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Papers - Enoki, Yuki

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Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination.

Moriyama M, Liu X, Enoki Y, Matsumoto K, Tanabe Y

Pharmaceuticals (Basel, Switzerland) (Pharmaceuticals) 14 ( 9 ) 938 - 938 2021.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 1424-8247

Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)-and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (> 98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)-and (S)-plymuthipyranones B and three (R)-and (S)-synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyra-none B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class.

Different intra-cerebrospinal distribution of linezolid in patients with inflammatory meningitis.

Ichinose N, Yoshikawa G, Fukao E, Ichisawa M, Takahata T, Enoki Y, Taguchi K, Oda T, Tsutsumi K, Matsumoto K

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (International Journal of Infectious Diseases) 110 382 - 384 2021.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1201-9712

Linezolid has excellent antibiotic activity against gram-positive organisms and is expected to be an alternative to vancomycin for the treatment of bacterial meningitis. Accumulated evidence has shown the superior pharmacokinetic characteristics of linezolid to vancomycin, such as cerebrospinal fluid penetration. However, in the treatment of meningitis, pharmacokinetic information regarding the intra-cerebrospinal distribution of linezolid and the effects of drainage on the linezolid concentration in the cerebrospinal fluid are unclear. This report describes two patient cases, in which the linezolid concentrations in the cerebrospinal fluid were in the following order: subarachnoid space (cisternal drainage and lumbar puncture) ≥ third ventricle > lateral ventricle. In addition, the linezolid concentration in the cerebrospinal fluid, collected via lumbar puncture, tended to increase after removal of the drainage. This report is novel in presenting two cases of meningitis that showed different intra-cerebrospinal distribution of linezolid in various parts of the central nervous system and an increased linezolid concentration in the cerebrospinal fluid after removal of the drainage.

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Augmented clearance of nivolumab is associated with renal functions in chronic renal disease model rats.

Taguchi K, Hayashi Y, Ohuchi M, Yamada H, Yagishita S, Enoki Y, Matsumoto K, Hamada A

Drug metabolism and disposition: the biological fate of chemicals (Drug metabolism and disposition: the biological fate of chemicals) 50 ( 6 ) 822 - 826 2021.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0090-9556

The clinically approved dose of nivolumab is 240 mg Q2W. However, previous studies have shown that baseline nivolumab clearance (CL) is associated with treatment outcomes in patients with solid cancers, thus motivating researchers to identify prognostic factors and indices influencing nivolumab CL. This study used chronic kidney disease model rats to investigate whether chronic renal impairment affected nivolumab CL and explored the surrogate markers associated with nivolumab CL. We observed that the total CL for nivolumab (CLtot) was approximately 1.42-times higher in chronic kidney disease model rats than that in sham rats with an increased urinary excretion. Additionally, CLtot showed positive correlation with renal CL for nivolumab (CLR), but not with extrarenal CL. Furthermore, the baseline levels of creatinine, blood urea nitrogen, creatinine CL, and urinary albumin/creatine ratio based on laboratory data were also significantly correlated with CLR Our findings suggest that nivolumab CL increases as renal function deteriorates due to an increased excretion of nivolumab in the urine; additionally, laboratory data reflecting renal function may be a feasible index to qualitatively estimate nivolumab CL prior to nivolumab treatment under conditions of renal impairment. Significance Statement We demonstrated that nivolumab was rapidly eliminated from the circulation in chronic kidney disease model rats compared to sham rats with an increased urinary nivolumab excretion. Moreover, nivolumab clearance was significantly correlated with the baseline levels of certain laboratory parameters reflecting renal functions. These results indicate the potential applicability of baseline renal function as a prognostic index to qualitatively estimate nivolumab clearance prior to nivolumab treatment under conditions with renal impairment.

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Species Distribution of Candidemia and Their Susceptibility in a Single Japanese University Hospital: Prior Micafungin Use Affects the Appearance of Candida parapsilosis and Elevation of Micafungin MICs in Non-parapsilosis Candida Species.

