Papers - IKEDA Ryuji
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Yoshikawa N., Ehara Y., Yamada Y., Matsusaki Y., Shimoda K., Ikeda R.
Scientific Reports 15 ( 1 ) 3364 2025.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Intra-patient variability in immunosuppressive blood drug concentrations is a potential biomarker in managing organ transplant patients. However, the association between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in preventing graft-versus-host disease remains unknown. In this study, we analyzed the relationship between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in acute graft-versus-host disease prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation. Eligible patients administered tacrolimus were categorized into two groups based on the grade of acute graft-versus-host disease, and propensity score matching was performed using graft-versus-host disease prophylaxis protocols and days to the disease onset to compare time in therapeutic range. In patients with tacrolimus blood concentration therapeutic range ≥ 10 ng/mL, time in therapeutic range during the first 4 weeks post-transplantation was significantly lower in the Grade II–III than in the Grade 0–I group. Among propensity score matching-extracted patients, the Grade II–III group had significantly lower time in therapeutic range during the first 2 and 4 weeks post-transplantation. Our results suggest that high time in therapeutic range early post-transplantation, particularly within 4 weeks, may avert the severity of acute graft-versus-host disease.
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Yasuda K., Hirano Y., Takeda R., Ikeda R., Ishida Y.
Neuropsychopharmacology Reports 45 ( 1 ) e12506 2025.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Neuropsychopharmacology Reports
Aim: Suvorexant is an orexin receptor antagonist (ORA) for the treatment of insomnia. The antagonistic action of suvorexant on orexin receptors is associated with an increase in rapid eye movement (REM) sleep, which can potentially lead to nightmares depending on the patient's condition. However, the precise risk factors for nightmares among patients taking ORAs, such as suvorexant, have yet to be identified. In this retrospective study, we aimed to identify the risk factors for the development of nightmares in patients treated with suvorexant. Methods: The risk factors were determined by comparing parameters between the nightmare group and the nonnightmare group. This study included 440 patients who received suvorexant at the University of Miyazaki Hospital from April 2014 to January 2021. Results: We found that 9.1% (n = 40) of the patients experienced suvorexant-induced nightmares. There was a significant difference in the median age, which was lower in the nightmare group than in the nonnightmare group (p < 0.01). Furthermore, both multiple logistic regression analysis and Cox proportional hazards regression analysis revealed increased odds ratios for nightmares for individuals aged 20–39 years. Conclusions: This study revealed that elderly patients taking suvorexant had fewer nightmares than nonelderly patients did.
DOI： 10.1002/npr2.12506
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Yamada Y., Ishitsuka Y., Fukaura-Nishizawa M., Kawata T., Ishii A., Shirakawa A., Sakai T., Tanaka M., Kondo Y., Takeo T., Nakagata N., Motoyama K., Higashi T., Arima H., Seki T., Kurauchi Y., Katsuki H., Higaki K., Ikeda R., Matsuo M., Era T., Irie T.
Life Sciences 350 122776 2024.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Life Sciences
Niemann–Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-β-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood–brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC.
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Yoshikawa N., Nagatomo T., Matsusaki Y., Yokota T., Yamada Y., Ikeda R.
Pharmazie 79 ( 6 ) 114 - 117 2024.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Pharmazie
The therapeutic effect of tacrolimus against ulcerative colitis (UC) is correlated with its trough blood concentration. Conventionally, oral tacrolimus for the treatment of UC is initiated under fasting conditions; once the symptoms improve, food intake is resumed. Tacrolimus blood concentration decreases with food intake compared with that under fasting conditions. The aim of this study was to explore the characteristics of patients with UC whose tacrolimus blood concentrations tended to decrease after food initiation. Medical data of 13 patients with UC and treated with tacrolimus were retrospectively obtained. The participant characteristics associated with the changes in tacrolimus blood concentrations after food initiation were analyzed using regression analysis based on the rate of decrease in the concentration/dose (C/D) ratio after food initiation. Single regression analysis showed that the number of days required from tacrolimus initiation to food resumption (P = 0.0071) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0247) were significantly associated with the rate of decrease in the C/D ratio after food initiation. Furthermore, multiple regression analysis showed a significant effect of the number of days to food resumption (P = 0.0004) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0012). The results suggest that the degree of change in blood tacrolimus concentration after food initiation may be related to the severity of the symptoms and pathology of UC. Early identification of participant characteristics may help control tacrolimus blood concentration fluctuations after food initiation.
