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糸原 光太郎
医学部附属病院 薬剤部
助教

研究者基本情報

■ 学位
  • 学士, 京都大学
■ 研究分野
  • ライフサイエンス / 医療薬学

研究活動情報

■ 受賞
  • 2023年11月 一般社団法人日本医療薬学会, 2023年度 Postdoctoral Award

■ 論文
  • Kotaro Itohara, Kazuhiro Yamamoto, Shunsuke Fujinaka, Mari Hashimoto, Naoki Tamura, Yumi Kitahiro, Tomohiro Omura, Kazumichi Fujioka, Ikuko Yano
    BACKGROUND: Valganciclovir (VGCV) is administered at a dose of 16 mg/kg 2 times daily for 6 months to treat symptomatic congenital cytomegalovirus (CMV) infections. During the treatment period, approximately 20% of the patients developed grade 3 or higher neutropenia. Currently, information on the pharmacokinetics and pharmacodynamics of ganciclovir, an active metabolite of VGCV, in infants is limited. In the current study, the relationship between ganciclovir concentration and neutropenia was investigated, and a population pharmacokinetic (PPK) model of ganciclovir in infants with symptomatic congenital CMV infection was developed. METHODS: Japanese infants who were prescribed oral VGCV for symptomatic congenital CMV infections between July 2017 and January 2021 were included. The relationship between the observed trough ganciclovir concentrations and neutrophil counts was examined. PPK analysis was performed to evaluate the covariates affecting the pharmacokinetics of ganciclovir. RESULTS: Twenty-seven ganciclovir serum samples from 8 patients were analyzed. A moderate negative correlation was observed between the observed trough ganciclovir concentration and neutrophil count. PPK model analysis showed that postmenstrual age (PMA) affected the total body clearance of ganciclovir after correcting for the empirical allometric scaling of body weight. Based on PMA and body weight, a nomogram to achieve the target area under the concentration-time curve from 0 to 24 hours of 40-60 mcg·h·mL -1 of ganciclovir was calculated. CONCLUSIONS: The relationship between neutrophil count and ganciclovir trough concentration in infants was clarified. The PPK model showed that the dose of VGCV should be reduced in patients with a low PMA to achieve target exposure.
    2025年06月, Therapeutic drug monitoring, 47(3) (3), 393 - 399, 英語, 国際誌
    研究論文（学術雑誌）

  • Yumi Kitahiro, Mari Hashimoto, Yukako Sonda, Miki Yagi, Kotaro Itohara, Takumi Kido, Kazumichi Fujioka, Hitomi Imafuku, Tomohiro Omura, Ikuko Yano
    BACKGROUND: Torasemide, a loop diuretic, is rarely used for pregnant women because of the risk of reduced placental blood flow resulting from decreased circulating plasma volume. We experienced a case of a newborn with metabolic alkalosis and mild polyuria. The mother was suspected of self-medicating as we detected torasemide in the neonatal serum by LC-MS/MS method. CASE PRESENTATION: A Japanese pregnant woman in her 20s with mental illness, symptoms of panic and eating disorders, and a history of overdosing on over-the-counter medications, was referred to our hospital for birth control. She presented with vomiting following bulimia nervosa and hypokalemia. Her baby was delivered vaginally at 36 weeks and 4 days of gestation. The baby's blood gas analysis on day 0 revealed metabolic alkalosis (pH > 7.42, HCO3- > 28 mmHg). Up to 16 h after birth, mild polyuria and a urine output of 3.3 mL/kg/h were observed without the administration of diuretics. We suspected diuretic intake by the mother before delivery, because she had a history of taking torasemide before being referred to the hospital. As expected, torasemide was detected in the baby's serum. The serum concentration on the first day after delivery (4.80 ng/mL) gradually decreased to 0.45 ng/mL on day 5, whereas torasemide was not detected in the maternal serum. Neonatal metabolic alkalosis improved by day 3 following birth. CONCLUSIONS: This case suggests close counseling and monitoring of pregnant women before childbirth regarding their past and present use of drugs, particularly in those with mental illness.
    2025年04月, Journal of pharmaceutical health care and sciences, 11(1) (1), 31 - 31, 英語, 国際誌
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Naoki Tamura, Kotaro Itohara, Yo Ueda, Yumi Kitahiro, Kazuhiro Yamamoto, Tomohiro Omura, Toshiyasu Sakane, Jun Saegusa, Ikuko Yano
    BACKGROUND: Valganciclovir (VGCV) is the first-line drug for preemptive therapy of cytomegalovirus (CMV) infections. However, even when administered at the dose specified in the package insert, there is significant interindividual variability in the plasma concentrations of ganciclovir (GCV). In addition, correlations have been reported between the area under the concentration-time curve and therapeutic efficacy or adverse events. Therefore, therapeutic drug monitoring (TDM) can be used to improve the efficacy and safety of preemptive VGCV therapy. OBJECTIVE: This study aims to evaluate whether the dosage adjustment of VGCV based on TDM in patients undergoing preemptive therapy for CMV infections is associated with the successful completion rate of treatment without severe hematological adverse effects. METHODS: This phase II, single-center, single-arm trial aims to enroll 40 patients admitted at the Department of Rheumatology and Clinical Immunology, Kobe University Hospital, who will receive oral VGCV as preemptive therapy for CMV infections. Participants will begin treatment with VGCV at the dose recommended in the package insert, with subsequent dose adjustments based on weekly TDM results. The primary end point will be the proportion of patients who achieve CMV antigenemia negativity within 3 weeks without severe hematological adverse events. The secondary end points will include weekly changes in CMV antigen levels, total VGCV dose, and duration of preemptive therapy. For safety evaluation, the occurrence, type, and severity of VGCV-related adverse events will be analyzed. Additionally, this study will explore the correlations between the efficacy and safety of preemptive therapy and the pharmacokinetic parameters of GCV, CMV-polymerase chain reaction values, and nudix hydrolase 15 (NUDT15) genetic polymorphisms. The correlation between GCV plasma concentrations obtained from regular venous blood and blood concentrations will be examined using dried blood spots. RESULTS: This study began with patient recruitment in September 2024, with 5 participants enrolled as of June 16, 2025. The target enrollment is 40 participants, and the anticipated study completion is set for July 2027. CONCLUSIONS: This is the first study to investigate the impact of TDM intervention in patients receiving VGCV as preemptive therapy. The findings are postulated to provide valuable evidence regarding the utility of TDM in patients receiving VGCV as preemptive therapy. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051240080; https://jrct.mhlw.go.jp/latest-detail/jRCTs051240080. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/72549.
    2025年02月, JMIR Research Protocols, 14, e72549, 英語, 国際誌
    研究論文（学術雑誌）

  • Tomoko Kurimura, Tomohiro Omura, Kazuhiro Yamamoto, Hidekazu Tanaka, Takeshi Kimura, Kotaro Itohara, Yumi Kitahiro, Yasushi Habu, Toshiyasu Sakane, Ikuko Yano
    A woman in her 70s who was taking warfarin 3.75 mg/day had a prothrombin time-international normalized ratio (PT-INR) within the therapeutic range. Her medication for pulmonary hypertension was changed from bosentan to macitentan. After 40 days, she developed respiratory distress, anorexia, and vomiting caused by common cold. When she visited the pharmaceutical outpatient clinic without reservation, the pharmacist suspected that bosentan discontinuation, which cancelled cytochrome P450 (CYP) 2C9 and CYP3A4 enzyme induction, and decreased vitamin K intake due to appetite loss had enhanced warfarin effect, causing PT-INR prolongation. The pharmacist requested the physician to examine the patient's PT-INR. Results showed that her PT-INR was >7. Hence, she was urgently hospitalized. Warfarin and macitentan were discontinued, and the patient's PT-INR decreased to 1.77 after the intravenous administration of vitamin K. Her appetite improved, and warfarin 2 mg/day was resumed. Additionally, when she had been administered macitentan, her hemoglobin levels decreased from 10.8 to 6.6 mg/dL. Therefore, the pharmacist and the physician during hospitalization planned to resume treatment with bosentan, but not with macitentan. The pharmacist proposed to increase the warfarin dose to 3.75 mg since the bosentan and warfarin interaction could lower PT-INR. Thereafter, the patient's PT-INR was controlled within the therapeutic range, and her hemoglobin level was 8-9 mg/dL. The patient was discharged on day 17 of admission. Thus, pharmacist intervention plays a significant role in warfarin control with consideration of drug-drug interaction in patients receiving pulmonary hypertension treatment.
    2025年02月, The Kobe journal of medical sciences, 70(4) (4), E125-E129, 英語, 国内誌
    研究論文（学術雑誌）

