研究者詳細 - 米澤　淳

論文 - 米澤　淳

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Development of extended pharmacokinetic models for propofol based on measured blood and brain concentrations

Kawata M., Yonezawa A., Mineharu Y., Itohara K., Mizota T., Matsui Y., Kikuchi T., Yamao Y., Hattori E.Y., Hamada M., Hira D., Furukawa K., Miyamoto S., Terada T., Matsubara K., Arakawa Y.

Scientific Reports （Scientific Reports） 14 （ 1 ） 6326 - 6326 2024年12月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 2045-2322

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.

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Subjective symptoms are triggers for the detection of immune checkpoint inhibitor-induced interstitial lung disease and associate with disease severity: a single-center retrospective study

Yokoi M., Yonezawa A., Hira D., Handa T., Tanizawa K., Nakagawa S., Tsuda M., Ikemi Y., Itotani R., Yoshida H., Nomura M., Matsubara J., Murakami K., Ozasa H., Muto M., Terada T.

Journal of Pharmaceutical Health Care and Sciences （Springer Science and Business Media LLC） 10 （ 1 ） 52 2024年12月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 2055-0294

Background: Interstitial lung disease (ILD) is one of the most common fatal immune-related adverse events (irAEs). ILD development adversely affects the continuation of anticancer drug therapy, including immune checkpoint inhibitor (ICI) therapy and prognosis. There are no established useful clinical indicators for the early detection of ILD. Furthermore, the factors that lead the attending physician to suspect ICI-induced ILD (ICI-ILD) remain unclear. This study aimed to investigate the ICI-ILD detection based on subjective symptoms and their relationship with disease severity in patients receiving anti-PD-1/PD-L1 antibody. Methods: This was a retrospective observational study. We enrolled the patients who received anti-PD-1/PD-L1 antibody at Kyoto University Hospital between September 2014 and April 2021. Patients who developed ICI-ILD were stratified into two distinct groups based on factors that triggered the suspicion of ILD development. The “Subjective symptoms” group was defined as patients in whom ILD was detected based on subjective symptoms. Conversely, the “Routine examinations” group was defined as patients in whom ILD was suspected based on scheduled routine examinations. The severity of ILD in each group was assessed and its association with changes in the respiratory symptoms was examined. Results: Of 926 patients who received anti-PD-1/PD-L1 antibody, 51 patients (5.5%) developed ICI-ILD. The incidence of ICI-ILD in patients with lung cancer was significantly higher than that in patients with other cancers (P < 0.001). Among the patients with ICI-ILD, 27 patients (52.9%) were classified into the “Subjective symptoms” group. The “Subjective symptoms” group exhibited a significantly higher proportion of Grade 3–5 ICI-ILD cases than the “Routine examinations” group (76.2% vs. 23.8%, P = 0.010). At the last visit, before the suspected onset of ILD, 21 of the 27 patients (77.8%) had no symptoms or no change in the respiratory symptoms. Conclusion: Subjective symptoms triggered the suspicion of Grade 3–5 ICI-ILD. Enhanced monitoring and patient education could be essential for the early detection of ICI-ILD because ILD may develop rapidly. Our findings might help to manage ICI-ILD in clinical practice.

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Selection of anti-cytokine biologics by pretreatment levels of serum leucine-rich alpha-2 glycoprotein in patients with inflammatory bowel disease

Amano T., Yoshihara T., Shinzaki S., Sakakibara Y., Yamada T., Osugi N., Hiyama S., Murayama Y., Nagaike K., Ogiyama H., Yamaguchi T., Arimoto Y., Kobayashi I., Kawai S., Egawa S., Kizu T., Komori M., Tsujii Y., Asakura A., Tashiro T., Tani M., Otake-Kasamoto Y., Uema R., Kato M., Tsujii Y., Inoue T., Yamada T., Kitamura T., Yonezawa A., Iijima H., Hayashi Y., Takehara T.