DOI： 10.1691/ph.2024.4501
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Ishii Saya, Ozaki Mineo, Takamura Norito, Ogata Kenji, Tokunaga Jin, Ikeda Ryuji
Biological and Pharmaceutical Bulletin 47 ( 1 ) 213 - 220 2024.1
Language：English Publishing type：Research paper (scientific journal) Publisher：The Pharmaceutical Society of Japan
Diclofenac instillation is useful in preventing intraoperative miosis and macular edema caused by postoperative inflammation in cataract surgery; however, optimum efficacy is not attained when the instilled diclofenac strongly binds to albumin in patients’ aqueous humor. Therefore, a method that inhibits diclofenac binding and increases the concentration of its free fraction is needed. We conducted a basic study regarding the effects of inhibitors on the binding of instilled diclofenac to albumin and endogenous substances in aqueous humor. Aqueous humor samples from 16 patients were pooled together for analysis. The free fraction of diclofenac was measured using ultrafiltration methods in various experiments with pooled and mimic aqueous humor. Free fraction of diclofenac, a site II drug, in pooled aqueous humor was 0.363 ± 0.013. The binding of diclofenac in the presence of phenylbutazone (PB), a site I inhibitor, was significantly inhibited (free fraction = 0.496 ± 0.013); however, no significant inhibition by ibuprofen, a site II inhibitor, (free fraction = 0.379 ± 0.004), was observed. The unexpected result was due to free fatty acids (FFAs; palmitic acid (PA)) and L-tryptophan (Trp). The inhibition of diclofenac binding by PB in the mimic aqueous humor containing these endogenous substances revealed significant binding inhibition in the presence of PA and Trp. Diclofenac is strongly rebound from site II to site I in the presence of FFAs and Trp in the aqueous humor because FFAs and Trp induce a conformational change in albumin. Therefore, PB significantly inhibits the binding of diclofenac to albumin.
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Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann-Pick disease type C treatment. Reviewed
Yamada Y, Fukaura-Nishizawa M, Nishiyama A, Ishii A, Kawata T, Shirakawa A, Tanaka M, Kondo Y, Takeo T, Nakagata N, Miwa T, Takeda H, Orita Y, Motoyama K, Higashi T, Arima H, Seki T, Kurauchi Y, Katsuki H, Higaki K, Minami K, Yoshikawa N, Ikeda R, Matsuo M, Irie T, Ishitsuka Y
Clinical and translational medicine 13 ( 8 ) e1350 2023.8
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Yasuda K., Takeda R., Ikeda R., Ishida Y.
Psychiatry and Clinical Neurosciences Reports 2 ( 1 ) e76 2023.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Psychiatry and Clinical Neurosciences Reports
Aim: Yokukansan is a Japanese herbal medicine used in psychiatry to treat behavioral and psychological symptoms of dementia and other psychiatric symptoms. However, the glycyrrhizic acid included in this medicine can cause pseudoaldosteronism and hypokalemia. We aimed to identify the risk factors for hypokalemia due to yokukansan. Methods: A retrospective cohort study was conducted on patients previously treated with yokukansan. The risk factors were determined by comparing the hypokalemia group with the non-hypokalemia group for each parameter. Results: This study included 304 patients who received yokukansan treatment between April 2009 and March 2019. We found that 17.4% (n = 53) of the patients experienced yokukansan-induced hypokalemia. Risk factors detected as significantly different between patients with and without yokukansan-associated hypokalemia were low serum potassium concentration before yokukansan administration, dose 7.5 g /day or more, and dementia. Hypokalemia occurred earlier in patients with low albumin, low potassium, and dementia. Conclusion: It is necessary to pay attention to hypokalemia onset when administering yokukansan at 7.5 g or more to patients with low potassium levels and dementia. Our findings suggest that potassium levels must be checked early after yokukansan administration, especially in patients with low albumin, low potassium, and dementia.
DOI： 10.1002/pcn5.76
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Koreeda H., Yoshikawa N., Minami K., Yokota T., Ochiai H., Ikeda R.
Pharmazie 77 ( 11-12 ) 348 - 351 2022.12
Publishing type：Research paper (scientific journal) Publisher：Pharmazie
Infections are the most common cause of mortality in patients with burns and are, therefore, a major challenge in burn treatment. Appropriate infection control measures are required for a good prognosis with respect to wound infections. Infection prevention improves the outcomes of burn patients. We aimed to determine the efficacy of early antimicrobial therapy in patients with severe flame burns. We conducted a single-centre, observational, case-control study to assess the relationship between prognosis and timing of antimicrobial therapy in the treatment of severe burns in emergency department patients from April 2018 to March 2020. The primary outcome was the association between the initiation of antimicrobial use and prognosis in patients with severe burns. Twenty-three participants were included in the study: 14 in the Control group, and nine in the Case group (patients with severe flame burns). Analysis of the association between the number of days from admission to the emergency department to the start of antimicrobial therapy and length of hospital stay showed a significant correlation in the Case group (P = 0.0006) but not in the Control group (P = 0.9630). Furthermore, in the Case group, the number of days from admission to initiation of antimicrobial therapy was significantly shorter in the group with a good skin condition prognosis (median, 4; range, 2-5) than in the group with a poor skin condition prognosis (median, 9; range, 7-14) (P = 0.0256). This study showed that early use of antimicrobials in patients with severe burns leads to improved skin graft outcomes and shorter hospital stays for patients.
