Details of a Researcher - Yonezawa, Atsushi

Papers - Yonezawa, Atsushi

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Association between time in therapeutic range of tacrolimus blood concentration and acute rejection within the first three months after lung transplantation.

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

Journal of pharmaceutical health care and sciences (Journal of Pharmaceutical Health Care and Sciences) 8 ( 1 ) 25 - 25 2022.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2055-0294

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.

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Use of proton pump inhibitors and macrolide antibiotics and risk of acute kidney injury: a self-controlled case series study.

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

BMC nephrology (BMC Nephrology) 23 ( 1 ) 383 - 383 2022.12

Research paper (scientific journal), Joint Work, Accepted

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.

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Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics

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

Clinical and Translational Science (Wiley) 15 ( 11 ) 2652 - 2662 2022.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 17528054

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.

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UNIVERSAL LCMS-BASED ASSAY PLATFORM, REFMAB-Q NSMOL, FOR MONITORING MONOCLONAL ANTIBODY THERAPEUTICS USING ONE REFERENCE ANTIBODY

Iwamoto, N; Koguchi, Y; Yokoyama, K; Hamada, A; Yonezawa, A; Piening, B; Tran, E; Fox, B; Redmond, W; Shimada, T

JOURNAL FOR IMMUNOTHERAPY OF CANCER 10 A9 - A9 2022.11

Research paper (scientific journal), Joint Work, Accepted

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N-terminus of Etanercept is Proteolytically Processed by Dipeptidyl Peptidase-4

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

Pharmaceutical Research (Springer Science and Business Media LLC) 39 ( 10 ) 2541 - 2554 2022.10

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 07248741

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.

Examination of the Bleeding Risk Involved in the Concomitant Use of Antidepressants and Direct Oral Anticoagulants

Kojima Yusuke, Katada Yoshiki, Nakagawa Shunsaku, Shigetsura Yuki, Endo Hiroki, Yamamoto Shota, Yonezawa Atsushi, Nakagawa Takayuki, Matsubara Kazuo, Sugita Naoko, Murai Toshiya, Terada Tomohiro

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 48 ( 9 ) 419 - 428 2022.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

Direct oral anticoagulants (DOACs) exert their anticoagulant effects by directly inhibiting thrombin and factor Xa; however, it is important to consider the interactions of DOACs with concomitant medications as some medication may increase the risk of bleeding. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) have been reported to reduce platelet aggregation and increase the risk of bleeding. However, there is little evidence regarding the interaction between DOACs and SSRIs or SNRIs in Japanese patients. Therefore, the aim of our study was to investigate the background of bleeding in Japanese patients using SSRIs or SNRIs in combination with DOACs. Seventeen patients who took DOACs in combination with SSRIs or SNRIs between January 2016 and December 2019 at Kyoto University Hospital were included in the study. The observation period was 6 months after commencing DOAC administration and 6 months after of the commencement of SSRI or SNRI administration; moreover, the pre- and post-treatment examinations were performed to assess the changes for each patient. There was no incidence of major bleeding when only DOAC was used, but four of the seventeen patients (23.5％) had major bleeding when antidepressants were administered in addition to DOACs. Known bleeding risk factors such as hypertension, liver dysfunction, smoking history, cancer, peptic ulcer, and thrombocytopenia were not identified as risk factors for major bleeding in this study.

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics

Iwamoto N., Koguchi Y., Yokoyama K., Hamada A., Yonezawa A., Piening B.D., Tran E., Fox B.A., Redmond W.L., Shimada T.

Analyst (Analyst) 147 ( 19 ) 4275 - 4284 2022.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 00032654

Accurate quantitation of antibodies is critical for development of monoclonal antibody therapeutics (mAbs). Therapeutic drug monitoring has been applied to measure levels of mAbs in clinics for dose adjustment for autoimmune disease. Trough levels of mAbs can be a biomarker for cancer immunotherapy. Thus, the deployment of a rapid and universal platform for mAb monitoring may benefit processes ranging from drug development to clinical practice for a wide spectrum of diseases. However, mAb monitoring often requires development and conduct of an individual ligand binding assay such as ELISA, which is impractical to scale. We streamlined quantitation of antibody therapeutics by a nano-surface and molecular-orientation limited (nSMOL) proteolysis assay using LC-MS with a universal reference antibody (refmAb-Q), for accurate multiplexed quantitation of unique signature peptides derived from mAbs. This innovative refmAb-Q nSMOL platform may provide a practical solution for quantitating an ever-increasing number of mAbs from developmental to clinical use settings.