Scientific Reports 14 （ 1 ） 29755 2024年12月

研究論文（学術雑誌）, 共著, 査読有り

Serum leucine-rich alpha-2 glycoprotein (LRG) can monitor disease activities during biologics treatment in patients with inflammatory bowel disease (IBD). It is unclear whether the pretreatment serum LRG level can predict clinical effectiveness including serum trough levels of ustekinumab in patients with IBD. This multicenter prospective cohort study included 184 patients (Crohn’s disease, 104; ulcerative colitis, 80) who received ustekinumab (n = 119) or anti-tumor necrosis factor (n = 65) between January 2019 and March 2023. Multivariate logistic regression analysis revealed serum LRG level at week 0 (0w-LRG, odds ratio 0.12, 95% confidence interval 0.02–0.68) as one of significant factors for clinical remission at week 8. We divided patients into the low- and the high-LRG groups by the median 0w-LRG (18.2 µg/mL) and compared the effectiveness. In patients who received ustekinumab, the proportion of clinical remission at week 8 was significantly different between in the low- (76.9%) and in the high-LRG group (59.3%, P = 0.038), and median serum trough level at week 8 was significantly different between in the low- (10.9 µg/mL, interquartile range 6.7–13.4) and the high-LRG group (5.3 µg/mL, interquartile range 2.4–8.3, P < 0.001). The 0w-LRG can predict the effectiveness including serum trough levels of ustekinumab during induction treatment for patients with IBD.

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Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis.

Sugimoto M, Yonezawa A, Kanda J, Itohara K, Hira D, Yamagiwa T, Taniguchi R, Hanyu Y, Watanabe M, Arai Y, Mizumoto C, Kitawaki T, Kondo T, Yamashita K, Takaori-Kondo A, Terada T

Therapeutic drug monitoring 46 （ 5 ） 611 - 618 2024年04月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 0163-4356

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.

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Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort

Kawakami, T; Masui, S; Onishi, A; Onizawa, H; Fujii, T; Murakami, K; Murata, K; Tanaka, M; Shimada, T; Nakagawa, S; Matsuda, S; Morinobu, A; Terada, T; Yonezawa, A

MODERN RHEUMATOLOGY 34 （ 6 ） 1135 - 1141 2024年03月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り, ISSN 1439-7595

Objectives: Biosimilars are anticipated to be widely used in the treatment of rheumatoid arthritis (RA), owing to their cost efficiency; LBEC0101 was the first etanercept (ETN) biosimilar approved in Japan. However, there are limited real-world data comparing its safety and effectiveness with those of a reference product. Methods: This study used data from the Kyoto University Rheumatoid Arthritis Management Alliance cohort, including patients with RA who received ETN therapy—ETN reference product (ETN-RP) or LBEC0101—between 2015 and 2021. Serum ETN levels were measured using liquid chromatography–tandem mass spectrometry. Results: The 1-year continuation rates of ETN-RP and LBEC0101 were 58.7% and 74.4%, respectively. Effectiveness of treatment was evaluated in 18 patients; both products significantly reduced the 28-joint RA disease activity score and erythrocyte sedimentation rate (DAS28-ESR). Moreover, to determine equivalence, we analysed 11 patients who switched from ETN-RP to LBEC0101; the DAS28-ESR and serum ETN levels before and after switching were not significantly different. Conclusions: This real-world cohort study confirmed that the biosimilar of ETN, LBEC0101, was comparable to the reference product in terms of continuation rate, effectiveness at initiation of introduction, and effect persistence before and after switching in clinical practice.

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Clinical characteristics of cryopyrin-associated periodic syndrome and long-term real-world efficacy and tolerability of canakinumab in Japan: results of a nationwide survey.

Miyamoto T, Izawa K, Masui S, Yamazaki A, Yamasaki Y, Matsubayashi T, Shiraki M, Ohnishi H, Yasumura J, Tomohiro K, Miyamae T, Matsubara T, Arakawa N, Ishige T, Takizawa T, Shimbo A, Shimizu M, Kimura N, Maeda Y, Maruyama Y, Shigemura T, Furuta J, Sato S, Tanaka H, Izumikawa M, Yamamura M, Hasegawa T, Kaneko H, Nakagishi Y, Nakano N, Iida Y, Nakamura T, Wakiguchi H, Hoshina T, Kawai T, Murakami K, Akizuki S, Morinobu A, Ohmura K, Eguchi K, Sonoda M, Ishimura M, Furuno K, Kashiwado M, Mori M, Kawahata K, Hayama K, Shimoyama K, Sasaki N, Ito T, Umebayashi H, Omori T, Nakamichi S, Dohmoto T, Hasegawa Y, Kawashima H, Watanabe S, Taguchi Y, Nakaseko H, Iwata N, Kohno H, Ando T, Ito Y, Kataoka Y, Saeki T, Kaneko U, Murase A, Hattori S, Nozawa T, Nishimura K, Nakano R, Watanabe M, Yashiro M, Nakamura T, Komai T, Kato K, Honda Y, Hiejima E, Yonezawa A, Bessho K, Okada S, Ohara O, Takita J, Yasumi T, Nishikomori R, Japan CAPS working group

