研究等業績 - 原著論文 - 赤嶺 由美子
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Hayato Yokota, Yumiko Akamine, Harumi Hatakeyama, Hideaki Kagaya, Sho Sakamoto, Mitsuru Saito, Masahide Takeda, Kazuhiro Sato, Katsutoshi Nakayama, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences ( Journal of Pharmaceutical Health Care and Sciences ) 11 ( 1 ) 20 - 20 2025年03月
研究論文（学術雑誌）
BACKGROUND: Azole antifungals are the standard treatment for pulmonary mycosis, which may develop during long-term immunotherapy for kidney transplant. Isavuconazole (ISCZ) is a cytochrome P450 (CYP) 3 A inhibitor that has a risk of interacting with the immunosuppressive drug tacrolimus (TAC). We report a case of simple pulmonary aspergilloma with renal dysfunction due to increased trough levels of TAC after ISCZ coadministration. CASE PRESENTATION: A male in his 60s was treated with TAC 3.0 mg/day orally to prevent graft rejection after kidney transplantation. He received a loading dose of ISCZ 600 mg/day orally for two days, followed by a maintenance dose of 200 mg/day for simple pulmonary aspergilloma. The TAC trough concentration increased markedly from 2.4 to 9.9 ng/mL on day 6 after coadministration. The creatinine level increased from 0.70 to 1.08 mg/dL, suggesting renal dysfunction due to TAC. Subsequently, the TAC dosage was reduced, leading to a decreased blood TAC concentration and improved renal function. The patient's genotype was CYP3A5*1/*3. CONCLUSIONS: In the early stages of ISCZ treatment, the blood TAC concentration is higher, and CYP3A5 polymorphisms may partially explain the extent of this interaction. We recommend more careful monitoring of TAC and serum creatinine levels for approximately one week after ISCZ administration.
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Hayato Yokota, Kazuhiro Sato, Sho Sakamoto, Yuji Okuda, Masahide Takeda, Yumiko Akamine, Katsutoshi Nakayama, Masatomo Miura
Cancer chemotherapy and pharmacology ( Cancer Chemotherapy and Pharmacology ) 95 ( 1 ) 49 - 49 2025年03月
研究論文（学術雑誌）
PURPOSE: The inflammatory cytokine interleukin (IL)-6 reduces the activity of drug metabolic enzymes and promotes tumor progression. We investigated the effect of IL-6 on the pharmacokinetics of osimertinib and the association between an IL-6 polymorphism and clinical outcomes in 30 patients with non-small cell lung cancer (NSCLC). METHODS: Osimertinib and IL-6 plasma concentrations were measured on day 15 after therapy initiation. The genotype of IL-6 1800796G > C was identified using polymerase chain reaction-restriction fragment length polymorphism. Risk factors affecting overall survival (OS) were assessed by Cox proportional hazard regression analysis. RESULTS: The IL-6 concentration was significantly correlated with the osimertinib trough plasma concentration (r = 0.423, P = 0.020) and area under the plasma concentration-time curve (r = 0.420, P = 0.021). The IL-6 concentration was significantly higher in patients with the IL-6 rs1800796G allele versus C/C genotype (P = 0.024). OS was significantly shorter in patients with the IL-6 rs1800796G allele versus C/C genotype (median: 15.1 vs. 48.9 months, P = 0.005). Univariate and multivariate analyses indicated that the IL-6 rs1800796G allele is an independent risk factor for OS (crude hazard ratio = 7.07; P = 0.014; adjusted hazard ratio = 6.38; P = 0.021). CONCLUSION: A higher IL-6 concentration was associated with reduced metabolic activity of osimertinib, leading to increased osimertinib exposure. As the IL-6 concentration was higher in NSCLC patients with the IL-6 rs1800796G allele, it might be an independent prognostic factor for patients treated with osimertinib.
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Takahiro Kobayashi, Honami Sato, Yumiko Akamine, Yayoi Fukushi, Naoto Takahashi, Masatomo Miura
Xenobiotica; the fate of foreign compounds in biological systems ( Xenobiotica ) 55 ( 1 ) 1 - 6 2024年12月
研究論文（学術雑誌）
The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.
