Research Achievements - Original paper -
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Simultaneous analysis of drugs administered to lung-transplanted patients using liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring.
Shinya Takasaki, Tensei Hirasawa, Yu Sato, Masamitsu Maekawa, Taku Tsukamoto, Masafumi Kikuchi, Jiro Ogura, Yoshihiro Hayakawa, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Hiroaki Yamaguchi, Nariyasu Mano
Biomedical chromatography : BMC 35 ( 6 ) e5067 2021.01 [Refereed]
Research paper (journal)
Several drugs are administered to lung-transplanted patients, which are monitored using therapeutic drug monitoring (TDM). Therefore, we developed and validated a liquid chromatography-tandem mass spectrometry method to simultaneously analyze immunosuppressive drugs such as mycophenolic acid, antifungal drugs such as voriconazole and itraconazole, and its metabolite hydroxyitraconazole. Chromatographic separation was achieved using a C18 column and gradient flow of mobile phase comprising 20 mM aqueous ammonium formate and 20 mM ammonium formate-methanol solution. A simple protein precipitation treatment was performed using acetonitrile/methanol and mycophenolic acid-2 H3 , voriconazole-2 H3 , itraconazole-2 H4 , and hydroxyitraconazole-2 H4 as internal standards. The linearity ranges of mycophenolic acid, voriconazole, itraconazole, and hydroxyitraconazole were 100-20,000, 50-10,000, 5-1000, and 5-1000 ng/mL, respectively. The retention time of each target was less than 2 min. The relative errors in intra- and inter-day were within ±7.6%, the coefficient of variation was 8.9% or less for quality control low, medium, and high, and it was 15.8% or less for lower limit of quantitation. Moreover, the patient samples were successfully quantified, and they were within the linear range of measurements. Therefore, our new method may be useful for TDM in lung-transplanted patients.
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Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation.
Hiroshi Yabuki, Yasushi Matsuda, Tatsuaki Watanabe, Shunsuke Eba, Fumihiko Hoshi, Takashi Hirama, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Akira Sakurada, Masafumi Kikuchi, Hiroaki Yamaguchi, Nariyasu Mano, Yoshinori Okada
Clinical transplantation 34 ( 12 ) e14088 2020.12 [Refereed]
Research paper (journal)
BACKGROUND: The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. METHODS: The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. RESULTS: The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3 ± 6.5, 36.8 ± 10.7, and 20.6 ± 9.6 µg·h/mL, respectively (P = .0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8 µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P = .0050). CONCLUSIONS: The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.
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Development of a Diagnostic Screening Strategy for Niemann-Pick Diseases Based on Simultaneous Liquid Chromatography-Tandem Mass Spectrometry Analyses of N-Palmitoyl-O-phosphocholine-serine and Sphingosylphosphorylcholine.
Anna Iwahori, Masamitsu Maekawa, Aya Narita, Akie Kato, Toshihiro Sato, Jiro Ogura, Yu Sato, Masafumi Kikuchi, Atsuko Noguchi, Katsumi Higaki, Torayuki Okuyama, Tsutomu Takahashi, Yoshikatsu Eto, Nariyasu Mano
Biological & pharmaceutical bulletin 43 ( 9 ) 1398 - 1406 2020.09 [Refereed]
Research paper (journal)
Early diagnosis of Niemann-Pick diseases (NPDs) is important for better prognosis of such diseases. N-Palmitoyl-O-phosphocholine-serine (PPCS) is a new NPD biomarker possessing high sensitivity, and with its combination with sphingosylphosphocholine (SPC) it may be possible to distinguish NPD-C from NPD-A/B. In this study, a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (method 1) and a validated LC-MS/MS analysis (method 2) of PPCS and SPC were developed, and we have proposed a diagnostic screening strategy for NPDs using a combination of serum PPCS and SPC concentrations. Nexera and API 5000 were used as LC-MS/MS systems. C18 columns with lengths of 10 and 50 mm were used for method 1 and 2, respectively. 2H3-Labeled PPCS and nor-SPC were used as internal standards. Selective reaction monitoring in positive-ion mode was used for MS/MS. Run times of 1.2 and 8 min were set for methods 1 and 2, respectively. In both methods 1 and 2, two analytes showed high linearity in the range of 1-4000 ng/mL. Method 2 provided high accuracy and precision in method validation. Serum concentrations of both analytes were significantly higher in NPD-C patients than those of healthy subjects in both methods. Serum PPCS correlated between methods 1 and 2; however, it was different in the case of SPC. The serum PPCS/SPC ratio was different in healthy subjects, NPD-C, and NPD-A/B. These results suggest that using a combination of the two LC-MS/MS analytical methods for PPCS and SPC is useful for diagnostic screening of NPDs.