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Improved absorption of itraconazole tablet by co-administration with lemon beverages in a lung transplant recipient: A case report.

Keisuke Umemura, Yoshiki Katada, Shunsaku Nakagawa, Mitsuhiro Sugimoto, Katsuyuki Matsumura, Atsushi Yonezawa, Miki Nagao, Akihiro Ohsumi, Hiroshi Date, Tomohiro Terada

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 8 ) 1203 - 1207 2022.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341321X

After lung transplantation, itraconazole (ITCZ) is used as a prophylaxis for aspergillosis. ITCZ is a weak base with high lipophilicity, and the dissolution and absorption of ITCZ tablets and capsules are pH dependent. Therefore, ITCZ may not achieve sufficient serum concentrations in patients with higher gastric pH because of its poor bioavailability. We report a case of a woman in fifties with post-COVID-19 respiratory failure who successfully underwent lung transplantation, followed by improved bioavailability of ITCZ tablets when given with acidic lemon beverages. The patient was initially administered ITCZ oral solution; this was discontinued because of its unpleasant taste, nausea, and vomiting. The ITCZ oral solution was replaced with ITCZ tablets 78 days after transplantation; however, serum concentrations of ITCZ and hydroxy-ITCZ were below the detection limit (100 ng/mL). We co-administered ITCZ tablets with commercially available lemon beverages. Subsequently, serum concentrations of ITCZ and hydroxy-ITCZ increased to 341 and 673 ng/mL, respectively, on the 125th day after transplantation. Infection with fungi, including Aspergillus spp., was not observed in this case. The patient had no adverse events such as gastric ulcer or hyperglycemia. These results suggest that the co-administration of lemon beverages and ITCZ tablets may help achieve better absorption of ITCZ in patients taking acid suppressants.

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Therapeutic Drug Monitoring of Antibody Drugs

Yonezawa Atsushi

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 45 ( 7 ) 843 - 846 2022.07

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 09186158

In recent years, many antibody drugs that play an important role in the pharmacotherapy of several diseases have been developed. Antibody drugs exhibit immunogenicity in vivo leading to the development of antibodies against the antibody drug (anti-drug antibody). Nonetheless, other factors also affect the pharmacokinetics of antibody drugs. Recently, therapeutic drug monitoring (TDM) of infliximab was introduced for personalized medicine. However, the usefulness of TDM in antibody therapy remains unclear. In addition to intervention studies, real-world data analysis is important. Unlike small-molecule drugs, antibody drugs do not have a uniform molecular weight; therefore, using the conventional analysis methods, it is impossible to determine the true pharmacokinetic outcomes of these agents. To analyze structural changes of antibody drugs in the body, new technologies are necessary. In the future, along with the development of new drugs, the establishment of novel analytical methods is essential to facilitate the promotion of personalized medicine.

Assessment of Suvorexant and Eszopiclone as Alternatives to Benzodiazepines for Treating Insomnia in Patients With Major Depressive Disorder

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

Clinical Neuropharmacology (Ovid Technologies (Wolters Kluwer Health)) 45 ( 3 ) 52 - 60 2022.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 03625664