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Hayato Yokota, Yumiko Akamine, Mizuki Kobayashi, Takuro Kitabayashi, Misato Horie, Tentaro Endo, Takechiyo Yamada, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences ( Journal of Pharmaceutical Health Care and Sciences ) 10 ( 1 ) 2024年08月
研究論文（学術雑誌）
BACKGROUND: Naldemedine is an orally available peripherally acting μ-opioid receptor antagonist approved to treat opioid-induced constipation (OIC). It is contraindicated for patients with known or suspected gastrointestinal obstruction to protect against naldemedine-induced perforation. Here, we report a clinical case of suspected perforation of a diverticulum in the sigmoid colon associated with naldemedine. CASE PRESENTATION: The patient was a 65-year-old man with a history of oral cancer who had been prescribed oxycodone (20 mg/day) for cancer pain. On day 0, the patient started naldemedine 0.2 mg once daily before bedtime for OIC. The dose of oxycodone was increased for pain control up to 60 mg/day. On day 35 of naldemedine treatment, the patient developed fever and abdominal pain, and his frequency of defecation had decreased. Initial laboratory results showed a C-reactive protein (CRP) level of 28.5 mg/dL and white blood cell (WBC) count of 13,500/µL. On day 37, the patient still had tenderness in his lower abdomen. Abdominal computed tomography revealed free air in the abdominal cavity suggesting an intestinal perforation. A Hartmann procedure was performed. Histopathological findings showed numerous diverticula in the sigmoid colon, some of which were perforated. CONCLUSIONS: These results suggest that the effects of OIC may have compressed the intestinal tract, which was followed by naldemedine-activation of peristalsis, which led to the onset of intestinal perforation. In patients with pre-existing diverticular disease, we should monitor for increased WBC counts and CRP levels after the initiation of treatment with naldemedine, and consider performing appropriate tests early in the event of abdominal complaints.
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Kazuma Fujita, Yumiko Akamine, Haruka Igarashi, Yayoi Fukushi, Katsuya Sasaki, Koji Fukuda, Masafumi Kikuchi, Hiroyuki Shibata
Japanese journal of clinical oncology ( Japanese Journal of Clinical Oncology ) 54 ( 11 ) 1165 - 1170 2024年06月
研究論文（学術雑誌）
BACKGROUND: The modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) are indicators of nutritional status in cancer patients; however, the effects of baseline mGPS and PNI on the duration of administration of the ghrelin receptor agonist anamorelin, which is used to treat cachexia in patients with cancer, are unclear. This study aimed to clarify the association of mGPS and PNI with the duration of oral anamorelin administration for patients who did not have beneficial effects from anamorelin. METHODS: The attending physician determined the duration of oral anamorelin administration based on discontinuation due to cancer progression, poor efficacy, adverse events, or death. RESULTS: The 12-week continuation rate of oral anamorelin was 30.4%. Univariate analysis revealed that an Eastern Cooperative Oncology Group performance status (ECOG-PS) of ≥2 (P < .001), concurrent chemotherapy (P = .002), albumin level (P = .005), C-reactive protein level (P = .013), and a mGPS of 2 (P = .014) were statistically significant predictors of the 12-week continuation rate of oral anamorelin. In the multivariate analysis, a mGPS of 2 remained a significant risk factor, and the ECOG-PS and concurrent chemotherapy had no effect on the association between the mGPS and 12-week continuation rate of oral anamorelin. CONCLUSION: Patients with a mGPS of 2, compared with mGPS of 0 or 1, are less likely to maintain oral anamorelin therapy, regardless of the ECOG-PS or concurrent chemotherapy. Therefore, it is necessary to consider initiating anamorelin administration at mGPS 0 or 1.
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Hayato Yokota, Ruriko Asahi, Yumiko Akamine, Mizuki Kobayashi, Hiyu Wakabayashi, Sho Sakamoto, Yuji Okuda, Kazuhiro Sato, Katsutoshi Nakayama, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences ( Journal of Pharmaceutical Health Care and Sciences ) 10 ( 1 ) 2024年06月
研究論文（学術雑誌）
BACKGROUND: Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer. CASE PRESENTATION: A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child-Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided. CONCLUSIONS: When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring.