Arthritis & rheumatology (Hoboken, N.J.) （Arthritis and Rheumatology） 76 （ 6 ） 949 - 962 2024年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

Objective: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Methods: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. Results: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)—unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti–tumor necrosis factor-α agents was effective for IBD– and CAPS-associated symptoms not resolved by canakinumab monotherapy. Conclusion: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti–IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment. (Figure presented.).

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Serum Leucine-rich Alpha-2 Glycoprotein Can be a Biomarker for Selecting Anti-Cytokine Biologics in Patients with Inflammatory Bowel Disease: A Multicentre Prospective Cohort Study

Amano, T; Yoshihara, T; Shinzaki, S; Sakakibara, Y; Yamada, T; Osugi, N; HIyama, S; Murayama, Y; Ogiyama, H; Nagaike, K; Tujii, Y; Asakura, A; Tashiro, T; Tani, M; Otake-Kasamoto, Y; Inoue, T; Yonezawa, A; Iijima, H; Hayashi, Y; Takehara, T

JOURNAL OF CROHNS & COLITIS 18 I1248 - I1248 2024年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1873-9946

Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series

Masuda T., Funakoshi T., Horimatsu T., Yamamoto S., Matsubara T., Masui S., Nakagawa S., Ikemi Y., Yanagita M., Muto M., Terada T., Yonezawa A.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 94 （ 4 ） 615 - 622 2024年

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り, ISSN 03445704

Purpose: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients. Methods: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry. Results: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase. Conclusion: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

A case report of a prolonged decrease in tacrolimus clearance due to co-administration of nirmatrelvir/ritonavir in a lung transplant recipient receiving itraconazole prophylaxis

Tsuzawa A., Katada Y., Umemura K., Sugimoto M., Nishikawa A., Sato Y.k., Yoshida Y., Kitada N., Yonezawa A., Nakajima D., Date H., Terada T.

Journal of Pharmaceutical Health Care and Sciences （Journal of Pharmaceutical Health Care and Sciences） 9 （ 1 ） 12 2023年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2055-0294

Background: Drug-drug interaction management is complex. Nirmatrelvir/ritonavir is a potent cytochrome P450 (CYP) 3A inhibitor and influences pharmacokinetics of co-administered drugs. Although there are several reports about drug-drug interactions of nirmatrelvir/ritonavir, an influence of a concomitant use of nirmatrelvir/ritonavir and another potent CYP3A inhibitor on tacrolimus remains unclear. Here, we experienced a lung transplant patient with the novel coronavirus disease 2019 (COVID-19). In this patient, nirmatrelvir/ritonavir was administered, and the inhibitory effect of itraconazole on CYP3A was prolonged. Case presentation: We present a case in forties who had undergone lung transplantation. He was administered itraconazole and tacrolimus 1.0 mg/d, with a trough value of 8–12 ng/mL. The patient contracted the COVID-19, and a nirmatrelvir/ritonavir treatment was initiated. During the antiviral treatment, tacrolimus administration was discontinued for 5 d. Tacrolimus was resumed at 1.0 mg/d after completion of the nirmatrelvir/ritonavir treatment, but the trough value after 7 d was high at 31.6 ng/mL. Subsequently, the patient was placed on another 36-h tacrolimus discontinuation, but the trough value decreased to only 16.0 ng/mL. Conclusions: Co-administration of ritonavir caused a prolonged decrease in tacrolimus clearance through its inhibitory effects on CYP3A in a patient taking itraconazole. Management of drug-drug interaction by pharmacists can be important for patients with multiple medications.