  • Kotaro Itohara, Kazuhiro Yamamoto, Shunsuke Fujinaka, Mari Hashimoto, Naoki Tamura, Yumi Kitahiro, Tomohiro Omura, Kazumichi Fujioka, Ikuko Yano
    BACKGROUND: Valganciclovir (VGCV) is administered at a dose of 16 mg/kg 2 times daily for 6 months to treat symptomatic congenital cytomegalovirus (CMV) infections. During the treatment period, approximately 20% of the patients developed grade 3 or higher neutropenia. Currently, information on the pharmacokinetics and pharmacodynamics of ganciclovir, an active metabolite of VGCV, in infants is limited. In the current study, the relationship between ganciclovir concentration and neutropenia was investigated, and a population pharmacokinetic (PPK) model of ganciclovir in infants with symptomatic congenital CMV infection was developed. METHODS: Japanese infants who were prescribed oral VGCV for symptomatic congenital CMV infections between July 2017 and January 2021 were included. The relationship between the observed trough ganciclovir concentrations and neutrophil counts was examined. PPK analysis was performed to evaluate the covariates affecting the pharmacokinetics of ganciclovir. RESULTS: Twenty-seven ganciclovir serum samples from 8 patients were analyzed. A moderate negative correlation was observed between the observed trough ganciclovir concentration and neutrophil count. PPK model analysis showed that postmenstrual age (PMA) affected the total body clearance of ganciclovir after correcting for the empirical allometric scaling of body weight. Based on PMA and body weight, a nomogram to achieve the target area under the concentration-time curve from 0 to 24 hours of 40-60 mcg·h·mL-1 of ganciclovir was calculated. CONCLUSIONS: The relationship between neutrophil count and ganciclovir trough concentration in infants was clarified. The PPK model showed that the dose of VGCV should be reduced in patients with a low PMA to achieve target exposure.
    2024年09月, Therapeutic drug monitoring, 英語, 国際誌
    研究論文（学術雑誌）

  • Ren Takahashi, Kotaro Itohara, Shunsaku Nakagawa, Yoshiki Katada, Mitsuhiro Sugimoto, Keisuke Umemura, Katsuyuki Matsumura, Daiki Hira, Masahiro Tsuda, Yurie Katsube, Satona Tanaka, Akihiro Ohsumi, Daisuke Nakajima, Miki Nagao, Hiroshi Date, Tomohiro Terada
    BACKGROUND: Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients. METHODS: This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed. RESULTS: A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug-drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation. CONCLUSIONS: This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.
    2024年08月, Therapeutic drug monitoring, 英語, 国際誌
    研究論文（学術雑誌）

  • Calvert式に用いる腎機能指標とカルボプラチンによる血液毒性発現の関連
    小林 理乃, 山本 和宏, 丹田 雅明, 糸原 光太郎, 北廣 優実, 大村 友博, 矢野 育子
    (一社)日本TDM学会, 2024年07月, TDM研究, 41(2) (2), 158 - 158, 日本語

  • Takashi Ogihara, Masato Kagawa, Rintarou Yamanaka, Satoshi Imai, Kotaro Itohara, Daiki Hira, Shunsaku Nakagawa, Atsushi Yonezawa, Michiho Ito, Takayuki Nakagawa, Tomohiro Terada, Kazuo Matsubara
    2024年06月, Journal of natural medicines, 78(3) (3), 803 - 803, 英語, 国内誌

  • Tomoyuki Sakaue, Kazuhiro Yamamoto, Kotaro Itohara, Yumi Kitahiro, Takahito Endo, Naoki Yokoyama, Takeshi Ishimura, Tomohiro Omura, Ikuko Yano
    2024年06月, Drug Metabolism and Pharmacokinetics
    研究論文（学術雑誌）

  • Mitsuhiro Sugimoto, Atsushi Yonezawa, Junya Kanda, Kotaro Itohara, Daiki Hira, Takeo Yamagiwa, Risa Taniguchi, Yuta Hanyu, Mizuki Watanabe, Yasuyuki Arai, Chisaki Mizumoto, Toshio Kitawaki, Tadakazu Kondo, Kouhei Yamashita, Akifumi Takaori-Kondo, Tomohiro Terada
    BACKGROUND: Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases. METHODS: The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output. RESULTS: In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea. CONCLUSIONS: PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.
    2024年04月, Therapeutic drug monitoring, 英語, 国際誌
    研究論文（学術雑誌）

  • Toru Konishi, Yumi Kitahiro, Naoko Fujiwara, Kazuhiro Yamamoto, Mari Hashimoto, Takahiro Ito, Kotaro Itohara, Kazumichi Fujioka, Hitomi Imafuku, Ikuo Otsuka, Tomohiro Omura, Ikuko Yano
    BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.
    2024年04月, Therapeutic drug monitoring, 英語, 国際誌
    研究論文（学術雑誌）

  • 川田将義, 米澤淳, 峰晴陽平, 峰晴陽平, 糸原光太郎, 溝田敏幸, 菊池隆幸, 山尾幸広, 山本悦子, 古川恵子, 寺田智祐, 荒川芳輝
    Propofol's pharmacokinetics have been extensively studied using human blood samples and applied to target-controlled infusion systems; however, information on its concentration in the brain remains scarce. Therefore, this study aimed to simultaneously measure propofol plasma and brain concentrations in patients who underwent awake craniotomy and establish new pharmacokinetic model. Fifty-seven patients with brain tumors or brain lesions who underwent awake craniotomy were sequentially assigned to model-building and validating groups. Plasma and brain (lobectomy or uncapping margins) samples were collected at five time-points. The concentration of propofol was measured using high-performance liquid chromatography. Population pharmacokinetic analysis was conducted through a nonlinear mixed-effects modeling program using a first-order conditional estimation method with interactions. Propofol's brain concentrations were higher than its plasma concentrations. The measured brain concentrations were higher than the effect site concentrations using the previous models. Extended models were constructed based on measured concentrations by incorporating the brain/plasma partition coefficient (Kp value). Extended models showed good predictive accuracy for brain concentrations in the validating group. The Kp value functioned as a factor explaining retention in the brain. Our new pharmacokinetic models and Kp value can predict propofol's brain and plasma concentrations, contributing to safer and more stable anesthesia.
    2024年03月, 日本Awake Surgery学会プログラム・抄録集, 14(1) (1), 6326 - 6326, 英語, 国際誌

  • Yasumasa Kakei, Ichiro Morioka, Takumi Imai, Kotaro Itohara, Ikuko Yano, Naoto Takahashi, Tetsushi Yoshikawa, Hiroyuki Moriuchi, Yoshinori Ito, Kazumichi Fujioka, Akira Oka
    INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.
    2024年03月, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 英語, 国際誌
    研究論文（学術雑誌）

  • Yumi Kitahiro, Kazuhiro Yamamoto, Kimikazu Yakushijin, Takeshi Ioroi, Masaaki Tanda, Kotaro Itohara, Tomohiro Omura, Hironobu Minami, Ikuko Yano
    2024年02月, JMIR Research Protocols
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Takeshi Tomida, Kotaro Itohara, Kazuhiro Yamamoto, Takeshi Kimura, Kohei Fujita, Atsushi Uda, Yumi Kitahiro, Naoki Yokoyama, Yoji Hyodo, Tomohiro Omura, Ikuko Yano
    2023年12月, Drug Metabolism and Pharmacokinetics
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Yoshiki Katada, Shunsaku Nakagawa, Miki Nagao, Keisuke Umemura, Kotaro Itohara, Asami Nishikawa, Sachiyo Hashi, Yurie Katsube, Daiki Hira, Akihiro Ohsumi, Daisuke Nakajima, Hiroshi Date, Tomohiro Terada
    2023年12月, Transplant Infectious Disease
    研究論文（学術雑誌）

  • Yumi Kitahiro, Kazuhiro Yamamoto, Kimikazu Yakushijin, Takeshi Ioroi, Masaaki Tanda, Kotaro Itohara, Tomohiro Omura, Hironobu Minami, Ikuko Yano
    2023年11月

  • Asami Nishikawa, Isao Ito, Atsushi Yonezawa, Kotaro Itohara, Takeshi Matsubara, Yuki Sato, Katsuyuki Matsumura, Satoshi Hamada, Naoya Tanabe, Shinichi Kai, Eishi Imoto, Kohei Yoshikawa, Shigeru Ohtsuru, Motoko Yanagita, Toyohiro Hirai, Tomohiro Terada
    Remdesivir plays a key role in the treatment of coronavirus disease in 2019 (COVID-19). Haemodialysis is sometimes required for hospitalised patients with COVID-19, and patients undergoing haemodialysis are at an increased risk of severe COVID-19. In the present study, we report the serum concentrations of GS-441524, the active metabolite of remdesivir, in four patients undergoing continuous renal replacement therapy (CRRT). Patient 1, a male aged 70s, received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg remdesivir from day 2, according to the package insert as in non-haemodialysis patients. The mean trough serum concentration of GS-441524 was 783.5 ng/mL, which was approximately 7-fold higher than the mean for patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min. Patients 2-4 received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg once every 2 days from day 2. The mean trough serum concentrations of GS-441524 were 302.2 ng/mL, 585.8 ng/mL and 677.3 ng/mL, respectively. These were 3 to 6-fold higher than the mean for patients with eGFR ≥60 mL/min. The target doses for patients 1, 2, 3, and 4 receiving CRRT were 13.6 mL/kg/h, 6.0-12.5 mL/kg/h, 20.1 mL/kg/h, and 15.1 mL/kg/h, respectively, using a polysulphone membrane. The package insert dose of remdesivir is an overdose for CRRT patients with a target dose of 10-20 mL/kg/h. In low-intensity CRRT, as in Japan, it may be necessary to extend the interval between the doses of remdesivir.
    2023年10月, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 英語, 国際誌