OBJECTIVES: We investigated the utility of switching from benzodiazepines to suvorexant or eszopiclone to manage benzodiazepine-unresponsive insomnia in patients with major depressive disorder (MDD) in a randomized, open-label study. METHODS: Patients with MDD who have insomnia symptoms (a score of >7 on the Insomnia Severity Index Japanese version [ISI-J]), who had received benzodiazepine treatment for more than 2 weeks (n = 18) were randomized to 4 weeks of suvorexant (20 or 15 mg/d) or eszopiclone (3 or 2 mg/d) treatment. The primary endpoint was an improvement in insomnia severity from baseline assessed by the ISI-J score at 2 and 4 weeks after switching from benzodiazepines. The secondary endpoints included changes in the scores of the Pittsburgh Sleep Quality Index Japanese version, the Beck Depression Inventory II, Generalized Anxiety Disorder 7, the digit span test, and the digit symbol substitution test from baseline. Adverse events were recorded throughout the study. RESULTS: Patients taking suvorexant or eszopiclone had improved ISI-J scores (-4.3 for suvorexant and -4.1 for eszopiclone at week 4; P = 0.04 for eszopiclone). Both drugs tended to improve the Beck Depression Inventory II and Generalized Anxiety Disorder 7 scores 2 and 4 weeks after switching. The Pittsburgh Sleep Quality Index Japanese version, digit symbol substitution test, and digit span test scores and the incidence of adverse events did not change from baseline. CONCLUSIONS: Switching to suvorexant or eszopiclone was well tolerated and improved the severity of benzodiazepine-unresponsive insomnia in MDD patients. Both drugs could be beneficial alternatives to benzodiazepines for treating insomnia in MDD patients.

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Recent advances in riboflavin transporter RFVT and its genetic disease.

Congyun Jin, Atsushi Yonezawa

Pharmacology & therapeutics (Pharmacology and Therapeutics) 233 108023 - 108023 2022.05

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted, ISSN 01637258

Riboflavin (vitamin B2) is essential for cellular growth and function. It is enzymatically converted to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which participate in the metabolic oxidation-reduction reactions of carbohydrates, amino acids, and lipids. Human riboflavin transporters RFVT1, RFVT2, and RFVT3 have been identified and characterized since 2008. They are highly specific transporters of riboflavin. RFVT3 has functional characteristics different from those of RFVT1 and RFVT2. RFVT3 contributes to absorption in the small intestine, reabsorption in the kidney, and transport to the fetus in the placenta, while RFVT2 mediates the tissue distribution of riboflavin from the blood. Several mutations in the SLC52A2 gene encoding RFVT2 and the SLC52A3 gene encoding RFVT3 were found in patients with a rare neurological disorder known as Brown-Vialetto-Van Laere syndrome. These patients commonly present with bulbar palsy, hearing loss, muscle weakness, and respiratory symptoms in infancy or later in childhood. A decrease in plasma riboflavin levels has been observed in several cases. Recent studies on knockout mice and patient-derived cells have advanced the understanding of these mechanisms. Here, we summarize novel findings on RFVT1-3 and their genetic diseases and discuss their potential as therapeutic drugs.

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Effect of Itraconazole and Its Metabolite Hydroxyitraconazole on the Blood Concentrations of Cyclosporine and Tacrolimus in Lung Transplant Recipients.

Yuya Matsuda, Shunsaku Nakagawa, Ikuko Yano, Satohiro Masuda, Satoshi Imai, Atsushi Yonezawa, Takashi Yamamoto, Mitsuhiro Sugimoto, Masahiro Tsuda, Tetsunori Tsuzuki, Tomohiro Omura, Takayuki Nakagawa, Toyofumi Fengshi Chen-Yoshikawa, Miki Nagao, Hiroshi Date, Kazuo Matsubara

Biological & pharmaceutical bulletin (The Pharmaceutical Society of Japan) 45 ( 4 ) 397 - 402 2022.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 09186158

Invasive Aspergillus infection is a major factor for poor prognosis in patients receiving lung transplantation (LT). An antifungal agent, itraconazole (ITCZ), that has antimicrobial activity against Aspergillus species, is used as a prophylactic agent against Aspergillus infection after LT. ITCZ and its metabolite, hydroxyitraconazole (OH-ITCZ), potently inhibit CYP3A and P-glycoprotein that metabolize or excrete calcineurin inhibitors (CNIs), which are the first-line immunosuppressants used after LT; thus, concomitant use of ITCZ and CNIs could induce an increase in the blood concentration of CNIs. However, no criteria for dose reduction of CNIs upon concomitant use with ITCZ in LT recipients have been defined. In this study, the effect of ITCZ and OH-ITCZ on the blood concentrations of two CNIs, tacrolimus and cyclosporine, after LT were retrospectively evaluated. A total of 39 patients who received LT were evaluated. Effects of ITCZ and OH-ITCZ on the concentration/dosage (C/D) ratio of tacrolimus and cyclosporine were analyzed using linear mixed-effects models. The plasma concentrations of OH-ITCZ were about 2.5-fold higher than those of ITCZ. Moreover, there was a significant correlation between the plasma concentrations of ITCZ and OH-ITCZ. Based on parameters obtained in the linear regression analysis, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.25- and 2.70-fold, respectively, when the total plasma concentration of ITCZ plus OH-ITCZ is 1000 ng/mL. In conclusion, the plasma levels of ITCZ and OH-ITCZ could be key factors in drawing up the criterion for dose reduction of CNIs.