DOI： 10.1691/ph.2022.2500
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Yoshikawa N., Takeshima H., Matsusaka K., Yokota T., Shimoda K., Ikeda R.
Pharmazie 77 ( 11-12 ) 335 - 337 2022.12
Publishing type：Research paper (scientific journal) Publisher：Pharmazie
Tacrolimus is a prophylactic for graft-versus-host disease (GVHD), a major cause of mortality in hematopoietic stem cell transplantation (HSCT) patients. Individuals homozygous for the ∗3 mutation in cytochrome P450 3A5-encoding gene (CYP3A5) lack CYP3A5 expression, affecting tacrolimus pharmacokinetics. Here, we investigated the relationship between CYP3A5∗3 polymorphism and GVHD in allogeneic HSCT patients receiving tacrolimus. The patients underwent their first allogeneic HSCT and were administered tacrolimus by continuous infusion. A quenching probe method was used to genotype the CYP3A5 6986A>G (∗3) allele. Based on CYP3A5 polymorphism analysis results, the subjects were divided into wild-type allele-bearing (∗1/∗3) and non-bearing (∗3/∗3) groups. The groups were compared regarding their characteristics at the time of transplantation and the frequency of acute GVHD. The ∗1/∗3 and ∗3/∗3 groups comprised nine and 11subjects, respectively. The frequency of acute GVHD during the observation period was higher in the ∗1/∗3 group than in the ∗3/∗3 group (P = 0.049). There was a significant difference in the cumulative incidence of acute GVHD between the two groups (P = 0.019). When GVHD was observed, the blood tacrolimus concentration was close to the target concentration (10-15 ng/mL). CYP3A5∗3 polymorphism could potentially predict clinical outcomes.
DOI： 10.1691/ph.2022.2435
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Yamada Yusei, Miwa Toru, Nakashima Masaki, Shirakawa Aina, Ishii Akira, Namba Nanami, Kondo Yuki, Takeo Toru, Nakagata Naomi, Motoyama Keiichi, Higashi Taishi, Arima Hidetoshi, Kurauchi Yuki, Seki Takahiro, Katsuki Hiroshi, Okada Yasuyo, Ichikawa Atsushi, Higaki Katsumi, Hayashi Ken, Minami Kentaro, Yoshikawa Naoki, Ikeda Ryuji, Ishikawa Yoshihide, Kajii Tomohito, Tachii Kyoko, Takeda Hiroki, Orita Yorihisa, Matsuo Muneaki, Irie Tetsumi, Ishitsuka Yoichi
155 113698 2022.11
Language：English Publishing type：Research paper (scientific journal)
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Okumura M., Iwakiri T., Yoshikawa N., Nagatomo T., Ayabe T., Tsuneyoshi I., Ikeda R.
International Journal of Molecular Sciences 23 ( 16 ) 2022.8
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences
Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.
DOI： 10.3390/ijms23169108
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Takumi S., Hashimoto K., Tomioka M., Sato M., He W., Komatsu Y., Aoki S., Ikeda R., Shiozaki K., Furukawa T., Komatsu M.