Sakamoto Y, Kawabe K, Suzuki T, Sano K, Ide K, Nishigaki T, Enoki Y, Taguchi K, Koike H, Kato H, Sahashi Y, Matsumoto K

Journal of fungi (Basel, Switzerland) (Journal of Fungi) 7 ( 8 ) 596 2021.07

Research paper (scientific journal), Joint Work, Accepted

Introduction: Micafungin is a recommended echinocandin antifungal agent for can-didemia treatment and prophylaxis. However, overuse of echinocandin antifungals may cause re-sistance. There is currently no information available regarding the low susceptibility associated with using micafungin. This study investigated the effect of micafungin use on changes in the detected Candida species and low susceptibility. Methods: We conducted a retrospective survey and included records of Candida spp. detected in blood cultures from January 2010 to December 2018 in our hospital. Survey items included clinical outcomes at 30 days after positive cultures, patient char-acteristics, and drug prescription status. Patient background information included gender, previous hospitalization, stay in the intensive care unit, comorbidities, and history of surgery (within 90 days before candidemia onset) and drug exposure. Species detected and their minimum inhibitory concentrations (MICs) and amount of antifungal prescriptions by department were investigated. Risk factors for detecting C. parapsilosis and for low susceptibility to micafungin were evaluated using multivariate analysis. Results: A total of 153 Candida clinical blood isolates were collected and C. albicans was the most prevalent species, followed by C. parapsilosis and C. glabrata. In the analysis by department, antifungal use and non‐albicans Candida species were most frequently detected in the hematology department. Multivariate analysis showed that prior micafungin use increased the risk of C. parapsilosis (odds ratio (OR) 4.22; 95% confidence interval (CI) 1.39–12.79; p = 0.011). MIC90 of micafungin on C. glabrata and C. parapsilosis was 1.0 μg/mL. Prior micafungin use was clarified as a risk factor resulting in MIC > 0.06 μg/mL for micafungin in non‐parapsilosis Candida species (OR 13.2; 95% CI 3.23–54.2; p < 0.01). Conclusion: Prior micafungin use increased the risk of C. parapsilosis and the MIC > 0.06 μg/mL of micafungin in non‐parapsilosis Candida species. Since there are only a few antifungal options, further antifungal stewardship considering azole antifungal agents use is re-quired.

Liposome-encapsulated methemoglobin as an antidote against cyanide poisoning.

Suzuki Y, Taguchi K, Kure T, Sakai H, Enoki Y, Otagiri M, Matsumoto K

Journal of controlled release : official journal of the Controlled Release Society (Journal of Controlled Release) 337 59 - 70 2021.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 0168-3659

Cyanide induces acute lethal poisoning resulting from inhibition of cytochrome c oxidase located in the complex IV (Complex IV) of mitochondria. However, current therapies for cyanide poisoning using hydroxocobalamin and nitrous acid compounds remain a clinical issue. Here, we show that liposome-encapsulated methemoglobin (metHb@Lipo), nanosized biomimetic red blood cells, replicate the antidotal mechanism of nitrous acid compounds against cyanide poisoning, achieving superior efficacy and fast action with no adverse effects. The structure of metHb@Lipo, which consists of concentrated methemoglobin in its aqueous core and a lipid membrane resembling the red blood cell membrane, provides favorable characteristics as a cyanide antidote, such as binding properties and membrane permeability. Upon cyanide exposure, metHb@Lipo maintained the mitochondrial function in PC12 cells, resulting in a cell viability comparable to treatment with nitrous acid compounds. In a mouse model of cyanide poisoning, metHb@Lipo treatment dramatically improved mortality with a rapid recovery from the symptoms of cyanide poisoning compared to treatment with nitrous acid compounds. Furthermore, metHb@Lipo also possesses satisfactory pharmacokinetic properties without long-term bioaccumulation and toxicity. Our findings showed a novel concept to develop drugs for cyanide poisoning and provide a promising possibility for biomimetic red blood cell preparations for pharmaceutical applications.