Plasma and Milk Concentrations of Active Metabolite of Ethyl Loflazepate in Two Lactating Mothers and Their Breastfed Infants

Morita Makiko, Yonezawa Atsushi, Omura Tomohiro, Nakagawa Shunsaku, Shida Ayumi, Imai Satoshi, Kawai Masahiko, Matsukura Takashi, Niwa Fusako, Iwanaga Kougorou, Io Shingo, Kondoh Eiji, Matsubara Kazuo

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 48 ( 4 ) 149 - 153 2022.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

Breastfeeding is important for the mental and physical health of mothers and newborn babies. The amount of ethyl loflazepate, an antidepressant drug, excreted into breast milk is not well clarified. Here, we measured the plasma and breastmilk levels of ethyl loflazepate in two lactating women on the third day after delivery and their breastfed infants on the fourth day after birth. The metabolite in plasma and breastmilk was measured by liquid chromatography/mass spectrometry. The metabolite concentrations in the respective milks of case 1 were 35.1 ng/mL (relative infant dose was 2.3％) and the metabolite concentrations of case 2 were 35.0 ng/mL (relative infant dose was 3.9％). The metabolite concentrations in mothers’ and infants’ plasma of case 1 were 128.9 ng/mL (mother), 67.5 ng/mL (infant). The metabolite concentrations in mothers’ and infants’ plasma of case 2 were 99.9 ng/mL (mother), 28.2 ng/mL (infant). Adverse drug symptoms, such as respiratory disorder and drowsiness, were observed in the case 1 infant from immediately after birth to day 2 and in the case 2 infant from immediately after birth until discharge on day 8. The present case report can contribute to the pharmacotherapy in pregnant and postpartum women with depression.

Infliximab Treatment Persistence among Japanese Patients with Chronic Inflammatory Diseases: A Retrospective Japanese Claims Data Study.

Sho Masui, Atsushi Yonezawa, Kenji Momo, Shunsaku Nakagawa, Kotaro Itohara, Satoshi Imai, Takayuki Nakagawa, Kazuo Matsubara

Biological & pharmaceutical bulletin (The Pharmaceutical Society of Japan) 45 ( 3 ) 323 - 332 2022.03

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 09186158

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.

抗真菌剤併用下で多剤併用がん化学療法による有害反応を回避できた肺移植後リンパ増殖性疾患の1例

梅山遥, 北田徳昭, 片田佳希, 杉本充弘, 櫻井香織, 野口葉子, 池見泰明, 中川俊作, 米澤淳, 中川貴之, 菱澤方勝, 高折晃史, 松原和夫

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 58 ( 3 ) 325 - 329 2022.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-8815

がん化学療法における薬物相互作用はときにがん化学療法の効果や副作用に影響をもたらすことがある。我々は移植後リンパ増殖性疾患患者に対し、シクロホスファミド、ピンクリスチン、プレドニゾロン併用療法(CVP療法)を施行するにあたり、抗がん薬、抗真菌薬および免疫抑制薬の相互作用による有害反応を回避するため、感染予防目的に投与したアゾール系抗真菌薬の変更および一時的休薬、免疫抑制薬の精密な投与設計を行うことで化学療法を完遂できた症例を経験した。これまでに免疫抑制薬、抗真菌薬を併用し、薬物相互作用を検討しつつ、がん化学療法を安全に施行した報告は少ない。今回の知見は、免疫抑制療法施行中という特殊条件下にある患者で、がん化学療法の副作用および合併症を制御しながら化学療法を施行するうえで有用と考えられる。(著者抄録)

Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients

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

Drug Metabolism and Pharmacokinetics (Elsevier BV) 42 100423 - 100423 2022.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

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.