Planta Medica 89 ( 6 ) 616 - 623 2022.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Planta Medica
The hepatotoxin microcystin-LR is a strong inhibitor of serine/threonine protein phosphatase (PP) 1 and PP2A. The onset of its cytotoxicity depends on its selective uptake via the hepatocyte uptake transporters, organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Understanding and preventing the cytotoxicity of microcystin-LR is crucial to maintain human health. This chemoprevention study demonstrates that the herbal plant extract of iwajisha (20 μg/mL) reduced microcystin-LR cytotoxicity in OATP1B3-expressing cells by approximately six times. In addition, 20 μM acteoside, which is one of the major compounds in iwajisha, reduced microcystin-LR cytotoxicity by approximately 7.4 times. Acteoside could also reduce the cytotoxicity of other compounds, such as okadaic acid and nodularin, which are both substrates of OATP1B3 and inhibitors of PP1/PP2A. To investigate the mechanism by which the cytotoxicity of microcystin-LR is attenuated by acteosides, microcystin-LR and microcystin-LR-binding proteins in cells were examined after microcystin-LR and acteosides were co-exposed. Thus, acteoside noncompetitively inhibited microcystin-LR uptake by OATP1B3-expressing cells. Furthermore, acteoside inhibited the intracellular interaction of microcystin-LR with its binding protein(s), including the 22 kDa protein. Furthermore, using immunoblot analysis, acteoside induced the phosphorylation of extracellular signal-regulated kinase (ERK), which is one of the survival signaling molecules. These results suggest that acteoside reduces microcystin-LR cytotoxicity through several mechanisms, including the inhibition of microcystin-LR uptake via OATP1B3, and decreased interaction between microcystin-LR and its binding protein(s), and that ERK signaling activation contributes to the attenuation effect of acteoside against microcystin-LR cytotoxicity.
DOI： 10.1055/a-1978-8768
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Tsuruda T., Sato Y., Tomita M., Tanaka H., Hatakeyama K., Otsu M., Kawano A., Nagatomo K., Yoshikawa N., Ikeda R., Asada Y., Kaikita K.
Frontiers in Cardiovascular Medicine 9 833649 2022.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Cardiovascular Medicine
Background: Cardiac troponin-T (TNNT2) is exclusively present in cardiac muscle. Measurement of TNNT2 is used for diagnosing acute coronary syndrome. However, its expression may not be limited in myocardium. This study aimed at evaluating the expression of TNNT2 in neoplastic tissues. Methods and Results: We used paraffin-embedded blocks of 68 patients with lung cancer (age, 68 ± 11 years old; early-stage, 33; advance-stage, 35) at Miyazaki University Hospital, Japan between January 1, 2017, and March 31, 2019. We stained the slide sections with primary monoclonal antibody against TNNT2 protein, and assessed the frequency of positive staining, and its association with pathological severity. In addition, we examined whether TNNT2 gene is detected in lung cancer tissues of four patients using reverse transcription-polymerase chain reaction. Immunoreactivity for TNNT2 protein was present in the cytoplasm and nucleus of lung cancer cells. The frequency was 37% (25 of 68) in all patients and was irrespective of histologic type (six of 13, squamous cell carcinoma; 18 of 50, adenocarcinoma; 0 of 4, neuroendocrine cell carcinoma; 1 of 1, large cell carcinoma). The prevalence increased with pathological staging [9% (3 of 33) at early-stage (Stage 0–I); 63% (22 of 35) at advance-stage (Stage II–IV and recurrence)]. In addition, frequency of positive staining for TNNT2 increased with pleural (χ2 = 5.877, P = 0.015) and vascular (χ2 = 2.449, P = 0.118) invasions but decreased with lymphatic invasion (χ2 = 3.288, P = 0.070) in specimens performed surgical resection. Furthermore, TNNT2 mRNA was detected in the resected squamous cell carcinoma and adenocarcinoma tissues. Conclusions: Our data suggest the aberrant expression of TNNT2 in lung cancer and its prevalence increases with pathological severity.
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Takeshima H., Yoshikawa N., Akizuki K., Hidaka T., Shimoda K., Ikeda R.
Journal of Clinical Pharmacy and Therapeutics 47 ( 2 ) 260 - 262 2022.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Pharmacy and Therapeutics
What is known and objective: Cyclosporine A (CyA) causes intrahepatic biliary stasis via inhibition of bile acid excretion through the bile salt export pump. We report a case of a patient in whom ursodeoxycholic acid (UDCA) markedly promoted the absorption of microemulsion-formulated CyA. Case summary: The patient was a 22-year-old Japanese man diagnosed with stage 3 aplastic anaemia. He was treated with CyA, and 2 h post-dose (C2) was increased by UDCA. What is new and conclusion: A remarkable interaction was observed between CyA and UDCA. This is a valuable finding for improving the treatment strategies for haematological disorders.
DOI： 10.1111/jcpt.13496
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池田 龍二
ジェネリック研究 16 22 - 33 2022
Publishing type：Research paper (scientific journal)
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Association between CYP3A5*3 polymorphism and graft-versus-host disease in allogeneic hematopoietic stem cell transplant patients receiving tacrolimus Reviewed
吉川 直樹, 池田 龍二
Die Pharmazie 77 35 - 337 2022
Publishing type：Research paper (scientific journal)
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Urata S., Yoshikawa N., Saito K., Tazaki T., Ohno R., Takeshima H., Ikeda R.