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セルフメディケーション税制に対する新人薬局薬剤師の認知・見解実態把握調査

田口和明, 榎木裕紀, 有賀聡美, 榊原幹夫, 堀里子, 山浦克典, 松元一明

医療薬学 ((一社)日本医療薬学会) 47 ( 7 ) 358 - 363 2021.07

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

ドラッグストアまたはドラッグストア併設の保険薬局に勤務し、在学中にセルフメディケーション税制(以下、本税制)が施行されていた薬剤師を対象に、本税制に関する認知・見解実態把握調査(アンケート)を実施した。調査対象者は、男性138名(44.5%)、女性172名(55.5%)の合計310名であった。本税制の認知度と理解度について調査したところ、284名(91.6%)の調査対象者が「よく知っている(説明できる)」または「聞いたことはあるが、内容はよく知らない」と回答し、理解度に差はあるものの、ほとんどの調査対象者が本税制について見聞があった。これらの調査対象者は、主に「テレビ」、「雑誌本」、「インターネット」などのメディアを通して本税制に関する情報を得ていた。また、教育現場や職場で本税制について知った調査対象者も多かった。調査対象者の97名(31.3%)が本税制に関する講義を受講したと回答した。本税制の認知度を集計した結果、大学で本税制の講義を受けたことのあると回答した調査対象者において、「よく知っている(説明できる)」と回答した割合が顕著に高かった。今後、薬剤師として働くうえで、多くの調査対象者(86.4%)が本税制の知識が必要だと感じており、半数の調査対象者が本税制に関する情報を収集するうえで携帯アプリを活用したいと回答した。

【難しい数式も、TDMもわからない!「ニガテさん」のための薬物動態】(第4章)患者背景によるADMEの変化に注目できる! 高齢者の薬物動態

榎木裕紀, 松元一明

調剤と情報 ((株)じほう) 27 ( 10 ) 1754 - 1761 2021.07

ISSN 1341-5212

Retrospective study of the efficacy and safety of metronidazole and vancomycin for Clostridioides difficile infection.

Misawa K, Iketani O, Enoki Y, Taguchi K, Uno S, Uwamino Y, Hasegawa N, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 27 ( 10 ) 1407 - 1412 2021.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-321X

Introduction: According to the Japanese guidelines for the management of Clostridioides difficile infection (CDI), the first choice is metronidazole (MNZ) for non-severe cases and vancomycin (VCM) for severe cases. However, the appropriateness of this first choice in Japanese patients is unclear. We therefore evaluated the appropriateness of the CDI management guidelines and the incidence of adverse drug reactions. Methods: The electronic chart data at Keio University Hospital between January 2012 and June 2019 were retrospectively reviewed. The response rate, the relapse rate, and the adverse reaction rate of treatment for CDI using MNZ or VCM were investigated according to the disease severity. Factorial analysis associated with the response, relapse, and adverse reaction was also performed. Results: In the 352 patients surveyed, no significant difference was observed in the response rate between MNZ and VCM regardless of the severity of CDI. The presence of cancer was a factor related to the persistence of diarrheal symptoms and older age was a risk factor for relapse. MNZ induced nausea significantly more frequently than VCM, and young age and female sex were risk factors for nausea. Conclusion: As no significant difference was observed in the response rate of CDI between MNZ and VCM, the Japanese CDI management guidelines, which recommend MNZ as the first choice, were demonstrated to be appropriate. Attention to nausea was also suggested to be necessary when administering MNZ to young females.

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Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease.

Samura M, Takada K, Yamamoto R, Ito H, Nagumo F, Uchida M, Kurata T, Koshioka S, Enoki Y, Taguchi K, Higashita R, Kunika N, Tanikawa K, Matsumoto K

Pharmaceutical research (Pharmaceutical Research) 38 ( 6 ) 1041 - 1055 2021.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0724-8741

Purpose: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. Methods: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration–time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. Results: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05–0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20–60 mL/min and aged 65–95 years were calculated as 200–500 mg q24h. Conclusion: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

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Surveying health seminar participants on the self-medication tax deduction system and extracting challenges associated with tax reform

Kazuaki Taguchi, Yuki Enoki, Satomi Aruga, Mikio Sakakibara, Satoko Hori, Katsunori Yamaura, Kazuaki Matsumoto

Japanese Journal of Pharmaceutical Health Care and Sciences (Japanese Scoiety of Pharmaceutical Health Care and Science) 47 ( 5 ) 256 - 263 2021.05