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Acute inhibition of AMPA receptors by perampanel reduces amyloid β-protein levels by suppressing β-cleavage of APP in Alzheimer's disease models

Ueda S., Kuzuya A., Kawata M., Okawa K., Honjo C., Wada T., Matsumoto M., Goto K., Miyamoto M., Yonezawa A., Tanabe Y., Ikeda A., Kinoshita A., Takahashi R.

FASEB Journal （FASEB Journal） 37 （ 11 ） e23252 2023年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 08926638

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aβ deposition in AD since enhanced neuronal activity promotes presynaptic Aβ production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aβ-evoked neuronal hyperexcitability, the acute effects of PER on Aβ metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aβ40 and Aβ42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aβ40/Aβ42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP βCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPβ levels, a direct byproduct of β-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aβ-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aβ clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aβ, indicating that the acute effect of PER is predominantly on Aβ production. In conclusion, acute treatment of PER reduces Aβ production by suppressing β-cleavage of amyloid-β precursor protein effectively, indicating a potential effect of PER against Aβ pathology in AD.

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Chapter 3: Management of kidney injury caused by cancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022

Ando, Y; Nishiyama, H; Shimodaira, H; Takano, N; Sakaida, E; Matsumoto, K; Nakanishi, K; Sakai, H; Tsukamoto, S; Komine, K; Yasuda, Y; Kato, T; Fujiwara, Y; Koyama, T; Kitamura, H; Kuwabara, T; Yonezawa, A; Okumura, Y; Yakushijin, K; Nozawa, K; Goto, H; Matsubara, T; Hoshino, J; Yanagita, M

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY （International Journal of Clinical Oncology） 28 （ 10 ） 1315 - 1332 2023年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-9625

Cisplatin should be administered with diuretics and Magnesium supplementation under adequate hydration to avoid renal impairment. Patients should be evaluated for eGFR (estimated glomerular filtration rate) during the treatment with pemetrexed, as kidney injury has been reported. Pemetrexed should be administered with caution in patients with a CCr (creatinine clearance) < 45 mL/min. Mesna is used to prevent hemorrhagic cystitis in patients receiving ifosfamide. Febuxostat is effective in avoiding hyperuricemia induced by TLS (tumor lysis syndrome). Preventative rasburicase is recommended in high-risk cases of TLS. Thrombotic microangiopathy could be triggered by anticancer drugs and there is no evidence of efficacy of plasma exchange therapy. When proteinuria occurs during treatment with anti-angiogenic agents or multi-kinase inhibitors, dose reductions or interruptions based on grading should be considered. Grade 3 proteinuria and renal dysfunction require urgent intervention, including drug interruption or withdrawal, and referral to a nephrologist should be considered. The first-line drugs used for blood pressure elevation due to anti-angiogenic agents are ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin receptor blockers). The protein binding of drugs and their pharmacokinetics are considerably altered in patients with hypoalbuminemia. The clearance of rituximab is increased in patients with proteinuria, and the correlation with urinary IgG suggests similar pharmacokinetic changes when using other antibody drugs. AIN (acute interstitial nephritis) is the most common cause of ICI (immune checkpoint inhibitor)-related kidney injury that is often treated with steroids. The need for renal biopsy in patients with kidney injury that occurs during treatment with ICI remains controversial.

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医薬品情報を利活用したがん薬物療法に対する薬学的介入

川上恵, 北田徳昭, 米澤淳, 岡村みや子, 尾崎淳子, 池見泰明, 中川俊作, 今井哲司, 中川貴之, 土井恵太郎, 秋月修治, 武藤学, 寺田智祐

医薬品情報学（一般社団法人　日本医薬品情報学会） 25 （ 2 ） 83 - 90 2023年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13451464