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Development of a precise quantitative method for monitoring sirolimus in whole blood using LC/ESI-MS/MS.
Kensuke Shigeta, Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Hisashi Oishi, Tetsu Sado, Yasushi Matsuda, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
Biomedical chromatography : BMC 34 ( 8 ) e4853 2020.08 [Refereed]
Research paper (journal)
Sirolimus is used on patients after solid organ transplantation and on lymphangioleiomyomatosis (LAM) patients, and therapeutic drug monitoring is required in clinical practice. We have previously reported an accurate method for quantitative determination of sirolimus, but its sample preparation step was complicated. In this study, we developed a modified liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for sirolimus quantification. A supported liquid extraction cartridge was used to purify sirolimus from whole blood and ion suppression was mostly prevented. The validation results met the acceptance criteria. This method was compared with the antigen conjugated magnetic immunoassay (ACMIA) and our previously reported method, using whole blood samples from LAM patients. Comparison of the Bland-Altman plots of the currently developed method and the previous method revealed no significant difference between the two methods (mean bias, -2.02%; 95% CI, -7.81-3.78). The values obtained using ACMIA were significantly higher than those obtained using the current method by 13.87% (95% CI, 6.49-21.25) owing to cross-reactivity. The degrees of cross reactivities in LAM patients and in organ transplant patients were similar, and our LC/ESI-MS/MS method precisely measured the blood concentrations of sirolimus.
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Importance of Therapeutic Drug Monitoring to Detect Drug Interaction between Pazopanib and Warfarin: A Case Report.
Shinya Takasaki, Hisanobu Adachi, Yoshihide Kawasaki, Masafumi Kikuchi, Akihiro Ito, Nariyasu Mano
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 23 200 - 205 2020 [Refereed]
Research paper (journal)
Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time- international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.
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Estimation of Blood Sirolimus Concentration Based on Tacrolimus Concentration/Dose Normalized by Body Weight Ratio in Lung Transplant Patients.
Masafumi Kikuchi, Kensuke Shigeta, Masaki Tanaka, Shinya Takasaki, Miki Akiba, Hisashi Oishi, Tetsu Sado, Yasushi Matsuda, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
Therapeutic drug monitoring 41 ( 5 ) 615 - 619 2019.10 [Refereed]
Research paper (journal)
BACKGROUND: Sirolimus and tacrolimus require accurate drug dosing based on their target blood levels to produce better clinical outcomes, specifically, the avoidance of drug-induced adverse effects and the maintenance of efficacy. However, because the ideal dose of sirolimus and the schedule for measuring its blood levels are unclear in lung transplant patients, an index is required for estimating sirolimus blood concentrations. The aim of this work is to study the correlation between the trough concentration/dose normalized by body weight (C0/D) ratios of sirolimus and tacrolimus in lung transplant patients. METHODS: Thirteen lymphangiomyomatosis patients who underwent lung transplantation and were treated with sirolimus and tacrolimus from February 2015 to July 2018 were divided into 2 groups, one receiving twice-daily (TD, n = 6) and the other once-daily (OD, n = 7) tacrolimus formulations. The correlation between the C0/D ratio of sirolimus and patient background was evaluated using Spearman's rank correlation coefficient. Correlations between sirolimus and tacrolimus C0/D ratios or doses were analyzed by single regression analysis. RESULTS: Significant correlations were found between the C0/D ratios of sirolimus and tacrolimus. The regression equations from the initial data of TD and OD groups at steady state were y = 1.880x + 32.636 (adjusted R = 0.743, P = 0.017) and y = 1.684x + 38.816 (adjusted R = 0.919, P < 0.001), respectively. In addition, the regression equations from all data of TD and OD groups were y = 1.883x + 4.170 (adjusted R = 0.546, P < 0.001) and y = 1.950x + 43.188 (adjusted R = 0.898, P < 0.001), respectively. A significant correlation between the dosage of sirolimus and tacrolimus was observed only in the OD group, with relatively low accuracy. CONCLUSIONS: Blood sirolimus concentrations can be estimated using the C0/D ratio of tacrolimus, suggesting that the C0/D ratio of tacrolimus is an index of required sirolimus dosage and the frequency of blood sirolimus concentration measurements.