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Risk factors of breakthrough aspergillosis in lung transplant recipients receiving itraconazole prophylaxis.

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

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 1 ) 54 - 60 2022.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341321X

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.

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Population pharmacokinetic modeling of GS-441524, the active metabolite of remdesivir, in Japanese COVID-19 patients with renal dysfunction.

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

CPT: pharmacometrics & systems pharmacology (CPT: Pharmacometrics and Systems Pharmacology) 11 ( 1 ) 94 - 103 2022.01

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 2163-8306

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.

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レテルモビルの中止によりボリコナゾールの血中濃度が著明に上昇した造血幹細胞移植後の1症例

石村裕樹, 片田佳希, 梅山遥, 杉本充弘, 北田徳昭, 米澤淳, 中川貴之, 新井康之, 高折晃史, 寺田智祐

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 58 ( 1 ) 35 - 39 2022.01

Joint Work, Accepted, ISSN 1341-8815

ボリコナゾール(voriconazole:以下、VRCZ)はチトクロームP450(cytochrome P450:以下、CYP)を介した併用薬剤との相互作用が多数報告されている。一方、併用薬中止後のVRCZ投与量や血中濃度の推移、および副作用を詳細に記述した報告は限られる。今回、CYP誘導作用を有するレテルモビル(letermovir:以下、LMV)中止後に、VRCZのトラフ値が著明に上昇した症例を経験した。40歳代の女性で、造血幹細胞移植後にLMVとVRCZの投与を開始した。VRCZのトラフ値は1.1～1.9μg/mLで推移していたが、LMV中止7日後に視覚障害、29日後に肝障害を認め、33日後にトラフ値が9.0μg/mLに上昇していた。LMV中止後は、酵素誘導解除に伴うCYP発現量の減少により、VRCZ血中濃度が上昇する可能性が高いため、きめ細やかなモニタリングが必要と考えられる。(著者抄録)

A Nationwide Questionnaire Survey on Awake Craniotomy in Japan.

Masayoshi Kawata, Ayaka Fukui, Yohei Mineharu, Takayuki Kikuchi, Yukihiro Yamao, Etsuko Yamamoto Hattori, Atsuko Shiraki, Toshiyuki Mizota, Keiko Furukawa, Susumu Miyamoto, Atsushi Yonezawa, Yoshiki Arakawa

Neurologia medico-chirurgica (The Japan Neurosurgical Society) 62 ( 6 ) 278 - 285 2022

Research paper (scientific journal), Joint Work, Accepted, ISSN 04708105

The number of awake craniotomies is increasing because of its beneficial features. However, not enough information is available regarding the current status of awake craniotomy in Japan. To evaluate the current status of awake craniotomy in institutes, a nationwide questionnaire survey was conducted. From June to August 2019, we conducted a questionnaire survey on awake craniotomy in the neurosurgery department of 45 institutes that perform awake craniotomies in Japan. Responses were obtained from 39 institutes (response rate, 86.7%). The main methods of awake craniotomy were almost the same in all institutes. Twenty-six institutes (66.7%) had fewer than 10 awake craniotomies (low-volume institutes) per year, and 13 high-volume institutes (33.3%) performed more than 10 awake craniotomies annually. Some institutes experienced a relatively high frequency of adverse events. In 11 institutes (28.2%), the frequency of intraoperative seizures was more than 10%. An intraoperative seizure frequency of 1%-9%, 10%-29%, and over 30% was identified in 12 (92%), 0 (0%), and 1 (8%) of the high-volume institutes, which was significantly less than in 16 (62%), 10 (38%), and 0 (0%) of the low-volume institutes (p = 0.0059). The routine usage of preoperative antiepileptic drugs was not different between them, but the old type was used more often in the low-volume institutes (p = 0.0022). Taken together, the annual number of awake craniotomies was less than 10 in over two-thirds of the institutes. Fewer intraoperative seizures were reported in the high-volume institutes, which tend not to preoperatively use the old type of antiepileptic drugs.

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