Abstract
Objective: In patients with specific backgrounds, comprehensive identification of health problems and proactive pharmacist intervention are crucial to providing safe and effective medical care. However, there are insufficient reports on chemotherapy regimen selection and supportive care management in patients taking immunosuppressants. In this study, to circumvent adverse events, pharmacists intervened with a patient administering tacrolimus (TAC) using known information, focusing on multiple factors attributable to the patient in addition to drug interactions.
Methods: The patient was a male in their 70s who received palliative chemotherapy for gastric cancer during their dermatomyositis treatment with TAC. Pharmaceutical support for cancer chemotherapy was provided using the following four procedures: (1) Patient information was collected from interviews and electronic medical records to identify patient-specific problems; (2) Basic pharmacological information was collected from tertiary sources, focusing on the interaction between TAC and aprepitant (APR). Furthermore, clinical reports were collected, and the pharmacokinetic drug interaction significance classification system was used for quantitative predictions; (3) The information obtained in steps 1) and 2) was evaluated, and comprehensive proposals linked to the patient information were presented; (4) Adverse events, TAC blood level, and patient outcomes were monitored after treatment initiation.
Results: A chemotherapy regimen consisting of S-1/oxaliplatin therapy without APR was selected. The adverse effects were controllable, and the treatment was completed without many adverse events. Meanwhile, TAC adherence was unaffected by cancer chemotherapy, and the TAC blood concentration or dose ratios were controlled within the same range as previously reported.
Conclusion: In cancer chemotherapy, for cases with limited evidence or information, comprehensive pharmaceutical support was provided using known patient information, considering multiple patient factors. This report is beneficial as an example of supportive care management by a pharmacist and contributes to providing optimal service in cases with specific backgrounds.

Serum Concentrations of Infliximab and IL-6 for Predicting One-Year Discontinuation of Infliximab Treatment Owing to Secondary Non-response in Patients with Rheumatoid Arthritis

Masui S., Yonezawa A., Nakamura M., Onishi A., Hashimoto M., Onizawa H., Fujii T., Murakami K., Murata K., Tanaka M., Yokoyama K., Iwamoto N., Shimada T., Itohara K., Hira D., Nakagawa S., Imai S., Nakagawa T., Hayakari M., Matsuda S., Morinobu A., Terada T., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 46 （ 8 ） 1112 - 1119 2023年08月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 09186158

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.

医薬品情報を利活用したがん薬物療法に対する薬学的介入　タクロリムスとアプレピタントの薬物相互作用に着目し薬学的支援を行った皮膚筋炎併発胃がんの1例

川上恵, 北田徳昭, 米澤淳, 岡村みや子, 尾崎淳子, 池見泰明, 中川俊作, 今井哲司, 中川貴之, 土井恵太郎, 秋月修治, 武藤学, 寺田智祐

医薬品情報学（(一社)日本医薬品情報学会） 25 （ 2 ） 83 - 90 2023年08月

筆頭著者, 最終著者, 責任著者, 査読有り, ISSN 1345-1464

医薬品情報を利活用した癌薬物療法に対する薬学的介入として、薬剤師がタクロリムスとアプレピタントの薬物相互作用に着目し薬学的支援を行った、皮膚筋炎併発胃癌患者の症例(70代男性)について報告した。薬剤師が収集した既知情報、文献的考察および定量評価結果を医師に示し、医師と治療レジメンおよび制吐療法を協議した。その結果、本患者が男性であること、および年齢が70代であり、催吐性リスクが必ずしも高くないことに鑑み、アプレピタントの使用は必須でないと判断された。これらの協議内容を踏まえ、総合的に判断した。その結果、制吐療法としてアプレピタントを使用せず、SOX療法を施行することが決定された。その結果、化学療法開始後の嘔気はコントロール可能な範囲であり、タクロリムスのアドヒアランスに影響はなかった。本症例のように、エビデンスや情報が少ないケースであっても、薬剤師が相互作用という単一的要因だけでなく、特定の背景を有する患者側に起因する複数の因子を同時に考慮し、情報収集、評価、提案およびモニタリングを行うことが、安全で適切な化学療法の提供つながることが示唆された。

Chapter 1: Evaluation of kidney function in patients undergoing anticancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022

Muto, S; Matsubara, T; Inoue, T; Kitamura, H; Yamamoto, K; Ishii, T; Yazawa, M; Yamamoto, R; Okada, N; Mori, K; Yamada, H; Kuwabara, T; Yonezawa, A; Fujimaru, T; Kawano, H; Yokoi, H; Doi, K; Hoshino, J; Yanagita, M

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY （International Journal of Clinical Oncology） 28 （ 10 ） 1259 - 1297 2023年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-9625

The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft–Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology’s GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy.

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Preparation and pharmaceutical properties of Hangeshashinto oral ointment and its safety and efficacy in Syrian hamsters with 5-fluorouracil-induced oral mucositis

Ogihara T., Kagawa M., Yamanaka R., Imai S., Itohara K., Hira D., Nakagawa S., Yonezawa A., Ito M., Nakagawa T., Terada T., Matsubara K.