  • Tomoko Kurimura, Kazuhiro Yamamoto, Hidekazu Tanaka, Takayoshi Toba, Takeshi Kimura, Yasushi Habu, Kotaro Itohara, Yumi Kitahiro, Tomohiro Omura, Ikuko Yano
    BACKGROUND: Optimised antithrombotic therapy requires clinical experience and an understanding of the current guidelines. This retrospective study aimed to evaluate whether pharmacist interviews and interventions with patients taking oral antithrombotic drugs in the pharmaceutical outpatient cardiology clinic had favourable clinical outcomes including decreased bleeding. METHODS: The participants included patients visiting the outpatient clinic of cardiovascular internal medicine at the Kobe University Hospital from January-December 2017, and were taking oral antithrombotic medication. The observation period was from the first visit to the outpatient clinic to October 2021 or death. Patients who received pharmacist intervention more than twice were defined as the pharmacist intervention group. Two control patients per one pharmacist intervention group individual were selected from the non-intervention pool matched for age, gender and antithrombotic medication type. RESULTS: Of the 895 eligible patients, 132 were in the pharmacist intervention group and 264 were selected for the matched non-intervention group. Bleeding events according to the Bleeding Academic Research Consortium criteria over type 2 were significantly lower in the pharmacist intervention group compared with the non-intervention group (17.4% versus 28.4%, P = 0.019). There were no significant differences in mortality and heart failure hospitalisation frequency, stroke, or cardiovascular events between the groups. Multivariate analysis identified age (≥ 65 years) and pharmacist intervention as factors associated with bleeding (odds ratio = 2.29 and 0.51, respectively). CONCLUSION: Pharmacist intervention in the outpatient clinic of cardiovascular internal medicine was effective in reducing the risk of bleeding in patients undergoing antithrombotic therapy.
    2023年09月, Journal of pharmaceutical health care and sciences, 9(1) (1), 28 - 28, 英語, 国際誌
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Sho Masui, Atsushi Yonezawa, Miyuki Nakamura, Akira Onishi, Motomu Hashimoto, Hideo Onizawa, Takayuki Fujii, Kosaku Murakami, Koichi Murata, Masao Tanaka, Kotoko Yokoyama, Noriko Iwamoto, Takashi Shimada, Kotaro Itohara, Daiki Hira, Shunsaku Nakagawa, Satoshi Imai, Takayuki Nakagawa, Makoto Hayakari, Shuichi Matsuda, Akio Morinobu, Tomohiro Terada, Kazuo Matsubara
    Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p = 0.017) and the most frequent disease worsening (90.0%, p < 0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.
    2023年, Biological & pharmaceutical bulletin, 46(8) (8), 1112 - 1119, 英語, 国内誌
    研究論文（学術雑誌）

  • Shunsaku Nakagawa, Aimi Shimazaki, Taro Funakoshi, Atsushi Yonezawa, Shigeki Kataoka, Takahiro Horimatsu, Daiki Hira, Kotaro Itohara, Satoshi Imai, Takayuki Nakagawa, Takeshi Matsubara, Motoko Yanagita, Manabu Muto, Kazuo Matsubara, Tomohiro Terada
    Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, the increased systemic fPt levels do not increase oxaliplatin-induced toxicities. We hypothesized that renal dysfunction has minimal effect on the elimination rate of reactive fPt, and that the DNA-binding capacity is one of the properties of reactive Pt species. This study aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics. The pharmacokinetics of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The platinum concentrations were determined using inductively coupled plasma-mass spectrometry. The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA. Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after drug administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 35.9 and 7.3% at 2 and 14 d after treatment, respectively. The plasma level of DNA-reactive fPt also decreased to 1.9 and 0.6%, respectively, on these days. This study showed that severe renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.
    2023年, Biological & pharmaceutical bulletin, 46(2) (2), 194 - 200, 英語, 国内誌
    研究論文（学術雑誌）

  • 成人肝移植患者におけるエベロリムスの母集団薬物動態解析と小児肝移植患者への外挿
    糸原 光太郎, 矢野 育子, 中川 俊作, 杉本 充弘, 平井 真智子, 米澤 淳, 平 大樹, 伊藤 孝司, 秦 浩一郎, 波多野 悦朗, 寺田 智祐, 松原 和夫
    (一社)日本臨床薬理学会, 2022年12月, 日本臨床薬理学会学術総会抄録集, 43回, 1 - 5, 日本語

  • Keiko Ikuta, Shunsaku Nakagawa, Chinami Yamawaki, Kotaro Itohara, Daiki Hira, Satoshi Imai, Atsushi Yonezawa, Takayuki Nakagawa, Minoru Sakuragi, Noriaki Sato, Eiichiro Uchino, Motoko Yanagita, Tomohiro Terada
    BACKGROUND: Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal disorders such as peptic ulcer disease and dyspepsia. However, several studies have suggested that PPI use increases the risk of acute kidney injury (AKI). PPIs are often concomitantly used with antibiotics, such as macrolides and penicillins for Helicobacter pylori eradication. Although macrolide antibiotics are considered to have relatively low nephrotoxicity, they are well known to increase the risk of AKI due to drug-drug interactions. In this study, we aimed to investigate the association between PPI use and the development of AKI. We also evaluated the effect of concomitant use of PPIs and macrolide antibiotics on the risk of AKI. METHODS: This self-controlled case series study was conducted using electronic medical records at Kyoto University Hospital. We identified patients who were prescribed at least one PPI and macrolide antibiotic between January 2014 and December 2019 and underwent blood examinations at least once a year. An adjusted incident rate ratio (aIRR) of AKI with PPI use or concomitant use macrolide antibiotics with PPIs was estimated using a conditional Poisson regression model controlled for the estimated glomerular filtration rate at the beginning of observation and use of potentially nephrotoxic antibiotics. RESULTS: Of the 3,685 individuals who received PPIs and macrolide antibiotics, 766 patients with episodes of stage 1 or higher AKI were identified. Any stage of AKI was associated with PPI use (aIRR, 1.80 (95% confidence interval (CI) 1.60 to 2.04)). Stage 2 or higher AKI was observed in 279 cases, with an estimated aIRR of 2.01 (95% CI 1.57 to 2.58, for PPI use). For the period of concomitant use of macrolide antibiotics with PPIs compared with the period of PPIs alone, an aIRR of stage 1 or higher AKI was estimated as 0.82 (95% CI 0.60 to 1.13). CONCLUSIONS: Our findings added epidemiological information for the association between PPI use and an increased risk of stage 1 or higher AKI. However, we did not detect an association between the concomitant use of macrolide antibiotics and an increased risk of AKI in PPI users.
    2022年11月, BMC nephrology, 23(1) (1), 383 - 383, 英語, 国際誌
    研究論文（学術雑誌）

  • Yoshiki Katada, Shunsaku Nakagawa, Kotaro Itohara, Takuya Suzuki, Ryota Kato, Hiroki Endo, Mitsuhiro Sugimoto, Atsushi Yonezawa, Takayuki Nakagawa, Akihiro Ohsumi, Daisuke Nakajima, Hiroshi Date, Tomohiro Terada
    BACKGROUND: Tacrolimus is a key drug in immunosuppressive therapy following lung transplantation. The blood tacrolimus levels are likely to fluctuate in the early postoperative period, and failure to maintain the tacrolimus trough level in target ranges is a risk factor for rejection. However, there is little information about the relationship between the time in therapeutic range (TTR) of the tacrolimus trough level (tacrolimus TTR) and clinical outcomes. This study aimed to evaluate the association between tacrolimus TTR and acute rejection (AR) within the first three months after lung transplantation. METHODS: This was a retrospective study of patients who underwent lung transplantation at a single center. The target tacrolimus trough levels were 10-15 ng/mL, and tacrolimus TTR was calculated using the Rosendaal method. The cut-off value of the tacrolimus TTR was estimated by receiver operating characteristic analysis based on AR. RESULTS: The study included 90 patients. AR was observed in 26 patients. In this study, ''early-AR'' was defined as any AR within 2 weeks post-transplant (n = 22) and ''late-AR'' was defined as any AR after 1-month post-transplant (n = 4). For early AR, the relationship between tacrolimus TTR and the onset of AR was examined. There were no differences in the tacrolimus TTR between the early-AR group and non-AR group (35.7 ± 22.4 vs 31.5 ± 19.9%, P = 0.416). For late-AR, the relationship with tacrolimus TTR was examined every 10 d. The tacrolimus TTR during postoperative days (POD) 21-30 and POD 31-onset was significantly lower in the late-AR group than the no-AR group (50.0 ± 7.1 vs. 71.8 ± 18.0% and 37.0 ± 26.6 vs. 68.9 ± 31.5%, P < 0.05, respectively). The cutoff value of the tacrolimus TTR during POD 21-30 was estimated as 55.0%. CONCLUSIONS: Our findings suggest that a lower tacrolimus TTR is a predictor of late AR. A tacrolimus TTR of 55% or higher is necessary to reduce the risk of AR during this period after lung transplantation.
    2022年10月, Journal of pharmaceutical health care and sciences, 8(1) (1), 25 - 25, 英語, 国際誌
    研究論文（学術雑誌）