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Yumiko Akamine, Miyuki Matsushita, Satoru Morikawa, Masatomo Miura
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan ( 公益社団法人 日本薬学会 ) 143 ( 4 ) 377 - 383 2023年
研究論文（学術雑誌）
Plasma concentrations of mycophenolic acid (MPA), an immunosuppressive agent, have been measured in clinical settings using immunoassay methods or HPLC. However, immunoassay methods show cross-reactivity with metabolites of MPA glucuronide. Recently, the LM1010 high-performance liquid chromatography instrument was approved as a new general medical device. In this study, we compared the results of MPA plasma concentrations analyzed using the LM1010 method and the previously described HPLC method. Plasma samples obtained from 100 renal transplant patients (32 women and 68 men) were evaluated using both HPLC instruments. Deming regression analyses showed a very high correlation between the two instruments, with a slope of 0.9892 and an intercept of 0.0235 µg/mL (r2=0.982). Bland-Altman analysis showed an average of -0.0012 µg/mL between the LM1010 method and the previously described HPLC method. For the LM1010 method, the total run time for MPA analysis was 7 min, and the analytical time was short; however, the extraction recovery when using a spin column was extremely low for frozen plasma samples stored at -20°C for 1 month, and the volume required for the assay (150 µL) could not be collected. Thus, for the LM1010 method, analysis using fresh plasma samples was optimal. Overall, our findings showed that the LM1010 method was a rapid, accurate HPLC assay for MPA analysis and could be used in clinical practice for routine monitoring of MPA in fresh plasma samples.
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Yayoi Fukushi, Yumiko Akamine, Miyuki Matsushita, Satoru Morikawa, Masatomo Miura
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan ( 公益社団法人 日本薬学会 ) 143 ( 11 ) 963 - 969 2023年
研究論文（学術雑誌）
LM1010 HPLC is an emerging automated method designed for use in clinical settings. The aim of this study was to compare the analytical performance of LM1010 with the performance of traditional HPLC and LC-MS/MS in the measurement of plasma concentrations of imatinib. Seventy-eight plasma samples from 20 patients (14 men and 6 women) were collected. Plasma concentrations of imatinib in samples from the same patient were analyzed simultaneously using LM1010, HPLC and LC-MS/MS (LSI Medience Corporation). Strong correlations were seen in pairwise comparisons of results from the LM1010 and HPLC methods, the LM1010 and LC-MS/MS methods, and the LC-MS/MS and HPLC methods (Spearman's r=0.936, 0.906, and 0.953, respectively); however, the results from the LC-MS/MS method showed a positive proportional bias in comparison with the results from the LM1010 and HPLC methods, according to Deming analyses (slope=1.064 and 1.105, respectively). In Bland-Altman analyses, the LC-MS/MS method showed a positive mean bias of 98.6 and 112 ng/mL in comparison with the LM1010 and HPLC methods, respectively. Notably, results obtained using the LM1010 method were comparable to those using the HPLC method (positive mean bias=13.6 ng/mL; 95% confidence interval, -7.9-35.1 ng/mL). Biochemical parameters or drugs taken concomitantly with imatinib were not found to affect the bias of the LM1010 method. The LM1010 method can be applied to routine therapeutic drug monitoring of imatinib.
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Yayoi Fukushi, Yumiko Akamine, Maiko Abumiya, Nagi Tozawa, Takaya Yamashita, Miho Nara, Yoshihiro Kameoka, Naoto Takahashi, Masatomo Miura
British journal of clinical pharmacology ( British Journal of Clinical Pharmacology ) 89 ( 5 ) 1695 - 1700 2022年12月
研究論文（学術雑誌）
The effects of polymorphisms of ABCB1 and ABCG2 on the dose-adjusted plasma trough concentrations and cerebrospinal fluid (CSF)-to-plasma ratios of ponatinib were evaluated. Blood (C4 ) and CSF (CSF4 ) concentrations at 4 h after administration were determined. The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in subjects homozygous for ABCB1 variants 1236T/T, 2677T/T + T/A or 3435T/T were significantly higher than that in a group of subjects with other genotypes (P = .026, .012 and .015, respectively). The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in 4 patients with the combination of ABCB1 variants 1236T/T-2677T/T + T/A-3435T/T was 2.62% (1.42-3.42%); this ratio was significantly higher than that in subjects with other genotypes (1.08% [0.89-1.47%]; P = .006). The brain distribution of ponatinib was affected by ABCB1 polymorphisms and therefore seems to be modulated by P-glycoprotein at the blood-brain and blood-CSF barriers.