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

健康セミナー参加者247名を対象に、セルフメディケーション税制に対する認知、理解度や関心などの実情に関するアンケートを実施し、本税制を取り巻く国民の実状と本税制の課題を明らかにすることを目的とした。調査の結果、過半数の調査対象者がドラッグストアを1ヵ月間に複数回利用しており、ドラッグストアを頻繁に利用している現状が示された。しかし、1年間のOTC医薬品の合計購入額が1万2千円以上10万円未満の調査対象者は11.8%(29人)と少なく、1年間のOTC医薬品の合計購入額が10万円以上の調査対象者はいなかった。セルフメディケーション税制の認知度について調査したところ、理解度に差はあるものの60%以上の調査対象者が本税制を認知していた。さらに、OTC医薬品の年間合計購入金額別に認知度を集計した。その結果、合計購入金額が1万2千円未満の調査対象者と合計購入金額が1万2千円以上の調査対象者で認知度は変わらなかったものの、合計購入金額が1万2千円以上の調査対象者のほうがセルフメディケーション税制について「知っている」と回答した割合が多かった。しかし、認知度に比べて申告件数は著しく少なかった。セルフメディケーション税制については、約50%(43人)が興味を示すとともに申告要件が揃っていれば控除を受けたいと回答した。

The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.

Tsutsuura M, Moriyama H, Kojima N, Mizukami Y, Tashiro S, Osa S, Enoki Y, Taguchi K, Oda K, Fujii S, Takahashi Y, Hamada Y, Kimura T, Takesue Y, Matsumoto K

BMC infectious diseases (BMC Infectious Diseases) 21 ( 1 ) 153 2021.02

Research paper (scientific journal), Joint Work, Accepted

Background: This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety. Methods: We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). Results: Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47–0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15–20 μg/mL (OR 2.39, 95% CI 1.78–3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18–0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13–3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28–1.01); however, it was not significant in the analysis of mortality. Conclusions: We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.

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The optimal trough-guided monitoring of vancomycin in children: Systematic review and meta-analyses.

Moriyama H, Tsutsuura M, Kojima N, Mizukami Y, Tashiro S, Osa S, Enoki Y, Taguchi K, Oda K, Fujii S, Takahashi Y, Hamada Y, Kimura T, Takesue Y, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 27 ( 5 ) 781 - 785 2021.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-321X

We carried out a systematic review and meta-analysis exploring the relationship between vancomycin (VCM) trough concentrations and its effectiveness and nephrotoxicity in pediatric patients. We conducted our analysis using MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials as electronic databases (June 29, 2019). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 16 studies that were eligible for the meta-analysis. A total of 351 and 3,266 patients were included in the analysis for effectiveness and nephrotoxicity, respectively. Pediatric MRSA infection patients with VCM trough concentrations ≥ 10 μg/mL had significantly lower treatment failure rates (OR 0.54, 95% CI 0.30–0.96). The incidence of nephrotoxicity was significantly higher in trough concentrations ≥ 15 μg/mL than when they were < 15 μg/mL (OR 3.02, 95% CI 2.08–4.38). We identified the optimal VCM trough concentrations associated with effectiveness and nephrotoxicity in pediatric patients with MRSA infection. Further prospective studies are needed to find optimal dosing and monitoring strategy on VCM in pediatric population.

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Pharmacokinetics/Pharmacodynamics Evaluation of Flomoxef against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli In Vitro and In Vivo in a Murine Thigh Infection Model.

Tashiro S, Hayashi M, Takemura W, Igarashi Y, Liu X, Mizukami Y, Kojima N, Enoki Y, Taguchi K, Yokoyama Y, Nakamura T, Matsumoto K

Pharmaceutical research (Pharmaceutical Research) 38 ( 1 ) 27 - 35 2021.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0724-8741

Purpose: Although flomoxef (FMOX) has attracted substantial attention as an antibiotic against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of FMOX against ESBL-producing E. coli is unclear. The aim of this study was to determine the PK/PD index of FMOX against ESBL-producing E. coli. Methods: In vitro time-kill curve studies and in vivo PK/PD experiments were carried out. Results: Time–kill curves exhibited a unique bactericidal activity: time-dependent activity at low concentrations and concentration-dependent activity at high concentrations. In neutropenic murine thigh infection experiments, the antibacterial activity of FMOX correlated with the time that the free drug concentration remaining above the minimum inhibitory concentration (MIC) (fT>MIC) and the ratio of the area under the free drug concentration–time curve for a 24 h period to the MIC (fAUC /MIC). However, the burden of ESBL producing E. coli significantly reduced when the time intervals for administration were shorter among three dosage regimens with same magnitude of fAUC /MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log kill reduction was 35.1%. Conclusions: fT>MIC is the most significant PK/PD index of FMOX against ESBL-producing E. coli and its target value is ≥ 40%. 24 24 10

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Dosing Optimization of Ampicillin-Sulbactam Based on Cystatin C in Elderly Patients with Pneumonia.