  • Kotaro Itohara, Ikuko Yano, Shunsaku Nakagawa, Mitsuhiro Sugimoto, Machiko Hirai, Atsushi Yonezawa, Satoshi Imai, Takayuki Nakagawa, Daiki Hira, Takashi Ito, Koichiro Hata, Etsuro Hatano, Tomohiro Terada, Kazuo Matsubara
    Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post-liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixed-effect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post-hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model-building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post-hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R2  = 0.330, p < 0.0001). The estimation accuracy in pediatric patients was considerably high, except for one infant out of 13 patients. In conclusion, population pharmacokinetic analysis clarified several significant covariates for everolimus pharmacokinetics in liver transplant patients. Everolimus pharmacokinetics moderately correlated with tacrolimus pharmacokinetics and could be extrapolated from adult to pediatric patients by body size correction, except for infants.
    Wiley, 2022年08月, Clinical and Translational Science, 15(11) (11), 2652 - 2662, 英語, 国際誌
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Takashi Ogihara, Masato Kagawa, Rintarou Yamanaka, Satoshi Imai, Kotaro Itohara, Daiki Hira, Shunsaku Nakagawa, Atsushi Yonezawa, Michiho Ito, Takayuki Nakagawa, Tomohiro Terada, Kazuo Matsubara
    Chemotherapy-induced oral mucositis (COM) is a common adverse effect of cancer chemotherapy. Several clinical studies reported that repetitive use of mouthwashes containing 2.5-6.25% Hangeshashinto (HST), a Kampo formula, relieves COM, but the effect is insufficient. To solve this problem, we produced an oral ointment of 12% HST extract (considered quantitatively equivalent to 20% commercially available HST), which will increase the local concentrations of its active ingredients and prolong the contact time with COM. In this study, we evaluated the pharmaceutical properties (spreadability and stability) of HST oral ointment. In addition, its safety (oral mucosal irritation) and therapeutic effects on 5-fluorouracil-induced oral mucositis were evaluated in male Syrian hamsters. The HST ointment showed good spreadability and stability for more than 8 weeks at 4 °C. In the oral mucosal irritation test, topical application of HST ointment (0.2 g) three times per day for 14 days had no adverse effect on the oral mucosa of hamsters. In hamsters treated with 5-fluorouracil (60 mg/kg) twice, COM was induced by a submucosal injection of 5% acetic acid into the cheek pouch. When HST ointment (50 µg) was topically applied to the mucositis area once per day for 12 days, the area and macroscopic score of mucositis were significantly decreased, and the depth of the wound tended to be reduced compared with the lactose ointment-treated control animals. These findings suggest that HST oral ointment shows good properties in spreadability, stability, and safety, and elicits a therapeutic effect in an animal model of COM.
    Springer Science and Business Media LLC, 2022年08月, Journal of Natural Medicines, 77(1) (1), 53 - 63, 英語, 国内誌
    研究論文（学術雑誌）

  • Sho Masui, Atsushi Yonezawa, Kotoko Yokoyama, Noriko Iwamoto, Takashi Shimada, Akira Onishi, Hideo Onizawa, Takayuki Fujii, Kosaku Murakami, Koichi Murata, Masao Tanaka, Shunsaku Nakagawa, Daiki Hira, Kotaro Itohara, Satoshi Imai, Takayuki Nakagawa, Makoto Hayakari, Shuichi Matsuda, Akio Morinobu, Tomohiro Terada, Kazuo Matsubara
    PURPOSE: Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties. METHODS: An analytical method using liquid chromatography-mass spectrometry (LC-MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-β was investigated using an in-house enzyme-linked immunosorbent assay. RESULTS: In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-β and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro. CONCLUSIONS: ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.
    2022年08月, Pharmaceutical research, 39(10) (10), 2541 - 2554, 英語, 国際誌
    研究論文（学術雑誌）

  • Yuki Shigetsura, Satoshi Imai, Hiroki Endo, Yumi Shimizu, Keita Ueda, Toshiya Murai, Kotaro Itohara, Shunsaku Nakagawa, Atsushi Yonezawa, Yasuaki Ikemi, Sachio Fukatsu, Noriaki Kitada, Tomohiro Terada, Takayuki Nakagawa, Kazuo Matsubara
    Ovid Technologies (Wolters Kluwer Health), 2022年05月, Clinical Neuropharmacology, 45(3) (3), 52 - 60
    研究論文（学術雑誌）

  • Sho Masui, Atsushi Yonezawa, Kenji Momo, Shunsaku Nakagawa, Kotaro Itohara, Satoshi Imai, Takayuki Nakagawa, Kazuo Matsubara
    Infliximab (IFX) has contributed to the treatment of several chronic inflammatory diseases, including Crohn's disease (CD), ulcerative colitis (UC), psoriasis (Pso), and rheumatoid arthritis (RA). However, the loss of response in some patients with long-term IFX therapy has been a major problem. Randomized controlled trials (RCTs) are limited in their short duration and lack of generalizability to the real-world population. We aimed to describe the persistence rates of IFX therapy to estimate its long-term effectiveness in clinical practice. Claims data from the Japan Medical Data Center database from January 2005 to June 2017 were used. The study population was identified based on the International Classification of Diseases, 10th Revision and the Anatomical Therapeutic Chemical Classification System. The 5-year persistence rates of IFX therapy were estimated using the Kaplan-Meier method. Overall, 281, 235, 41, and 222 patients with CD, UC, Pso, and RA, respectively, were selected. The 5-year persistence rates for IFX claims were 62.9, 38.9, 22.1, and 28.1% in patients with CD, UC, Pso, and RA, respectively. Patients with CD and UC administered IFX beyond the median dose had higher persistence rates. In patients with RA, female sex and no prior use of other biologics were associated with longer persistence. In conclusion, IFX persistence rates differed across chronic inflammatory diseases, which did not correspond to the results of the major RCTs. Factors associated with longer IFX persistence were identified in each disease group. Our findings may provide useful information to facilitate the proper use of IFX.
    2022年, Biological & pharmaceutical bulletin, 45(3) (3), 323 - 332, 英語, 国内誌
    研究論文（学術雑誌）

  • Asami Sukeishi, Kotaro Itohara, Atsushi Yonezawa, Yuki Sato, Katsuyuki Matsumura, Yoshiki Katada, Takayuki Nakagawa, Satoshi Hamada, Naoya Tanabe, Eishi Imoto, Shinichi Kai, Toyohiro Hirai, Motoko Yanagita, Shigeru Ohtsuru, Tomohiro Terada, Isao Ito
    Remdesivir, a prodrug of the nucleoside analog GS-441524, plays a key role in the treatment of coronavirus disease 2019 (COVID-19). However, owing to limited information on clinical trials and inexperienced clinical use, there is a lack of pharmacokinetic (PK) data in patients with COVID-19 with special characteristics. In this study, we aimed to measure serum GS-441524 concentrations and develop a population PK (PopPK) model. Remdesivir was administered at a 200 mg loading dose on the first day followed by 100 mg from day 2, based on the package insert, in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min. In total, 190 concentrations from 37 Japanese patients were used in the analysis. The GS-441524 trough concentrations were significantly higher in the eGFR less than 60 ml/min group than in the eGFR greater than or equal to 60 ml/min group. Extracorporeal membrane oxygenation in four patients hardly affected the total body clearance (CL) and volume of distribution (Vd ) of GS-441524. A one-compartment model described serum GS-441524 concentration data. The CL and Vd of GS-441524 were significantly affected by eGFR readjusted by individual body surface area and age, respectively. Simulations proposed a dose regimen of 200 mg on day 1 followed by 100 mg once every 2 days from day 2 in patients with an eGFR of 30 ml/min or less. In conclusion, we successfully established a PopPK model of GS-441524 using retrospectively obtained serum GS-441524 concentrations in Japanese patients with COVID-19, which would be helpful for optimal individualized therapy of remdesivir.
    2022年01月, CPT: pharmacometrics & systems pharmacology, 11(1) (1), 94 - 103, 英語, 国際誌
    研究論文（学術雑誌）

