学術雑誌）, 共著, 査読有り

母集団薬物動態解析による硫酸アルベカシンの成人患者における1日1回投与法の有用性検討

佐藤信雄，三浦有紀，三富奈由，林　宏行，鈴木　尚，芝崎茂樹，黒沢　亨，谷川原祐介

ＴＤＭ研究 27 （ 2 ） 98-110 2010年

研究論文（学術雑誌）, 単著, 査読有り

硫酸アルベカシンの血中濃度モニタリング施行患者に対する特定使用成績調査

河野　仁，谷川原祐介

ＴＤＭ研究 27 （ 2 ） 55-71 2010年

研究論文（学術雑誌）, 単著, 査読有り

小児及び成人の通年性アレルギー性鼻炎患者に対するロラタジン投与試験　有効性及び安全性に関する報告

鈴木五男, 谷川原祐介

アレルギー・免疫 16 （ 12 ） 1966 - 1978 2009年11月

共著

Carboplatinの血中濃度モニタリングに基づいた血液透析スケジュール設定が有用であった慢性腎不全合併肺癌患者の１例

鎌田　浩史，浅野　浩一郎，副島　研造，白畑　亨，中谷　理恵，稲本　元，池谷　修，山吉　康子，谷川原　祐介，石坂　彰敏，

Japanese Journal of Cancer and Chemotherapy 36 （ 9 ） 1529 - 1532 2009年09月

ISSN 0385-0684

A 69-year-old woman undergoing hemodialysis due to ANCA-associated nephritis and chronic renal failure developed lung adenocarcinoma and underwent radical surgery. Upon recurrence of her cancer, she received combination chemotherapy with carboplatin (CBDCA) 150 mg/m² and docetaxel 35-70 mg/m². Concentration of free CBDCA in serum was monitored for 6 days after drug administration. Hemodialysis was performed 1 hour after administration of CBDCA, and on day 4. Despite the lower maximum concentration, serum CBDCA levels 20-24 h after chemotherapy in this patient were 15 to 20 times higher than in subjects with normal renal function who received CBDCA at the area under the curve (AUC) of 5. She experienced moderate to severe nausea and vomiting which persisted for 12 days. During her second course of chemotherapy, hemodialysis was performed for 3 consecutive days after drug administration. The serum CBDCA levels on day 2 or later remained lower than in the first course, and the patient experienced fewer severe side effects. Based on the data from therapeutic drug monitoring of CBDCA, hemodialysis for 3 consecutive days after drug administration has been demonstrated to be useful for treatment of a patient with chronic renal failure receiving chemotherapy with CBDCA.

Impact of pharmacokinetics and pharmacogenetics on the efficacy of pranlukast in Japanese asthmatics

Asano Koichiro, Nakade Susumu, Shiomi Tetsuya, Nakajima Takeshi, Suzuki Yusuke, Fukunaga Koichi, Oguma Tsuyoshi, Sayama Koichi, Fujita Hirofumi, Tanigawara Yusuke, Ishizaka Akitoshi

Respirology 14 （ 6 ） 822 - 827 2009年08月

ISSN 1323-7799

Background and objective: Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC₄ synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC₄ synthase gene polymorphisms, were also investigated. Methods: The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV₁ after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed. Results: Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC ₄ synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05). Conclusions: There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug. © 2009 The Authors.

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A phase I escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors.

K. Shirao, T. Yoshino, N. Boku, K. Kato, T. Hamaguchi, H. Yasui, N. Yamamoto, Y. Tanigawara, A. Nolting, S. Yoshino

Cancer Chemotherap. Pharmacol 64 （ 3 ） 557-564 2009年

研究論文（学術雑誌）, 共著, 査読有り

Levofloxacin 500mg 経口投与時の母集団薬物動態／薬力学解析

谷川原祐介,清水貴子,戸塚恭一

日本化学療法学会雑誌 57 （ S-2 ） 47-54 2009年

研究論文（学術雑誌）, 共著, 査読有り

A pharmacokinetic and dose escalation study of pegfilgrastim (KRN125) in lung cancer patients with chemotherapy-induced neutropenia

Yamamoto Nobuyuki, Sekine Ikuo, Nakagawa Kazuhiko, Takada Minoru, Fukuoka Masahiro, Tanigawara Yusuke, Saijo Nagahiro

Japanese Journal of Clinical Oncology 39 （ 7 ） 425 - 430 2009年

ISSN 0368-2811

Objective: The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Methods: Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts <0.5 × 10⁹ cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 μg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Results: Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration - time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. Conclusions: A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia. © The Author (2009). Published by Oxford University Press. All rights reserved.

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