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Natsuki Fukuda, Takahiro Kobayashi, Honami Sato, Yumiko Akamine, Naoto Takahashi, Masatomo Miura
Journal of Chromatographic Science ( Oxford University Press (OUP) ) 62 ( 1 ) 58 - 64 2022年10月
研究論文（学術雑誌）
Abstract
A simple, highly sensitive and specific method based on high-performance liquid chromatography (HPLC) with ultraviolet detection was developed for the measurement of venetoclax concentrations in plasma samples. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH2PO4 (pH 3.5) (80/20, v/v) on a CAPCELL PAK C18 UG120 column at a flow rate of 0.5 mL/min. The quantitative method was validated based on standards described in “Bioanalytical Method Validation: Guidance for Industry” published by the US Food and Drug Administration. The separation of venetoclax and the internal standard R051012 was satisfactory, and the chromatograms were free of interfering peaks from the biological matrix. The intra- and inter-day coefficients of variation for venetoclax assays were &lt;12.9%, whereas intra- and inter-day accuracies were within 13.6%. Only 100 μL of human plasma was required to detect a lower limit of quantification of 10 ng/mL for venetoclax. The recoveries of venetoclax extracted with an Oasis HLB cartridge were between 81 and 85%. The developed HPLC method was successfully applied to the determination of venetoclax concentrations in plasma of acute myeloid leukemia patients taking venetoclax. The degree of drug interactions between venetoclax and CYP3A4 inhibitors can be determined by this HPLC assay. -
Fukuda N.
Cancer Chemotherapy and Pharmacology ( Cancer Chemotherapy and Pharmacology ) 89 ( 5 ) 609 - 616 2022年05月
研究論文（学術雑誌）
PURPOSE: We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice. METHODS: For the 26 patients enrolled in this study, at 3, 6, 12, and 24 months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated. RESULTS: Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3 months than in patients without an MMR (809 and 420 ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3 months for predicting MMR achievement was 619 ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619 ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0 months, respectively; P = 0.020) and higher rates of DMR by 2 years in Kaplan-Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619 ng/mL. CONCLUSION: For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619 ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.
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MAHO KUMAGAI, MITSUJI NAGAHAMA, YUMIKO AKAMINE, TOMOKO OZEKI, AKIFUMI SUZUKI, KIMINORI SUGINO, KOICHI ITO, MASATOMO MIURA
Cancer Diagnosis & Prognosis ( Anticancer Research USA Inc. ) 2 ( 3 ) 336 - 344 2022年05月
研究論文（学術雑誌）
Background/Aim: The purpose of this study was to investigate the relationships between the plasma concentration of Lenvatinib (C0), the levels of angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in patients with thyroid cancer. Patients and Methods: Lenvatinib C0 and Ang were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. Results: The median decrease rates of Ang-1 and Ang-2 at 1 month after treatment from baseline were –15.3% and –48.4%, respectively. However, the decrease in the levels of Ang-1 and Ang-2 at 1 month from baseline did not correlate with C0. In patients with partial response (PR) and stable disease, Ang-2 at 1 month was significantly lower than Ang-2 at baseline. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of decrease rate of Ang-2 of –49.83%. Conclusion: The decrease in Ang-2 at 1 month of treatment from baseline may be important as a biomarker of the inhibitory effect of lenvatinib on angiogenesis.