Journal of Natural Medicines （Journal of Natural Medicines） 77 （ 1 ） 53 - 63 2023年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13403443

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. Graphical abstract: [Figure not available: see fulltext.]

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Effect of Severe Renal Dysfunction on the Plasma Levels of DNA-Reactive Platinum after Oxaliplatin Administration

Nakagawa S., Shimazaki A., Funakoshi T., Yonezawa A., Kataoka S., Horimatsu T., Hira D., Itohara K., Imai S., Nakagawa T., Matsubara T., Yanagita M., Muto M., Matsubara K., Terada T.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 46 （ 2 ） 194 - 200 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09186158

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.

Pharmacokinetics of GS-441524, the active metabolite of remdesivir, in patients receiving continuous renal replacement therapy: A case series

Nishikawa A., Ito I., Yonezawa A., Itohara K., Matsubara T., Sato Y., Matsumura K., Hamada S., Tanabe N., Kai S., Imoto E., Yoshikawa K., Ohtsuru S., Yanagita M., Hirai T., Terada T.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 30 （ 4 ） 348 - 351 2023年

研究論文（学術雑誌）, 責任著者, 査読有り, ISSN 1341321X

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.

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Removal rate of 5-fluorouracil and its metabolites in patients on hemodialysis: a report of two cases of colorectal cancer patients with end-stage renal failure

Imamaki H., Oura M., Oguro F., Nishikawa Y., Nakagawa S., Funakoshi T., Kataoka S., Horimatsu T., Yonezawa A., Matsubara T., Watanabe N., Muto M., Yanagita M., Ozaki Y.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 93 （ 2 ） 161 - 167 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03445704

Purpose: Hyperammonemia is a serious adverse effect of 5-fluorouracil (5FU) administration. Hemodialysis can be used for its management, but detailed data on the concentrations and removal rate of 5FU and its metabolites during hemodialysis remain unclear. Here, we present two cases of hemodialysis patients with end-stage renal disease who received concurrent 5FU infusion. Methods: Blood samples were collected from the hemodialysis circuit before and after the dialyzer during day 2 hemodialysis sessions, and from the internal shunt just before and after day 4 hemodialysis sessions. The serum levels of 5FU and its metabolites—α-fluoro-β-alanine (FBAL) and monofluoroacetate (FA)—were measured using liquid chromatography-tandem mass spectrometry. Results: Seven sets of blood samples were collected for case 1; the removal rates (mean ± standard deviation) of 5FU and FBAL by the dialyzer were 81.2 ± 23.2% and 96.1 ± 8.6%, respectively (p < 0.001). Three sets of blood samples were collected for case 2; the removal rates of 5FU and FBAL were 81.7 ± 3.9% and 94.8 ± 2.7%, respectively (p = 0.03). Twenty-seven sets of blood samples were collected for case 1; reductions in blood FBAL and FA levels were 49.3 ± 8.8% (p < 0.001) and 64.2 ± 30.3% (p = 0.04), respectively. Bayesian estimation yielded similar results. Three sets of blood samples were collected for case 2; reductions in the blood FBAL and FA levels were 49.9 ± 6.9% and 50.6 ± 33.0%, respectively. Conclusion: In this study, 5FU and its metabolite FBAL were directly removed from the blood by approximately 90% during hemodialysis, and the blood levels of FBAL and FA were reduced by approximately 50% with a single hemodialysis session.

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Comparison of cisplatin-based versus standard preoperative chemotherapy in patients with operable triple-negative breast cancer: propensity score matching and inverse probability of treatment weighting analysis

Yamaguchi A., Kawaguchi K., Kawanishi K., Maeshima Y., Nakakura A., Kataoka T.R., Takahara S., Nakagawa S., Yonezawa A., Takada M., Kawashima M., Kawaguchi-Sakita N., Kotake T., Suzuki E., Shimizu H., Torii M., Morita S., Ishiguro H., Toi M.

Breast Cancer Research and Treatment （Breast Cancer Research and Treatment） 204 （ 2 ） 261 - 275 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01676806

Purpose: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. Methods: This retrospective study consecutively included previously untreated patients with stage I–III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. Results: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). Conclusion: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment.

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