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Fundamental Study of Behaviors of In-Source Collision Induced Dissociation and Shifting the Linear Range of Calibration Curves of Various Drugs and the Metabolites Used for Therapeutic Drug Monitoring.
Maekawa M, Tsukamoto T, Takasaki S, Kikuchi M, Sato Y, Ogura J, Hayakawa Y, Yamaguchi H, Mano N
Chromatography 40 ( 2 ) 71 - 78 2019.05 [Refereed]
Research paper (journal)
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Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients.
Masaki Tanaka, Masafumi Kikuchi, Shinya Takasaki, Tensei Hirasawa, Kensuke Sigeta, Aoi Noda, Miki Akiba, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 22 ( 1 ) 407 - 417 2019 [Refereed]
Research paper (journal)
PURPOSE: The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. METHODS: Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). RESULTS: The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. CONCLUSION: LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.
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Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study.
Shinya Takasaki, Hiroaki Yamaguchi, Yoshihide Kawasaki, Masafumi Kikuchi, Masaki Tanaka, Akihiro Ito, Nariyasu Mano
Journal of pharmaceutical health care and sciences 5 6 - 6 2019 [Refereed]
Research paper (journal)
Background: Everolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC. Methods: Patients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated. Results: The median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1-28.0) ng/mL and 14.8 (6.4-58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26-288) and 235 days (95% CI, 28-291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436). Conclusions: This study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.
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Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma.
Shinya Takasaki, Yoshihide Kawasaki, Masafumi Kikuchi, Masaki Tanaka, Masato Suzuka, Aoi Noda, Yuji Sato, Shinichi Yamashita, Koji Mitsuzuka, Hideo Saito, Akihiro Ito, Hiroaki Yamaguchi, Yoichi Arai, Nariyasu Mano
International journal of clinical oncology 23 ( 5 ) 936 - 943 2018.10 [Refereed]
Research paper (journal)
BACKGROUND: The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC). METHODS: Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6 weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated. RESULTS: Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6 weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50 ng/mL than in those with concentrations ≥ 50 ng/mL. CONCLUSIONS: The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50-100 ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC.
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中川直人, 渡邊桂子, 菊地正史, 菊地正史, 石田孝宣, 木皿重樹, LAI Leanne
医薬品相互作用研究 42 ( 2 ) 95 - 102 2018.06 [Refereed]
Research paper (journal)
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Simultaneous analysis of oral anticancer drugs for renal cell carcinoma in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry.
Shinya Takasaki, Masaki Tanaka, Masafumi Kikuchi, Masamitsu Maekawa, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Biomedical chromatography : BMC 32 ( 6 ) e4184 2018.06 [Refereed]
Research paper (journal)
An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry has been developed and validated for simultaneous measurement of four tyrosine kinase inhibitors used for renal cell carcinoma and their metabolites in human plasma. Despite their similar structures, it is difficult to measure plasma levels of these compounds simultaneously using optimal MS parameters for each compound because a quantitative range exceeding 50,000-fold is required. To overcome this problem, we used a linear range shift technique using in-source collision-induced dissociation. Linearity ranges of sorafenib, sorafenib N-oxide, sunitinib, N-desethyl sunitinib, axitinib and pazopanib were 100-10,000, 10-1,000, 1-100, 1-100, 1-100 and 500-50,000 ng/mL, respectively. The intra- and inter-day precision and accuracy were high, and coefficients of variation and relative error were <10.3% and within ±11.8%, respectively. The matrix effects of all analytes ranged from 87.7 to 114.8%. Extraction recoveries and overall recoveries showed small extraction loss (<15.0%) for all analytes. Moreover, all cancer patient samples used in this study were successfully quantified and fell within the linear range of measurement. Therefore, this novel analytical system using in-source collision-induced dissociation has sufficient performance to measure plasma concentrations of these four tyrosine kinase inhibitors and their metabolites for therapeutic drug monitoring.