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カペシタビン併用によるワルファリンの抗凝固能への影響とその時期に関する検討
齋藤 豪, 赤嶺 由美子, 三浦 昌朋, 平泉 達哉
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 57 ( 1 ) 79 - 85 2021年01月
研究論文（学術雑誌）
カペシタビンはCYP2C9に対する阻害作用を有するため、その基質であるワルファリンとの併用で、その血中濃度を上昇させ、プロトロンビン時間国際標準比(prothrombin time-international normalized ratio:以下、PT-INR)を上昇させることが知られている。しかしながら実際にPT-INRがどの程度上昇するのか、また相互作用が起こる時期について検討した報告は少ない。そこで我々は、カペシタビン併用によるワルファリンの抗凝固能に及ぼす影響と影響時期について検討した。対象患者7名のPT-INRの平均値は併用前1.86から併用後4.73と約2.5倍に上昇した(p=0.010)。ワルファリンが減量・中止されるまでの期間は8.0〜43.0日であった。ワルファリンの抗凝固能亢進はカペシタビン併用後1ヵ月以内に発現する可能性が高く、併用開始1ヵ月間はPT-INRを毎週測定しワルファリンの用量を調節していくことが重要であると考える。(著者抄録)
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 6 ) 1800 - 1803 2021年
研究論文（学術雑誌）
What is known and objective: We aim to add to the few reports on tacrolimus concentrations in breast milk and in maternal, umbilical vein and neonatal blood after maternal renal transplantation. Case summary: In a 30-year-old pregnant woman, the tacrolimus concentration at delivery was the same in maternal, umbilical vein and neonatal blood. The breast milk/maternal blood tacrolimus ratio ranged from 0.40 to 0.64. What is new and conclusion: The maternal and neonatal blood tacrolimus concentrations at birth are equivalent; thus, one must assume that maternal tacrolimus concentrations directly affect the foetus and/or neonate. Tacrolimus is not detectable in the neonate 3 weeks after birth, suggesting that there is minimal transfer through breast milk.
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 5 ) 1312 - 1318 2021年
研究論文（学術雑誌）
What is known and objective: The schizophrenia guidelines in Japan and many other countries describe clozapine as the first-choice drug for patients with treatment-resistant schizophrenia. However, there have been no reports to date on the effects of the introduction of clozapine on the prescription of other antipsychotics and concomitant drugs. Methods: In this study, we retrospectively investigated the prescription of antipsychotics and concomitant drugs before vs 6 months after and 12 months after switching to clozapine. Results and discussion: Clozapine was introduced to 62 patients with treatment-resistant schizophrenia, and 51 patients continued on clozapine therapy. Six months after switching to clozapine, there was a significant decrease in the mean number of antipsychotic drugs (2.04 ± 0.75 vs 1.10 ± 0.30: p < 0.001) and in the mean chlorpromazine equivalent value (1024 ± 73 mg/day vs 781 ± 391 mg/day: p < 0.001) compared to before switching. Moreover, antipsychotic monotherapy increased from 24% to 90% after switching to clozapine. In addition, the number of concomitant benzodiazepines, anti-parkinson drugs and antidepressants also significantly decreased 6 and 12 months after switching to clozapine (p < 0.001 for benzodiazepines and anti-parkinson drugs, and p < 0.05 for antidepressants). What is new and conclusion: Our study suggests that switching to clozapine may reduce the use of antipsychotic combination therapy, and may also reduce the number of concomitant drugs.
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Sakamoto S.
Investigational New Drugs ( Investigational New Drugs ) 38 ( 6 ) 1687 - 1695 2020年12月
研究論文（学術雑誌）
ATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the area under the curve (AUC) values for 24-h gefitinib concentrations. We also compared these parameters among four groups distinguished according to the presence or absence of the polymorphism and PPI use. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 vs. 454.5 ng/mL, respectively, P = 0.021; AUC: 9949.9 vs. 13,085.4 ng・h/mL, respectively, P = 0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 vs. 340.5 ng/mL, respectively, P = 0.033). The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.