  • Yoshiki Katada, Shunsaku Nakagawa, Miki Nagao, Yuko Yoshida, Yuya Matsuda, Yuki Yamamoto, Kotaro Itohara, Satoshi Imai, Atsushi Yonezawa, Takayuki Nakagawa, Kazuo Matsubara, Satona Tanaka, Daisuke Nakajima, Hiroshi Date, Tomohiro Terada
    INTRODUCTION: Invasive Aspergillus infection (IA) in lung transplantation can result in poor outcomes. Itraconazole has been shown to be effective for fungal prophylaxis in lung transplant recipients. However, IA remains a major cause of death after lung transplantation. Therefore, we aimed to clarify the risk factors for IA on itraconazole prophylaxis. METHODS: We examined 120 recipients to uncover their IA epidemiology, clinical characteristics, and outcomes. In addition, a case-control study was performed to identify risk factors of IA. RESULTS: Of the 120 patients, 12 developed IA under itraconazole prophylaxis. The patient demographics and clinical characteristics were compared among the following two groups: IA group, 12 patients, and control group, 108 patients. Significant differences were observed in age (p = 0.004), history of interstitial pneumonia (p = 0.032), and CMV infection (p < 0.001) between the groups. Before the onset of IA, 92% (11/12) of the patients received itraconazole with trough concentrations above the therapeutic range. IA developed at 272.9 ± 114.1 days after lung transplantation. Of the 12 patients who developed IA, 66.7% (8/12) had early cessation of cytomegalovirus (CMV) prophylaxis due to toxicity of valganciclovir, as follows: leukocytopenia in 4 patients, and renal dysfunction in 4 patients. Of the 8 patients who stopped valganciclovir, 75% (6/8) developed CMV infection subsequently. CONCLUSION: This study suggests that older age, history of interstitial pneumonia, and CMV infection may be important risk factors for IA on itraconazole prophylaxis. These results may help clinicians optimize prophylactic strategies for IA.
    2021年10月, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 28(1) (1), 54 - 60, 英語, 国際誌
    研究論文（学術雑誌）

  • Kotaro Itohara, Ikuko Yano, Shunsaku Nakagawa, Atsushi Yonezawa, Tomohiro Omura, Satoshi Imai, Takayuki Nakagawa, Atsuro Sawada, Takashi Kobayashi, Akira Tochio, Kaoru Sakai, Kojiro Taura, Osamu Ogawa, Kazuo Matsubara
    Physiologically based pharmacokinetic (PBPK) modeling is useful for evaluating differences in drug exposure among special populations, but it has not yet been employed to evaluate the absorption process of tacrolimus. In this study, we developed a minimal PBPK model with a compartmental absorption and transit model for renal transplant patients using available data in the literature and clinical data from our hospital. The effective permeability value of tacrolimus absorption and parameters for the single adjusting compartment were optimized via sensitivity analyses, generating a PBPK model of tacrolimus for renal transplant patients with good predictability. Next, we extrapolated the pharmacokinetics of tacrolimus for liver transplant patients by changing the population demographic parameters of the model. When the physiological parameters of a population with normal liver function were changed to those of a population with impaired hepatic function (Child-Pugh class A) in the constructed renal transplant PBPK model, the predicted tacrolimus concentrations were consistent with the observed concentrations in liver transplant patients. In conclusion, the constructed tacrolimus PBPK model for renal transplant patients could predict the pharmacokinetics in liver transplant patients by slightly reducing the hepatic function, even at three weeks post-transplantation.
    Elsevier {BV}, 2021年10月, Drug Metabolism and Pharmacokinetics, 42, 100423 - 100423, 英語, 国際誌
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Yuika Osada, Shunsaku Nakagawa, Kanako Ishibe, Shota Takao, Aimi Shimazaki, Kotaro Itohara, Satoshi Imai, Atsushi Yonezawa, Takayuki Nakagawa, Kazuo Matsubara
    Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60 min, renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion. Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to ischemia-reperfusion injury.NEW & NOTEWORTHY This study aimed to determine the impact of antibiotic-induced microbiome depletion (AIMD) on renal glucose metabolism in mice. This is the first report confirming that AIMD is associated with decreased levels of pyruvate, a key intermediate in glucose metabolism, which may have been caused by activation of renal gluconeogenesis. We hypothesized that AIMD can increase the susceptibility of the kidney to ischemia-reperfusion injury.
    2021年10月, American journal of physiology. Renal physiology, 321(4) (4), F455-F465, 英語, 国際誌
    研究論文（学術雑誌）

  • Keiko Ikuta, Shunsaku Nakagawa, Kenji Momo, Atsushi Yonezawa, Kotaro Itohara, Yuki Sato, Satoshi Imai, Takayuki Nakagawa, Kazuo Matsubara
    OBJECTIVES: This study aimed to assess whether the combined use of proton pump inhibitors (PPIs) with non-steroidal anti-inflammatory drugs (NSAIDs) or antibiotics (penicillins, macrolides, cephalosporins or fluoroquinolones) was associated with an increased risk of acute kidney injury (AKI). DESIGN: A nested case-control study. SETTING: A health insurance claims database constructed by the Japan Medical Data Center. PARTICIPANTS: Patients were eligible if they were prescribed a PPI, NSAID and antibiotic at least once between January 2005 and June 2017. The patients who were new PPI users and did not have any history of renal diseases before cohort entry were included (n=219 082). The mean age was 45 and 44% were women. INTERVENTIONS: Current use of PPIs, NSAIDs, or antibiotics. PRIMARY OUTCOME MEASURES: Acute kidney injury. RESULTS: During a mean follow-up of 2.4 (SD, 1.7) years, 317 cases of AKI were identified (incidence rate of 6.1/10 000 person-years). The current use of PPIs was associated with a higher risk of AKI compared with past PPI use (unadjusted OR, 4.09; 95% CI, 3.09 to 5.44). The unadjusted ORs of AKI for the current use of PPIs with NSAIDs, cephalosporins and fluoroquinolones, compared with the current use of PPIs alone, were 3.92 (95% CI, 2.40 to 6.52), 2.57 (1.43 to 4.62) and 3.08 (1.50 to 6.38), respectively. The effects of concurrent use of PPIs with NSAIDs, cephalosporins or fluoroquinolones remain significant in the adjusted model. The analyses on absolute risk of AKI confirmed the results from the nested case-control study. CONCLUSIONS: Concomitant use of NSAIDs with PPIs significantly increased the risk for AKI. Moreover, the results suggested that concomitant use of cephalosporins or fluoroquinolones with PPIs was associated with increased risk of incident AKI.
    2021年02月, BMJ open, 11(2) (2), e041543, 英語, 国際誌
    研究論文（学術雑誌）

  • Tomohiro Omura, Luna Nomura, Ran Watanabe, Hiroki Nishiguchi, Kazuhiro Yamamoto, Satoshi Imai, Shunsaku Nakagawa, Kotaro Itohara, Atsushi Yonezawa, Takayuki Nakagawa, Junichi Kunimasa, Ikuko Yano, Kazuo Matsubara
    Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson's disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3' untranslated region, and an miR-101 mimic suppressed the 6-OHDA-induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.
    2021年, Frontiers in molecular neuroscience, 14, 748026 - 748026, 英語, 国際誌
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • Kazuto Nakae, Sho Masui, Atsushi Yonezawa, Motomu Hashimoto, Ryu Watanabe, Koichi Murata, Kosaku Murakami, Masao Tanaka, Hiromu Ito, Kotoko Yokoyama, Noriko Iwamoto, Takashi Shimada, Miyuki Nakamura, Masaya Denda, Kotaro Itohara, Shunsaku Nakagawa, Yasuaki Ikemi, Satoshi Imai, Takayuki Nakagawa, Makoto Hayakari, Kazuo Matsubara
    Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.
    2021年, PloS one, 16(10) (10), e0258601, 英語, 国際誌
    研究論文（学術雑誌）

  • Congyun Jin, Yoshihiro Matsui, Atsushi Yonezawa, Satoshi Imai, Takashi Ogihara, Kotaro Itohara, Shunsaku Nakagawa, Takayuki Nakagawa, Kazuo Matsubara
    Riboflavin (vitamin B2) plays an important role in cellular growth and function. Riboflavin transporter 2 (RFVT2) is widely expressed in several tissues, especially in the brain and salivary glands, and plays an important role in the tissue disruption of riboflavin. During the last 10 years, mutations in SLC52A2 have been documented in patients with a rare neurological disorder known as Brown-Vialetto-Van Laere syndrome. However, no suitable animal model of this disease has been reported. Here, we aimed to clarify the physiological role of RFVT2 using Slc52a2-mutant mice. The appearance, body weight, and plasma riboflavin concentration of Slc52a2 heterozygous mutant (Slc52a2+/-) mice were similar to those of wild-type (WT) mice. However, intercrossing between Slc52a2+/- mice failed to generate Slc52a2 homozygous mutant (Slc52a2-/-) mice. This suggested that Slc52a2 gene deficiency results in early embryonic lethality. Our findings suggested that RFVT2 is essential for growth and development, and its deletion may influence embryonic survival.
    2021年, Biological & pharmaceutical bulletin, 44(2) (2), 283 - 286, 英語, 国内誌
    研究論文（学術雑誌）