Matsubara K, Matsumoto K, Yokoyama Y, Watanabe E, Enoki Y, Shigemi A, Ikawa K, Terazono H, Morikawa N, Ohshige T, Takeda Y

Biological & pharmaceutical bulletin (Biological and Pharmaceutical Bulletin) 44 ( 5 ) 732 - 736 2021

Research paper (scientific journal), Joint Work, Accepted, ISSN 0918-6158

Ampicillin-sulbactam is a first-line therapy for pneumonia and is mainly excreted by the kidney. It is important to optimize the dose and dosing interval of ampicillin-sulbactam because in patients with decreased renal function and low skeletal muscle mass, such as the elderly, excess drug may burden renal function. In this study, we evaluated indices of renal function and optimized the dose and dosing interval of ampicillin-sulbactam based on pharmacokinetics (PK) and pharmacodynamics theory in elderly patients. The serum concentrations of ampicillin and sulbactam were measured by HPLC, and PK parameters were calculated. Correlations between the clearance of ampicillin or sulbactam and renal function were evaluated, and dosing optimization was calculated based on PK parameters. The PK parameters of ampicillin were CL=6.5±4.0L/h, Vd=19.3±0.2L, Ke=0.4±0.2, and t1/2=2.7±1.6h. The most correlated renal function index was estimated glomerular filtration rate (eGFRcys-c) calculated by serum cystatin-c (r=0.7374, correlation formula; CL of ampicillin=0.1937×eGFRcys-c-0.6726). Based on this formula, we calculated the clearance of ampicillin and developed dosing regimens for the elderly. Serum cystatin-c concentration is an ideal index to optimize ampicillin-sulbactam antimicrobial therapy in elderly patients with pneumonia.

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Rational dosage regimens for cephalothin and cefazolin using pharmacokinetics and pharmacodynamics analysis in healthy horses.

Kuroda T, Minamijima Y, Niwa H, Tamura N, Mita H, Fukuda K, Kaimachi M, Suzuki Y, Enoki Y, Taguchi K, Matsumoto K, Toutain PL, Bousquet-Melou A, Kasashima Y

Equine veterinary journal (Equine Veterinary Journal) 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0425-1644

Background: First-generation cephalosporins have good activity against gram-positive bacteria and are extensively used in horses. There are few reports of pharmacokinetics and pharmacodynamics (PK/PD) analysis of cephalosporins in horses. Objective: To optimise the dosages of the two first-generation cephalosporins cephalothin (CET) and cefazolin (CEZ) in horses using PK/PD concepts. Study design: Experimental study with single administration. Methods: Drug plasma concentrations following a single intravenous (i.v.) administration of 22 mg/kg bodyweight (bwt) CET in 12 horses and of 10 mg/kg bwt CEZ in six horses were measured using LC-MS/MS. Data were modelled using a nonlinear mixed effect modelling followed by Monte Carlo simulations. Minimum inhibitory concentrations (MICs) against Streptococcus zooepidemicus and Staphylococcus aureus isolated from horses were determined by the microbroth dilution method. Results: The percentages of CET and CEZ binding to serum proteins were 19.9% ± 8.4% and 15.2% ± 8.5% respectively. For both CET and CEZ, the MIC against S. zooepidemicus was 0.12 mg/L and against S. aureus was 0.5 mg/L. For CET, to achieve a probability of target attainment (PTA) of 90% for a PK/PD target of a free serum plasma concentration exceeding the MIC for 40% of the dosing interval, an empirical CET dosage regimen of 22 mg/kg bwt q8h and 22 mg/kg bwt q4h i.v. administration were required for S. zooepidemicus and S. aureus respectively. For CEZ, the corresponding dosage regimens were 10 mg/kg bwt q12h and 10 mg/kg bwt q8h. Main limitations: Small sample size only in healthy horses. Conclusions: For CET, more frequent administration than that currently recommended (22 mg/kg bwt q6–12h) is required to empirically control S. aureus infection in horses. For CEZ, less frequent administration compared to the dosage regimen currently proposed (10–22 mg/kg bwt q6h) could control S. zooepidemicus and S. aureus infections in horses. 90 90