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加藤 駿介, 赤嶺 由美子, 石川 誠, 三浦 昌朋
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 44 ( 3 ) 153 - 158 2020年12月
研究論文（学術雑誌）
術前3ヵ月以上前から睡眠薬を定期内服していた白内障手術患者28名(男性12名、女性16例、平均年齢69±13歳)を対象として、術後の睡眠薬処方状況を後方視的に調査し、白内障術後の睡眠薬の適正使用について検討した。術後に処方された睡眠薬のジアゼパム換算値の増減を評価した。その結果、ジアゼパム換算値は年齢や併用薬剤にかかわらず、術後1ヵ月以降より減少し、術後6ヵ月の時点で有意な減少が確認された。臨床検査値や併用薬剤数、副腎皮質ステロイド内服患者のヒドロコルチゾン換算値は睡眠薬処方の変化に影響を及ぼす有意な要因ではなかった。本研究より、白内障手術患者においては術後6ヵ月以降に睡眠薬を減薬できる可能性が示唆されたが、減薬・休薬のタイミングは難しく、患者の睡眠状況を確認し、長期的なモニタリングを経て減薬を提案することが望ましい。
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インドメタシンが未熟児動脈管開存症患者の尿量へ及ぼす影響と血清電解質の変化
大久保 翔, 赤嶺 由美子, 安達 裕行, 高橋 勉, 三浦 昌朋
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 44 ( 2 ) 96 - 101 2020年09月
研究論文（学術雑誌）
インドメタシン(IND)が未熟児の尿量へ与える影響、尿量減少の発生時期とその経過、IND投与後の血清電解質の変化を後方視的に検討した。在胎37週未満の早産児のうち、動脈管開存症(PDA)と診断された患者でINDを投与した24名をIND群、PDAと診断されたが早急なIND投与の必要性はないと判断され経過観察となった13名を対照群とした。IND群の尿量変化率の中央値は-38.5%であったのに対して、対照群は-10.0%と有意にIND群で尿量減少がみられた。水分率が90mL/kg/day未満に調整されている患者はIND群では24名中18名、対照群は13名中5名に認められており、IND群で有意に多くみられた。また、IND群では血清ナトリウム(Na)値が基準値以下まで低下したのは24名中11名、対照群では13名中1名とIND群で有意に多かった。血清カリウム値が基準値以上になったのはIND群で1名のみであった。IND投与が尿量へ与える影響は大きく、INDによる尿量減少は高い確率で投与後24時間以内に発生し、さらに希釈性の低Na血症を引き起こしていた。
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Sato S.
Pharmacological Reports ( Pharmacological Reports ) 72 ( 3 ) 622 - 630 2020年06月
研究論文（学術雑誌）
Background: The purpose of this study was to evaluate the effects of concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the PCSK9 and mTORC1 genes in 53 renal transplant recipients. Methods: Prior to and on day 15 after everolimus administration, the concentrations of everolimus in blood and PCSK9 and LDL cholesterol in plasma were evaluated. Additionally, mTORC1 (rs2536T>C and rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, and rs11593680C>T) polymorphisms were analyzed. Results: Mean PCSK9 plasma concentrations on day 15 after everolimus treatment were significantly higher than those before treatment (295 versus 214 ng/mL, respectively; p = 0.004). Significant correlations between the area under the blood concentration–time curves (AUC)0–12 on day 15 of everolimus treatment and the change rate in PCSK9 concentrations were found (r = 0.316, p = 0.021). However, there were no significant correlations between the change rate in PCSK9 and LDL cholesterol concentrations. The change rate in PCSK9 concentrations by everolimus treatment was significantly greater in patients with the mTORC1 rs2295080G allele than the T/T genotype (p = 0.006); however, there were no significant differences between PCSK9 rs505151G>A and rs11583680C>T genotypes. In multivariate analyses, patients with mTORC1 rs2295080G (p = 0.010), higher everolimus AUC0–12 (p = 0.006), and female sex (p = 0.029) showed higher change rates of PCSK9 following everolimus therapy. Conclusions: Administration of everolimus significantly elevated plasma PCSK9 concentrations, potentially causing everolimus-induced hyperlipidemia.
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Ohkubo S.
Journal of Chromatographic Science ( Journal of Chromatographic Science ) 58 ( 10 ) 915 - 921 2020年
研究論文（学術雑誌）
Abstract
Here, we developed a novel high-performance liquid chromatography (HPLC) method for quantification of perampanel in clinical practice and investigated the relationships between the plasma concentrations of perampanel obtained by this HPLC method and the CYP3A4*1G polymorphism. The developed HPLC method was validated based on US Food and Drug Administration. The developed HPLC method could be performed with a plasma volume of only 200 μL and had a limit of quantification (LOQ) of 2.5 ng/mL. The coefficients of variation (CVs) for intra- and inter-day assays were less than 10.4 and 7.2%, respectively, and the accuracy was &lt;2.4% for both assays. A total of 12 patients who received 2 mg perampanel had C0 values ranging from 70.5 to 451 ng/mL, and the CV showed a large variation of 51.4%. No correlations were observed between the dose-adjusted C0 and the CYP3A4*1G polymorphism. This method was superior to previously reported methods in terms of plasma volume and LOQ and was clinically applicable. Perampanel showed high variations in individual plasma concentrations; however, individual differences could not be predicted from analysis of the CYP3A4*1G polymorphism before perampanel administration. Therefore, after beginning perampanel treatment, the dose should be determined based on the observed plasma concentration.