  • Congyun Jin, Atsushi Yonezawa, Hiroki Yoshimatsu, Satoshi Imai, Madoka Koyanagi, Kaori Yamanishi, Shunsaku Nakagawa, Kotaro Itohara, Tomohiro Omura, Takayuki Nakagawa, Junya Nagai, Kazuo Matsubara
    Riboflavin transporter 3 (RFVT3), encoded by the SLC52A3 gene, is important for riboflavin homeostasis in the small intestine, kidney, and placenta. Our previous study demonstrated that Slc52a3 knockout (Slc52a3-/-) mice exhibited neonatal lethality and metabolic disorder due to riboflavin deficiency. Here, we investigated the influence of Slc52a3 gene disruption on brain development using Slc52a3-/- embryos. Slc52a3-/- mice at postnatal day 0 showed hypoplasia of the brain and reduced thickness of cortical layers. At embryonic day 13.5, the formation of Tuj1+ neurons and Tbr2+ intermediate neural progenitors was significantly decreased; no significant difference was observed in the total number and proliferative rate of Pax6+ radial glia. Importantly, the hypoplastic phenotype was rescued upon riboflavin supplementation. Thus, it can be concluded that RFVT3 contributes to riboflavin homeostasis in embryos and that riboflavin itself is required during embryonic development of the cerebral cortex in mice.
    2020年10月, Scientific reports, 10(1) (1), 18443 - 18443, 英語, 国際誌
    研究論文（学術雑誌）

  • Miko Kondo, Shunsaku Nakagawa, Satoru Orii, Kotaro Itohara, Mitsuhiro Sugimoto, Tomohiro Omura, Yuki Sato, Satoshi Imai, Atsushi Yonezawa, Takayuki Nakagawa, Kazuo Matsubara
    Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive infections. For adult patients, treatment with vancomycin requires effective therapeutic drug-monitoring (TDM) to achieve clinical outcomes and reduce the incidence of adverse effects. However, it remains still unclear whether the TDM with vancomycin is beneficial in yielding better clinical outcomes in pediatrics. The objective of our study was to evaluate whether the clinical response to treatment was associated with initial trough concentrations of vancomycin in pediatric patients. A retrospective observation study of 60 patients (age: 1 month-15 years) who had completed and qualified for analysis was conducted at Kyoto University Hospital. The response to treatment was assessed by the time to resolution of fever and time to 50% decline in C-reactive protein (CRP). In addition, we explored whether vancomycin trough level was associated with the baseline characteristics. Trend analysis showed that there were significant correlations between vancomycin trough level and age, body weight, estimated glomerular filtration rate, and serum albumin levels. The time to resolution of fever of the patients with higher initial trough level (≥ 5 µg/mL) was significantly lower than that of the patients with lower trough level (< 5 µg/mL). The higher vancomycin concentration tended to be associated with the shorter time to 50% decline in CRP. The findings suggest that initial trough concentration is important in achieving better outcomes with vancomycin treatment in pediatrics.
    2020年, Biological & pharmaceutical bulletin, 43(10) (10), 1463 - 1468, 英語, 国内誌
    [査読有り]
    研究論文（学術雑誌）

  • Kotaro Itohara, Ikuko Yano, Tetsunori Tsuzuki, Miwa Uesugi, Shunsaku Nakagawa, Atsushi Yonezawa, Hideaki Okajima, Toshimi Kaido, Shinji Uemoto, Kazuo Matsubara
    In adult patients after living-donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically-based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living-donor liver transplantation. The clearance was about 1.35-fold higher in the recipients who had a liver with the CYP3A5*1 allele than in those with the CYP3A5*3/*3 genotype, whereas bioavailability was ~0.7-fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically-based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.
    2019年08月, CPT: pharmacometrics & systems pharmacology, 8(8) (8), 587 - 595, 英語, 国際誌
    [査読有り]
    研究論文（学術雑誌）
    神戸大学リポジトリ（Kernel）へのリンク

  • 小児におけるトリクロホスの投与量の最適化
    井上美帆, 佐藤博貴, 糸原光太郎, 加藤祐子, 石井祥代, 伊藤由起, 中平有紀, 那須民江, 上島通浩, 矢野育子, 松原和夫, 佐和貞治, 橋本悟
    (公財)臨床薬理研究振興財団, 2017年, 臨床薬理の進歩, 38(38) (38), 71 - 78, 日本語
    [査読有り]

  • Haruka Onoue, Ikuko Yano, Atsuko Tanaka, Kotaro Itohara, Akiko Hanai, Hiroshi Ishiguro, Hideyuki Motohashi, Satohiro Masuda, Kazuo Matsubara
    2016年06月, European journal of clinical pharmacology, 72(6) (6), 703 - 10, 英語, 国際誌
    [査読有り]
    研究論文（学術雑誌）

■ MISC
  • フルオロウラシルによるメラニン産生を抑制する化合物の探索
    野網万那, 北廣優実, 糸原光太郎, 大村友博, 矢野育子
    2025年, 日本薬学会年会要旨集(Web), 145th

  • オシメルチニブによる間質性肺疾患のin vitroモデルの作製と評価
    高橋大, 山本和宏, 山本和宏, 太田かなる, 北廣優実, 糸原光太郎, 大村友博, 矢野育子
    2025年, 日本薬学会年会要旨集(Web), 145th

  • 小林 理乃, 山本 和宏, 丹田 雅明, 糸原 光太郎, 北廣 優実, 大村 友博, 矢野 育子
    (一社)日本TDM学会, 2024年07月, TDM研究, 41(2) (2), 158 - 158, 日本語

  • 臓器移植における免疫抑制薬の適正使用を目指したファーマコメトリクス研究
    糸原 光太郎
    (一社)日本医療薬学会, 2024年04月, 医療薬学, 50(4) (4), 208 - 211, 日本語

  • 血中インフリキシマブおよびインターロイキン6濃度の測定は関節リウマチ患者のインフリキシマブ治療の継続予測に有用である
    増井翔, 増井翔, 増井翔, 中村美由紀, 中村美由紀, 大西輝, 橋本求, 橋本求, 鬼澤秀夫, 藤井貴之, 藤井貴之, 村上孝作, 村田浩一, 村田浩一, 田中真生, 横山琴子, 岩本典子, 嶋田崇史, 糸原光太郎, 平大樹, 中川俊作, 今井哲司, 中川貴之, 早狩誠, 松田秀一, 森信暁雄, 森信暁雄, 寺田智祐, 松原和夫, 米澤淳, 米澤淳, 米澤淳
    2024年, 日本薬学会年会要旨集(Web), 144th

  • CYP3A5遺伝子多型を考慮したイトラコナゾール併用時のタクロリムス投与設計のための母集団薬物動態モデル構築
    小谷絹花, WILDSCHUT Ajano C., WILDSCHUT Ajano C., 平大樹, 高橋連, 片田佳希, 梅村圭祐, 勝部友理恵, 糸原光太郎, 糸原光太郎, 中川俊作, 寺田智祐
    2024年, 医療薬学フォーラム講演要旨集, 32nd

  • 生理学的薬物動態モデルを活用したタクロリムスの薬物動態予測
    糸原 光太郎
    (一社)日本臨床薬理学会, 2024年01月, 日本臨床薬理学会学術総会抄録集, 44回, 3 - 3, 日本語

  • 肺移植レシピエントにおけるバルガンシクロビルによる重篤な白血球減少の予測因子に関する薬物動態学的探索
    片田 佳希, 梅村 圭祐, 西川 有沙美, 糸原 光太郎, 長尾 美紀, 中川 俊作, 端 幸代, 勝部 友理恵, 平 大樹, 中島 大輔, 大角 明宏, 伊達 洋至, 寺田 智祐
    (公社)日本化学療法学会, 2023年07月, 日本化学療法学会雑誌, 71(4) (4), 507 - 508, 日本語

  • ニルマトレルビル/リトナビル併用時にタクロリムス濃度の異常高値を認めた腎移植症例
    冨田 猛, 木村 丈司, 山本 和宏, 宇田 篤史, 藤田 浩平, 荻原 孝史, 糸原 光太郎, 北廣 優実, 大村 友博, 矢野 育子
    (一社)日本医薬品情報学会, 2023年06月, 日本医薬品情報学会総会・学術大会講演要旨集, 25回, 147 - 147, 日本語

  • 周産期薬物療法における患者モニタリング 生理学的薬物動態モデルを活用した妊娠時の薬物動態予測
    糸原 光太郎
    (一社)日本TDM学会, 2023年06月, TDM研究, 40(2) (2), 73 - 73, 日本語

  • 高度腎機能低下患者におけるバンコマイシンAUC-guided TDMの安全性に関する検討
    藤田 浩平, 山本 和宏, 宇田 篤史, 荻原 孝史, 阪上 倫行, 田村 直暉, 木村 丈司, 糸原 光太郎, 北廣 優実, 大村 友博, 矢野 育子
    (一社)日本TDM学会, 2023年06月, TDM研究, 40(2) (2), 176 - 176, 日本語

  • 高橋 連, 糸原 光太郎, 中川 俊作, 片田 佳希, 杉本 充弘, 梅村 圭祐, 松村 勝之, 今吉 菜月, 勝部 友里恵, 平 大樹, 今井 哲司, 米澤 淳, 中川 貴之, 田中 里奈, 大角 明宏, 中島 大輔, 長尾 美紀, 伊達 洋至, 寺田 智祐
    (一社)日本TDM学会, 2023年06月, TDM研究, 40(2) (2), 183 - 183, 日本語