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Masamitsu MAEKAWA, Masaru MORI, Masachika FUJIYOSHI, Hisaki SUZUKI, Kazunari YANAI, Aoi NODA, Masaki TANAKA, Shinya TAKASAKI, Masafumi KIKUCHI, Kazutoshi AKASAKA, Shigeki KISARA, Masaki MATSUURA, Kanehiko HISAMICHI, Mayumi SATO, Junichi GOTO, Miki SHIMADA, Hiroaki YAMAGUCHI, Nariyasu MANO
CHROMATOGRAPHY 39 ( 1 ) 41 - 47 2018 [Refereed]
Research paper (journal)
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Comparison of PETINIA and LC-MS/MS for determining plasma mycophenolic acid concentrations in Japanese lung transplant recipients.
Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Akiko Takahashi, Miki Akiba, Yasushi Matsuda, Masafumi Noda, Kanehiko Hisamichi, Hiroaki Yamaguchi, Yoshinori Okada, Nariyasu Mano
Journal of pharmaceutical health care and sciences 4 7 - 7 2018 [Refereed]
Research paper (journal)
Background: Mycophenolic acid (MPA) treatment requires therapeutic drug monitoring to improve the outcome after organ transplantation. The aim of this study was to compare two methods, a particle enhanced turbidimetric inhibition immunoassay (PETINIA) and a reference liquid chromatography tandem mass spectrometry (LC-MS/MS) for determining plasma MPA concentrations from Japanese lung transplant recipients. Methods: Plasma MPA concentrations were determined from 20 Japanese lung transplant recipients using LC-MS/MS and the PETINIA on the Dimension Xpand Plus-HM analyzer. Results: The mean MPA concentration measured by PETINIA was significantly higher than that measured by LC-MS/MS (3.26 ± 2.73 μg/mL versus 2.82 ± 2.71 μg/mL, P < 0.0001). The result of the Passing Bablok analysis was a slope of 1.104 (95% confidence interval [CI], 1.036-1.150) and an intercept of 0.229 (95%CI, 0.144-0.315). Bland-Altman analysis revealed PETINIA overestimates plasma MPA concentration by 26.25% and 95%CI from 21.43 to 31.07%. Conclusion: The measurement of MPA by the PETINIA in Japanese lung transplant patients should evaluate the result with attention to positive bias.
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Development of a Liquid Chromatography-Tandem Mass Spectrometric Method for Quantification of Mycophenolic Acid and Its Glucuronides in Dried Blood Spot Samples.
Hiromasa Iboshi, Hiroaki Yamaguchi, Hiroyuki Suzuki, Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Akiko Takahashi, Masamitsu Maekawa, Miki Shimada, Yasushi Matsuda, Yoshinori Okada, Nariyasu Mano
Therapeutic drug monitoring 39 ( 6 ) 648 - 653 2017.12 [Refereed]
Research paper (journal)
BACKGROUND: Personalized immunosuppressive therapy, including accurate drug dosing based on the drug blood level, leads to better clinical outcomes, specifically regarding avoidance of drug-induced adverse effects and maintenance of efficacy. Mycophenolic acid (MPA) is used as an immunosuppressant in transplantation of various solid organs. The aim of this study was to develop a method for quantification of MPA and its metabolites, mycophenolic acid 7-O-glucuronide (MPAG) and mycophenolic acid acyl glucuronide, in dried blood spot (DBS) samples, using liquid chromatography/electrospray ionization/tandem mass spectrometry. METHODS: For sample preparation, a microwave-drying approach was used to deactivate enzymes and reduce drying time. Blood volume was calculated in a DBS disk of 3 mm diameter. Concentrations of analytes in plasma from patients receiving mycophenolate mofetil were compared with DBS samples after hematocrit correction. RESULTS: The method yielded good recoveries of all 3 analytes (90.3%-104.2%). Blood volume in the disk was calculated as 3.0 ± 0.2 μL. Linearity over concentration ranges of 0.1-30 mcg/mL MPA, 0.1-200 mcg/mL MPAG, and 0.125-10 mcg/mL mycophenolic acid acyl glucuronide was obtained with r ≥0.999. Intraday and interday variations were less than 14.6%, and accuracy was within ±11.9%. Passing-Bablok analysis showed no significant differences between plasma concentrations and DBS concentrations after hematocrit correction of MPA and MPAG. CONCLUSIONS: We developed and validated a liquid chromatography/electrospray ionization-tandem mass spectrometry method for analysis of MPA in DBS samples. The method is useful for monitoring the MPA blood level.