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Use of an alternative signature peptide during development of a LC-MS/MS assay of plasma nivolumab levels applicable for multiple species.

Ohuchi M, Yagishita S, Taguchi K, Goto Y, Fukahori M, Enoki Y, Shimada T, Yamaguchi M, Matsumoto K, Hamada A

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences (Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences) 1162 122489 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1570-0232

Recently, immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1) antibodies, have dramatically changed treatment strategies for several cancers. In pharmacokinetic/pharmacodynamic studies, experiments using a variety of animal species are assumed. We have identified optimal multiple reaction monitoring transitions for signature candidate peptides of nivolumab in human, mouse, and rat plasma and developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify nivolumab (an anti-PD-1 antibody) using trastuzumab as the internal standard. Calibration curves were linear in the range of 1–200 µg/mL. The intra- and inter-day precision and accuracy in human plasma fulfilled Food and Drug Administration guideline criteria for bioanalytical validation. There was no need to change the measurement method in mouse plasma. On the other hand, in rat plasma, an interference peak was observed at a retention time similar to that of the surrogate peptide ASGITFSNSGMHWVR (550.75 > 661.50) employed in human and mouse plasma. Therefore, we confirmed that ASQSVSSYLAWYQQKPGQAPR (785.0 > 940.2) can be used as an alternate nivolumab surrogate peptide in rat plasma at the same concentration range as used in human and mouse plasma. Using our method, the concentration range and a gradual increase in trough value were confirmed in clinical samples from two antibody-treated patients, including one with gastric cancer and one with non-small-cell lung cancer. The time course and blood concentration transition also were evaluated in nivolumab administration experiments in mouse and rat. The present study showed that the selection of the optimal peptide is essential for accurate LC-MS/MS measurement of nivolumab concentration in human, mouse, and rat plasma. The method developed here is expected to be of use in non-clinical and clinical pharmacokinetic studies.

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Remdesivir for the treatment of coronavirus COVID-19: A meta-analysis of randomised controlled trials.

Enoki Y, Igarashi Y, Watabe Y, Honma K, Suzuki Y, Hayashi Y, Hiraoka K, Taguchi K, Matsumoto K

Journal of global antimicrobial resistance (Journal of Global Antimicrobial Resistance) 24 81 - 82 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2213-7165

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Pharmacokinetic/pharmacodynamic evaluation of teicoplanin against Staphylococcus aureus in murine thigh infection model.

Watanabe E, Matsumoto K, Ikawa K, Yokoyama Y, Shigemi A, Enoki Y, Umezaki Y, Nakamura K, Ueno K, Terazono H, Morikawa N, Takeda Y

Journal of global antimicrobial resistance (Journal of Global Antimicrobial Resistance) 24 83 - 87 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2213-7165

Objectives: Pharmacokinetic/pharmacodynamic (PK/PD) analysis using murine infection models is a well-established methodology for optimising antimicrobial therapy. Therefore, we investigated the PK/PD indices of teicoplanin againstStaphylococcus aureus using a murine thigh infection model. Methods: Mice were rendered neutropenic by administration of a two-step dosing of cyclophosphamide. Then, isolates of methicillin-susceptibleS. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) were inoculated into the thighs of neutropenic mice. PK/PD analyses were performed by non-linear least-squared regression using the MULTI program. Results: Target values offC /MIC (r = 0.94) of teicoplanin for static effect and 1 log kill against MSSA were 4.44 and 15.44, respectively. Target values of fAUC /MIC (r = 0.92) of teicoplanin for static effect and 1 log kill against MSSA were 30.4 and 70.56, respectively. Target values of fC /MIC (r = 0.91) of teicoplanin for static effect and 1 log kill against MRSA were 8.92 and 14.16, respectively. Target values of fAUC /MIC (r = 0.92) of teicoplanin for static effect and 1 log kill against MRSA were 54.8 and 76.4, respectively. Conclusion: These results suggest thatfC /MIC and fAUC /MIC are useful PK/PD indices of teicoplanin against MSSA and MRSA. max 10 24 10 max 10 24 10 max 24 2 2 2 2

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Stability of antimicrobial agents in an elastomeric infusion pump used for outpatient parenteral antimicrobial therapy.