  • バルガンシクロビル投与中の肺移植患者におけるガンシクロビル血中濃度と副作用である重篤な白血球減少との関係
    片田 佳希, 中川 俊作, 長尾 美紀, 梅村 圭祐, 糸原 光太郎, 西川 有沙美, 端 幸代, 勝部 友理恵, 平 大樹, 中島 大輔, 大角 明宏, 伊達 洋至, 寺田 智祐
    (一社)日本移植学会, 2023年04月, 移植, 57(4) (4), 423 - 423, 日本語

  • レムデシビルの活性代謝物GS-441524の母集団薬物動態解析と個別投与設計の検討
    西川 有沙美[助石], 糸原 光太郎, 片田 佳希, 伊藤 功朗
    (公社)日本化学療法学会, 2023年03月, 日本化学療法学会雑誌, 71(2) (2), 240 - 240, 日本語

  • 肺移植レシピエントにおけるバルガンシクロビルによる重篤な白血球減少の予測因子に関する薬物動態学的探索
    片田 佳希, 梅村 圭祐, 西川 有沙美, 糸原 光太郎, 長尾 美紀
    日本感染症学会・日本化学療法学会, 2023年03月, 日本感染症学会総会・学術講演会・日本化学療法学会学術集会合同学会プログラム・抄録集, 97回・71回, O - 327, 日本語

  • プロポフォールの血中・脳中実測濃度に基づく薬物動態モデルの再構築
    川田将義, 米澤淳, 米澤淳, 峰晴陽平, 糸原光太郎, 溝田敏幸, 山尾幸広, 服部悦子, 古川恵子, 荒川芳輝, 寺田智祐
    2023年, 医療薬学フォーラム講演要旨集, 31st

  • 薬剤師外来が抗血栓薬服用患者の長期臨床アウトカムに与える影響
    栗村朋子, 山本和宏, 田中秀和, 鳥羽敬義, 木村丈司, 土生康司, 糸原光太郎, 北廣優実, 大村友博, 矢野育子
    2023年, 日本医療薬学会年会講演要旨集(Web), 33rd

  • 臓器移植における免疫抑制薬の適正使用を目指したファーマコメトリクス研究
    糸原光太郎
    2023年, 日本医療薬学会年会講演要旨集(Web), 33rd

  • 先天性サイトメガロイウルス感染症患者におけるガンシクロビルのPK/PD解析
    糸原光太郎, 藤中俊輔, 山本和宏, 橋本真梨, 田村直暉, 北廣優実, 大村友博, 藤岡一路, 矢野育子
    2023年, 日本医療薬学会年会講演要旨集(Web), 33rd

  • パーキンソン病発症に関連する小胞体ストレス関連分子SEL1Lを制御するmicroRNAの探索と血漿中microRNA発現量の検討
    西口大生, 大村友博, 大村友博, 野村月渚, 渡邉蘭, 北廣優実, 糸原光太郎, 山本和宏, 國正淳一, 松原和夫, 松原和夫, 矢野育子
    2023年, 医療薬学フォーラム講演要旨集, 31st

  • 糸原 光太郎, 矢野 育子, 中川 俊作, 杉本 充弘, 平井 真智子, 米澤 淳, 平 大樹, 伊藤 孝司, 秦 浩一郎, 波多野 悦朗, 寺田 智祐, 松原 和夫
    (一社)日本臨床薬理学会, 2022年12月, 日本臨床薬理学会学術総会抄録集, 43回, 1 - 5, 日本語

  • 平 大樹, 中川 俊作, 糸原 光太郎, 今井 哲司, 上島 智, 岡野 友信, 角本 幹夫, 米澤 淳, 中川 貴之, 寺田 智祐
    (一社)日本TDM学会, 2022年05月, TDM研究, 39(2) (2), 170 - 170, 日本語

  • 平 大樹, 中川 俊作, 糸原 光太郎, 今井 哲司, 上島 智, 岡野 友信, 角本 幹夫, 米澤 淳, 中川 貴之, 寺田 智祐
    (一社)日本TDM学会, 2022年05月, TDM研究, 39(2) (2), 170 - 170, 日本語

  • 末梢神経障害の発症メカニズム解析を目的とした新規3次元感覚神経オルガノイドの開発
    守屋茜里, 今井哲司, 荻堂亮甫, 小柳円花, 糸原光太郎, 平大樹, 中川俊作, 米澤淳, 中川貴之, 寺田智祐
    2022年, 鎮痛薬・オピオイドペプチドシンポジウムプログラム・抄録集, 41st (CD-ROM)

  • 幾田 慧子, 中川 俊作, 百 賢二, 米澤 淳, 糸原 光太郎, 佐藤 夕紀, 今井 哲司, 中川 貴之, 松原 和夫, 寺田 智祐
    (一社)日本薬剤疫学会, 2021年11月, 薬剤疫学, 26(Suppl.) (Suppl.), S117 - S118, 日本語

  • プロトンポンプ阻害薬使用患者においてNSAIDs又は抗菌薬の併用が急性腎障害発症に及ぼす影響
    幾田 慧子, 中川 俊作, 百 賢二, 米澤 淳, 糸原 光太郎, 佐藤 夕紀, 今井 哲司, 中川 貴之, 松原 和夫, 寺田 智祐
    (一社)日本薬剤疫学会, 2021年11月, 薬剤疫学, 26(Suppl.) (Suppl.), S117 - S118, 日本語

  • レムデシビルの活性代謝物GS-441524の母集団薬物動態解析と個別投与設計の検討
    助石有沙美, 糸原光太郎, 片田佳希, 伊藤功朗
    (公社)日本化学療法学会, 2021年, 日本感染症学会西日本地方会学術集会・日本感染症学会中日本地方会学術集会・日本化学療法学会西日本支部総会合同開催プログラム・抄録集, 91st-64th-69th(2) (2), 280 - 281, 日本語

  • Slc52a3遺伝子欠損がマウス大脳皮質の形成に及ぼす影響
    金叢芸, 金叢芸, 米澤淳, 米澤淳, 吉松宏樹, 吉松宏樹, 今井哲司, 小柳円花, 小柳円花, 山西香里, 山西香里, 中川俊作, 糸原光太郎, 大村友博, 中川貴之, 永井純也, 松原和夫
    2020年, トランスポーター研究会年会抄録集, 15th

  • 体重に応じたテイコプラニン初期投与設計の有効性と安全性に関する検討
    片田佳希, 片田佳希, 中川俊作, 山嶋仁実, 杉本充弘, 木全柾典, 吉田優子, 松田裕也, 高橋悠, 糸原光太郎, 北田徳昭, 今井哲司, 深津祥央, 津田真弘, 米澤淳, 中川貴之, 山本正樹, 山本正樹, 松村康史, 松村康史, 長尾美紀, 長尾美紀, 松原和夫
    (公社)日本化学療法学会, 2020年, 日本化学療法学会雑誌, 68(6) (6), 608 - 618, 日本語

  • 腎移植患者におけるタクロリムスPBPKモデル構築と肝移植患者の薬物動態との比較
    糸原光太郎, 矢野育子, 矢野育子, 中川俊作, 米澤淳, 米澤淳, 中川貴之, 今井哲司, 小川修, 小林恭, 坂井薫, 松原和夫
    (一社)日本臨床薬理学会, 2020年, 臨床薬理, 51(Supplement) (Supplement), S293 - S293, 日本語

  • 抗インフルエンザ薬の適正使用指針(フォーミュラリ)導入のアウトカム評価
    片田佳希, 片田佳希, 米澤淳, 杉本充弘, 木全柾典, 吉田優子, 糸原光太郎, 中川俊作, 北田徳昭, 今井哲司, 池見泰明, 深津祥央, 中川貴之, 松村康史, 松村康史, 長尾美紀, 長尾美紀, 松原和夫
    (一社)日本病院薬剤師会, 2020年, 日本病院薬剤師会雑誌, 56(10) (10), 1155 - 1160, 日本語

  • 歯科口腔外科における経口抗菌薬適正化の取り組みとその効果
    川田将義, 片田佳希, 糸原光太郎, 木全柾典, 吉田優子, 別所和久, 長尾美紀
    (一社)日本環境感染学会, 2020年, 日本環境感染学会総会・学術集会(Web), 35th, O39 - 2, 日本語

  • Liposomal amphotericin Bによる腎機能障害発現に関連する因子の探索
    髙橋悠, 片田佳希, 中川俊作, 杉本充弘, 吉田優子, 木全柾典, 糸原光太郎, 北田徳昭, 深津祥央, 米澤淳, 中川貴之, 松村康史, 長尾美紀, 松原和夫
    2019年11月04日, 日本医療薬学会年会講演要旨集, 29th

  • イトラコナゾールが投与された肺移植患者のアスペルギルス感染に関連する因子の探索
    片田 佳希, 木全 征典, 福井 彩香, 川本 雄士, 糸原 光太郎, 長尾 美紀, 中川 俊作, 松田 裕也, 杉本 充弘, 山本 由貴, 深津 祥央, 米澤 淳, 中川 貴之, 陳 豊史, 伊達 洋至, 松原 和夫
    (公社)日本化学療法学会, 2019年03月, 日本化学療法学会雑誌, 67(2) (2), 252 - 252, 日本語