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Severe toxicity induced by accumulation of active sunitinib metabolite in a Japanese patient with renal cell carcinoma: a case report.
Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Journal of medical case reports 11 ( 1 ) 28 - 28 2017.02 [Refereed]
Research paper (journal)
BACKGROUND: Sunitinib is a multi-targeted tyrosine kinase inhibitor that is approved for treatment of renal cell carcinoma as an oral anticancer drug. Therapeutic drug monitoring of total sunitinib (sunitinib and N-desethyl sunitinib) is used in our hospital to improve therapeutic efficacy, while preventing adverse effects. Here, we report the first case of a patient with metastatic renal cell carcinoma undergoing hemodialysis and presenting severe adverse events induced by the accumulation of N-desethyl sunitinib. CASE PRESENTATION: A 60-year-old Japanese man was diagnosed with metastatic renal cell carcinoma requiring hemodialysis. On day 26 of the first cycle of sunitinib therapy, our patient presented grade 3 thrombocytopenia and leukopenia, which required interruption of therapy although the plasma levels of total sunitinib in the patient were less than the effective concentration of 50 ng/mL. The elimination half-life of sunitinib was normal at 50.8 hours, but that of N-desethyl sunitinib was an extended 211.4 hours. Moreover, the N-desethyl sunitinib/sunitinib trough level ratio was higher than 1.0. We attribute our patient's severe adverse events to the excessive accumulation of N-desethyl sunitinib owing to its delayed excretion. Although the reason for the delayed excretion of N-desethyl sunitinib in this patient was unknown, it may have been caused by genetic polymorphisms related to the pharmacokinetics of sunitinib rather than the hemodialysis. In this case, the patient was homozygous for the ABCG2 421C allele, but was capable of potentially harboring polymorphisms in other genes, such as ABCB1, an efflux pump of sunitinib. In addition, even though there is no clear evidence, urinary excretion of the metabolic products of N-desethyl sunitinib could be inhibited by the interaction of transporters such as the organic ion transporter. CONCLUSIONS: The monitoring of not only total sunitinib concentration but also N-desethyl sunitinib concentration and their elimination half-lives during sunitinib therapy is recommended to avoid critical adverse events.
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エベロリムス誘発肝機能障害により血中エベロリムス濃度高値と高血糖を示した腎細胞癌患者の1例
高崎 新也, 菊地 正史, 川崎 芳英, 伊藤 明宏, 荒井 陽一, 山口 浩明, 眞野 成康
癌と化学療法 ( (株)癌と化学療法社 ) 44 ( 1 ) 87 - 89 2017.01 [Refereed]
Research paper (journal)
エベロリムス誘発肝機能障害により,血中エベロリムス濃度高値と高血糖を示した腎細胞癌患者の1例を経験したので報告する.症例は74歳,男性.右腎細胞癌,多発肺転移の診断で右腎摘除術後,インターフェロン,ソラフェニブにより治療されたが病勢進行となり,エベロリムスを開始した.エベロリムス投与15日目にgrade 3の肝機能障害および高血糖が認められ,血中エベロリムス濃度が58.4ng/mLと高値を示したことから,エベロリムスを休薬した.肝機能検査値の回復後にエベロリムスを減量して再開したが,再び肝機能障害が認められたため,エベロリムスの血中濃度が高値を示す前に投与を中止した.肝機能検査値の回復後にアキシチニブへ変更し,その後は肝機能障害および高血糖を認めなかった.腎細胞癌患者に対するエベロリムス治療において肝機能障害が認められた場合,血中エベロリムス濃度が高値を示す可能性が示唆された.したがって,血中エベロリムス濃度測定は有害事象の管理に重要であると考えられた.(著者抄録)