Journal of Clinical Pharmacy and Therapeutics 46 ( 6 ) 1796 - 1799 2021.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Pharmacy and Therapeutics
What is known and objective: Methotrexate (MTX) is an important agent for the treatment of primary central nervous system lymphomas (PCNSL) but needs to be given in big doses by intravenous infusions to achieve therapeutic concentrations in the cerebrospinal fluid. However, co-administration with many drugs may delay the excretion of MTX which may cause serious adverse effects if the serum concentration exceeds 0.1 µmol/L 72 h after an intravenous infusion. Case summary: A 67-year-old Japanese female with PCNSL was treated with high-dose MTX-based chemotherapy. The serum MTX concentration 72 h post-infusion was 0.153 µmol/L when she was taking levofloxacin (LVFX) but <0.1 µmol/L 72 h after 4 subsequent infusions when she was not taking LVFX. She was given many other drugs but the timing of the short course of LVFX and the fact that ciprofloxacin also delays MTX excretion suggests that LVFX was the cause. What is new and conclusion: Co-administration of LVFX may delay the excretion of MTX. Therefore, serum concentrations of MTX should be monitored to help prevent and improve the management of potentially serious MTX drug-drug interaction.
DOI： 10.1111/jcpt.13425
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Nagata T., Minami K., Yamamoto M., Hiraki T., Idogawa M., Fujimoto K., Kageyama S., Tabata K., Kawahara K., Ueda K., Ikeda R., Kato Y., Komatsu M., Tanimoto A., Furukawa T., Sato M.
International Journal of Molecular Sciences 22 ( 21 ) 2021.11
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences
Lung cancer constitutes a threat to human health. BHLHE41 plays important roles in circadian rhythm and cell differentiation as a negative regulatory transcription factor. This study investigates the role of BHLHE41 in lung cancer progression. We analyzed BHLHE41 function via in silico and immunohistochemical studies of 177 surgically resected non-small cell lung cancer (NSCLC) samples and 18 early lung squamous cell carcinoma (LUSC) cases. We also examined doxycycline (DOX)-inducible BHLHE41-expressing A549 and H2030 adenocarcinoma cells. BHLHE41 expression was higher in normal lung than in lung adenocarcinoma (LUAD) tissues and was associated with better prognosis for the overall survival (OS) of patients. In total, 15 of 132 LUAD tissues expressed BHLHE41 in normal lung epithelial cells. Staining was mainly observed in adenocarcinoma in situ and the lepidic growth part of invasive cancer tissue. BHLHE41 expression constituted a favorable prognostic factor for OS (p = 0.049) and cause-specific survival (p = 0.042) in patients with LUAD. During early LUSC, 7 of 18 cases expressed BHLHE41, and this expression was inversely correlated with the depth of invasion. DOX suppressed cell proliferation and increased the autophagy protein LC3, while chloroquine enhanced LC3 accumulation and suppressed cell death. In a xenograft model, DOX suppressed tumor growth. Our results indicate that BHLHE41 expression prevents early lung tumor malignant progression by inducing autophagic cell death in NSCLC.
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Yoshikawa N., Yamada A., Yokota T., Yamada Y., Kinoshita M., Moritake H., Ikeda R.
Cancers 13 ( 18 ) 2021.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Cancers
Intrathecal administration of anticancer drugs is an effective dosage strategy, but the elimination of intraventricular drugs is not uniform in all patients. For safety, a system to evaluate local pharmacokinetics in the ventricles after administration is desired. In this study, we developed a simple and reproducible method to measure topotecan concentration in the cerebrospinal fluid (CSF) and confirmed its clinical applicability. High-performance liquid chromatography (HPLC) analysis was performed using a C18 column to measure the total topotecan concentration in the CSF. Clinical CSF samples were obtained from a 1-year old child with poor CSF absorption and stagnation. The patient received topotecan via an intraventricular subcutaneous reservoir. The HPLC method complied with the validation criteria. The lower limit of quantitation of this method was 0.04 µM. Using the developed method, we could determine the difference in topotecan CSF concentrations at 24 and 48 h after administration. The patient’s topotecan elimination rate was extremely low, and signs of adverse effects were observed at high CSF concentration of topotecan. The developed method could detect the delay in topotecan elimination after intrathecal injection. The findings of this study are valuable for the development of personalized treatments for the intrathecal administration of anticancer drugs.
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High-trough plasma concentration of afatinib is associated with dose reduction Reviewed
Takahashi T., Terazono H., Suetsugu T., Sugawara H., Arima J., Nitta M., Tanabe T., Okutsu K., Ikeda R., Mizuno K., Inoue H., Takeda Y.
Cancers 13 ( 14 ) 2021.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Cancers
Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.