  • 抗真菌薬に関する適正使用支援チームにおける薬剤師の役割
    木全柾典, 中川俊作, 片田佳希, 杉本充弘, 吉田優子, 糸原光太郎, 深津祥央, 佐藤夕紀, 今井哲司, 米澤淳, 米澤淳, 中川貴之, 松村康史, 長尾美紀, 松原和夫
    2019年, 日本医療薬学会年会講演要旨集(Web), 29

  • クロザピン及び活性代謝物の母集団薬物動態解析:入院・外来の影響
    小岸かれん, 小岸かれん, 大村友博, 大村友博, 山本将太, 中川俊作, 米沢淳, 米沢淳, 糸原光太郎, 糸原光太郎, 竹内理人, 竹内理人, 松尾研志, 松尾研志, 橋本凱朝, 橋本凱朝, 諏訪太朗, 佐藤夕紀, 今井哲司, 中川貴之, 村井俊哉, 矢野育子, 矢野育子, 松原和夫
    2019年, 日本医療薬学会年会講演要旨集(Web), 29

  • イトラコナゾールを併用した肺移植患者におけるタクロリムス体内動態の経時的変化
    川本雄士, 片田佳希, 中川俊作, 杉本充弘, 糸原光太郎, 山本由貴, 福井彩香, 松田裕也, 松村勝之, 大村友博, 米澤淳, 米澤淳, 中川貴之, 長尾美紀, 陳豊史, 伊達洋至, 松原和夫
    2018年, 日本医療薬学会年会講演要旨集(Web), 28

  • 肝移植患者におけるミコフェノール酸の薬物動態に関する検討
    杉本充弘, 木全征典, 佐藤裕紀, 糸原光太郎, 佐藤夕紀, 中川俊作, 米澤淳, 中川貴之, 穴澤貴行, 伊藤孝司, 岡島英明, 海道利実, 上本伸二, 松原和夫
    2018年, 日本医療薬学会年会講演要旨集(Web), 28

  • 肺移植患者におけるイトラコナゾールおよびリファブチン併用下でのタクロリムス血中濃度管理
    福井彩香, 中川俊作, 片田佳希, 糸原光太郎, 杉本充弘, 山本由貴, 石橋直哉, 傳田将也, 深津祥央, 米澤淳, 中川貴之, 長尾美紀, 野口実紗, 濱路政嗣, 青山晃博, 陳豊史, 伊達洋至, 松原和夫
    2018年, 日本医療薬学会年会講演要旨集(Web), 28

  • イトラコナゾールが投与された肺移植患者のアスペルギルス感染に関連する因子の探索
    片田佳希, 木全柾典, 福井彩香, 川本雄士, 糸原光太郎, 長尾美紀
    (公社)日本化学療法学会, 2018年, 日本感染症学会西日本地方会学術集会・日本感染症学会中日本地方会学術集会・日本化学療法学会西日本支部総会合同開催プログラム・抄録集, 88th-61st-66th(2) (2), 252 - 252, 日本語

  • 小児におけるトリクロロエタノールの薬物動態・薬力学の発達・成長に伴う変化の解析
    井上美帆, 糸原光太郎, 佐藤博貴, 加藤祐子, 石井祥代, 伊藤由起, 那須民江, 上島通浩, 矢野育子, 矢野育子, 松原和夫, 佐和貞治, 橋本悟
    (一社)日本臨床薬理学会, 2017年, 臨床薬理, 48(Supplement) (Supplement), S274 - S274, 日本語

  • トリクロロエタノール小児薬物動態試験のためのモデリング&シミュレーション
    糸原光太郎, 糸原光太郎, 矢野育子, 矢野育子, 井上美帆, 松原和夫
    (一社)日本TDM学会, 2015年, TDM研究, 32(2) (2), 193 - 193, 日本語

■ 共同研究・競争的資金等の研究課題
  • バルガンシクロビルの精密投与設計のためのファーマコメトリクス
    矢野 育子, 糸原 光太郎
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2025年04月01日 - 2028年03月31日

  • ファーマコメトリクスを用いた免疫抑制剤の個別化投与設計法の構築
    糸原 光太郎
    日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 2021年04月01日 - 2024年03月31日
    令和3年度の研究計画は、肝移植患者におけるエベロリムスの母集団解析であった。京都大学医学部附属病院において2018年から2020年に新規にエベロリムスを開始した肝移植患者症例を集積し、非線形混合効果モデル(NONMEM)を用いて母集団解析を行い、エベロリムスの薬物動態パラメータに影響を与える共変量の探索を行なった。また、抽出した共変量に基づいた投与量シミュレーションよりエベロリムスの適切な投与量についての検討を行った。また、肝移植領域においてはエベロリムスは術後４週目以降に開始されることが推奨されているため、事前に免疫抑制剤としてタクロリムスなどのカルシニューリン阻害剤を使用しているケースが多い。そこで、エベロリムスの母集団モデルから算出した個別のクリアランス から患者個別の推奨投与量を算出し、タクロリムスの投与量/血中濃度比との間の単回帰分析により、適切なエベロリムスの投与量を求めることができるかについての検討も行なった。エベロリムスの推奨投与量とタクロリムスの投与量/血中濃度比の間には中等度の相関があることが判明し、事前情報としてのタクロリムスの血中濃度はエベロリムスの投与量設計に利用できる可能性が示唆された。また、小児におけるエベロリムスの投与症例の集積も行い、成人で作成した母集団モデルが小児に外挿できるかどうかをを検討した。現在、解析は終了しており、令和4年度中に学術誌に報告予定である。

  • 矢野 育子, 糸原 光太郎, 井上 美帆, 山本 和宏
    日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2016年04月01日 - 2019年03月31日
    生体肝移植患者から得られたタクリムス血中濃度推移に適した生理学的薬物動態モデルを構築し，肝再生および肝臓・小腸CYP3A5遺伝子多型が薬物動態に与える影響を定量的に評価した．その結果，肝機能は生体肝移植後早期に回復し，タクロリムスの全身クリアランスへの寄与は移植後の限られた期間のみであることが判明した．また，見かけのクリアランスは肝および小腸のCYP3A5遺伝子多型の影響を同程度受けることが判明した．さらに，得られた薬物動態パラメータを用いて，肝・小腸CYP3A5遺伝子多型別の投与量ノモグラムを作成した．

  • 糸原 光太郎
    日本学術振興会, 科学研究費助成事業 奨励研究, 奨励研究, 京都大学, 2019年 - 2019年
    エベロリムスの物理学的データを文献値より収集し。エベロリムスのPBPKモデルを構築した。また、京都大学医学部附属病院にて2018年3月から2019年11月の期間に新規にエベロリムスを導入した患者について血中濃度のデータを収集した。実測値の収集において、遺伝子多型等を考慮しない場合、エベロリムスの血中濃度投与量比(C/D比)はタクロリムスのC/D比と相関が見られないことがわかった。

  • PBPKモデルを用いた生体肝移植患者におけるタクロリムスの薬物動態解析
    糸原 光太郎
    日本学術振興会, 科学研究費助成事業 奨励研究, 奨励研究, 京都大学, 2018年 - 2018年
    研究目的 : カルシニューリン阻害薬であるタクロリムスは、肝移植後の急性拒絶反応予防をはじめとして、臨床現場において広く用いられている。タクロリムスのバイオアベイラビリティには大きな個体差が存在し、タクロリムスを経口投与した際に得られる血中濃度は、静脈内投与を行った際と比較して、患者間のばらつきが大きくなる。そこで本研究では、生理学的薬物速度論(Physiologically based Pharmacokinetic, PBPK)に基づくモデル構築とその有用性評価を行うことを目的とした。PBPKモデルはいわゆる”bottom up”によるモデル構築法であり、解析対象者や研究施設の特性によって影響を受けやすい母集団薬物動態解析と比較して、一般化可能性の高いモデル構築が行えることを利点とする。 研究方法 : 本研究では、PBPKモデルを用いて、CYP3A5の遺伝子多型及び肝臓の再生という生理学的な変化がタクロリムスの薬物動態に及ぼす影響を定量的に評価するとともに、タクロリムスの投与設計を援助する薬物動態モデル構築を目指した。具体的には、文献値または実測データとPBPKモデルのシミュレータであるSimcypを用いることにより、生体肝移植患者のポピュレーションデータおよびタクロリムスのPBPKモデル作成を行なった。また、作成したモデルを用いてドナーとレシピエントの多型ごと、肝移植後の日数ごとの適切なタクロリムスの投与量を推定した。 研究結果 : 本研究において、生体肝移植患者の肝機能を考慮したPBPKモデルを構築し、モデルから予測されるタクロリムス血中濃度は実測値とよく相関することを示した。また、本モデルを用いて、患者の特性や移植後日数に応じた最適な投与方法を提案することができた。

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