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菊地 正史, 小林 美奈子, 中川 直人, 木皿 重樹, 松浦 正樹, 久道 周彦, 山田 卓郎, 佐々木 孝雄, 石岡 千加史, 眞野 成康
日本病院薬剤師会雑誌 = Journal of Japanese Society of Hospital Pharmacists ( 日本病院薬剤師会 ) 52 ( 12 ) 1493 - 1498 2016.12 [Refereed]
Research paper (journal)
がん化学療法の外来化が進むなかで,安全で安心ながん治療の提供には,保険薬局を含めた地域における多職種連携が重要となっている.東北大学病院では,患者情報とがん化学療法の基礎知識の共有を目的に,がんの治療手帳(以下,治療手帳)を作成するとともに,宮城県薬剤師会と宮城県各地域における多職種連携セミナー(以下,セミナー)を開催した.治療手帳は,アンケート調査に基づく保険薬局薬剤師が必要とする情報ばかりか,患者自らが副作用の発現状況や経口抗がん薬の服薬状況を記入できる情報共有ツールとなった.また,セミナーの平均参加人数は約137名/回であり,アンケート調査の結果,参加者の約97%が内容に満足またはやや満足と回答し,90%以上がセミナーで得られた情報は抗がん薬の調剤や服薬指導時に有益であると回答した.今回の取り組みは,地域における多職種連携を強化し,安全で質の高いがん化学療法を実施するうえで役立つものと期待される.(著者抄録)
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イトラコナゾールの併用によりシロリムスの全血中トラフ濃度が高値を示したリンパ脈管筋腫症患者の2例
菊地 正史, 野田 あおい, 田中 雅樹, 高橋 阿希子, 秋場 美紀, 松田 安史, 星川 康, 久道 周彦, 山口 浩明, 岡田 克典, 眞野 成康
TDM研究 ( (一社)日本TDM学会 ) 33 ( 3 ) 104 - 108 2016.09 [Refereed]
Research paper (journal)
症例1:49歳,女性.リンパ脈管筋腫症(LAM)の進行に伴う右片肺移植施行後,シロリムス(SRL)を開始し,2mg/日の連日投与で全血中トラフ濃度は6.7〜7ng/mLで安定していた.深在性真菌症の予防にイトラコナゾール(ITCZ)50mg/日の連日投与を開始するため,SRL1mg/日の連日投与に減量したが,併用13日目に治療濃度域の上限(15ng/mL)に近い13.2ng/mLまで上昇した.SRLを1mg/日の隔日投与に変更し,併用17日目に8.6ng/mLまで低下した.症例2:40歳,女性.LAMの進行に伴う両肺移植施行後,深在性真菌症の予防にITCZを50mg/日で連日投与していた.SRLを1mg/日の連日投与で開始したところ,併用6日目の全血中トラフ濃度は治療濃度域の上限を超える28.4ng/mLとなった.SRLを1mg/日の3日毎投与に変更し,併用9日目に11.3ng/mLまで低下した.肺移植後のLAM患者において,SRLとITCZを併用する場合,SRLの減量や投与間隔の延長を検討し,全血中トラフ濃度を頻回に測定しながら投与量を調節することが重要である.(著者抄録)
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The correlation among the blood concentration of mycophenolic acid, the dosage of mycophenolate mofetil and the number of leukocyte in patients after lung transplantation
Yabuki Hiroshi, Funahashi Junichi, Okada Yoshinori, Watanabe Tatsuaki, Kikuchi Masafumi, Notsuda Hirotsugu, Niikawa Hiromichi, Matsuda Yasushi, Noda Masafumi, Sakurada Akira, Hoshikawa Yasushi
Organ Biology ( 一般社団法人 日本臓器保存生物医学会 ) 23 ( 2 ) 141 - 144 2016
Research paper (journal)
Mycophenolate mofetil (MMF) has been used as a standard immunosuppressive agent after lung transplantation. MMF is rapidly metabolized to active constituent, mycophenolic acid (MPA), after intake. Gastrointestinal side- effects and leukocytopenia are common adverse effects of MMF. Although, therapeutic drug monitoring (TDM) for calcineurin inhibitors is widely used, the role of TDM for MPA is unclear in lung transplantation. We investigated the correlation among the blood concentration of MPA, the dosage of MMF and the number of leukocyte in lung transplant recipients. The correlation coefficient between the blood concentration of MPA and the dosage of MMF was not significant, so MMF might require TDM. On the other hand, neither the correlation coefficients between the number of leukocyte and the blood concentration of MPA nor the correlation coefficients between the number of leukocyte and the dosage of MMF were not significant. Further investigation is necessary to find the meanings of TDM for MPA after lung transplantation.