Akahane M, Enoki Y, Saiki R, Hayashi Y, Hiraoka K, Honma K, Itagaki M, Gotoda M, Shinoda K, Hanyu S, Hamamura Y, Miyajima T, Ito C, Taguchi K, Uno S, Uwamino Y, Iketani O, Hasegawa N, Matsumoto K

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (International Journal of Infectious Diseases) 103 464 - 468 2020.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1201-9712

Objectives: The long-term stability of antimicrobials dissolved in infusion solution is necessary to establish and spread the outpatient parenteral antimicrobial therapy (OPAT). In this study, we evaluated the stability of antimicrobial agents dissolved in infusion solutions. Methods: The antimicrobial agents were dissolved in infusion solutions and kept at 25 °C and 31.1 °C for 24 h or 4 °C for 10 days in a polypropylene tube or an elastomeric infusion pump. The stability was measured by high-performance liquid chromatography. Results and conclusion: The residual ratio of cefazolin (CEZ), cefmetazole (CMZ), piperacillin (PIPC), and tazobactam (TAZ) at 31.1 °C for 24 h was as follows: 95.7 ± 3.0%, 94.8 ± 0.9%, 102.6 ± 1.8%, and 103.9 ± 3.6% in saline, respectively; 94.7 ± 3.0%, 94.3 ± 1.5%, 106.1 ± 3.0%, and 107.3 ± 2.4% in 5% dextrose solution, respectively. The residual ratio of these antimicrobials at 4 °C for 10 days was maintained above 90% in both saline and 5% dextrose solution. The residual ratio of all the above antimicrobials in an elastomeric infusion pump at 31.1 °C for 24 h was equivalent to that in the polypropylene tube. On the other hand, doripenem and meropenem were not stable in any infusion solution at 31.1 °C. CEZ, CMZ, and PIPC/TAZ dissolved in saline or 5% dextrose solution can be used in OPAT with continuous infusion pumps.

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Multivalent cation and polycation polymer preparations influence pharmacokinetics of dolutegravir via chelation-type drug interactions.

Enoki Y, Kishi N, Sakamoto K, Uchiyama E, Hayashi Y, Suzuki N, Ito M, Taguchi K, Yokoyama Y, Kizu J, Matsumoto K

Drug metabolism and pharmacokinetics (Drug Metabolism and Pharmacokinetics) 37 100371 2020.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1347-4367

Dolutegravir (DTG) is an integrase inhibitor, whose gastrointestinal absorption is impaired by the formation of chelates with multivalent metal cation preparations. However, little is known regarding the interactions of DTG with preparations containing other multivalent metal cations or with polycation polymer preparations. This study examined how the pharmacokinetics of DTG are affected by co-administration with Al(OH) , LaCO , and the polycation polymers bixalomer (Bxl) and sevelamer (Svl). Prior to oral administration of DTG (5 mg/kg), rats were orally administered Al(OH) (150 or 300 mg/kg), LaCO (50 or 75 mg/kg), Bxl (250 or 500 mg/kg), or Svl (300 or 600 mg/kg). Serum concentrations of DTG were then measured over the next 24 h. Compared to the administration of DTG alone, its co-administration with Al(OH) , LaCO , Bxl, and Svl led to reduced serum concentration of DTG, and consequently, a significantly reduced area under the curve. These comparisons also revealed a considerable reduction in the maximum concentration, suggesting that the interactions of these agents with DTG in the intestinal tract inhibit absorption of DTG. The above results demonstrate that Al(OH) , LaCO , Bxl, and Svl affect the pharmacokinetics of DTG and indicate the need for caution when combining any of the above preparations with DTG. 3 3 3 3 3 3 3 3

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