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We evaluated the association of signal transducer and activator of transcription 3 (STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (1697C/G). We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% vs. 23.1%, odds ratio=11.67, 95% confidential interval=3.0644.46). There were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin, and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.

We investigated the utility of switching from benzodiazepines to suvorexant or eszopiclone to manage benzodiazepine-unresponsive insomnia in patients with major depressive disorder (MDD) in a randomized, open-label study.Patients with MDD who have insomnia symptoms (a score of7 on the Insomnia Severity Index Japanese version [ISI-J]), who had received benzodiazepine treatment for more than 2 weeks (n = 18) were randomized to 4 weeks of suvorexant (20 or 15 mg/d) or eszopiclone (3 or 2 mg/d) treatment. The primary endpoint was an improvement in insomnia severity from baseline assessed by the ISI-J score at 2 and 4 weeks after switching from benzodiazepines. The secondary endpoints included changes in the scores of the Pittsburgh Sleep Quality Index Japanese version, the Beck Depression Inventory II, Generalized Anxiety Disorder 7, the digit span test, and the digit symbol substitution test from baseline. Adverse events were recorded throughout the study.Patients taking suvorexant or eszopiclone had improved ISI-J scores (-4.3 for suvorexant and -4.1 for eszopiclone at week 4; P = 0.04 for eszopiclone). Both drugs tended to improve the Beck Depression Inventory II and Generalized Anxiety Disorder 7 scores 2 and 4 weeks after switching. The Pittsburgh Sleep Quality Index Japanese version, digit symbol substitution test, and digit span test scores and the incidence of adverse events did not change from baseline.Switching to suvorexant or eszopiclone was well tolerated and improved the severity of benzodiazepine-unresponsive insomnia in MDD patients. Both drugs could be beneficial alternatives to benzodiazepines for treating insomnia in MDD patients.

Background Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). On the other hand, in some patients, the efficacy of IFX therapy is not adequate, or gradually diminishes with the lapse of the treatment. Although previous studies have reported a positive relationship between serum IFX levels and therapeutic efficacy, the potential application of IFX therapeutic drug monitoring (TDM) in clinical practice remains unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Methods Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance, KURAMA,cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. Results Out of the 311 RA patients who received IFX therapy, 41 were eligible for analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.4 µg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the High-IFX group (n = 31) than in the Low-IFX group (n = 10). Conversely, at the maximum effect point, when DAS28-ESR (the 28 joint disease activity score incorporating erythrocyte sedimentation rate) was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the Low- and High-IFX groups. Conclusions In clinical practice, IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement. However, IFX TDM could facilitate the identification of secondary non-responders, and in turn, proper IFX use.

Biosimilar products of therapeutic antibodies have been launched all over the world. They can relieve some of the economic burden of medicines. Although clinical trials have demonstrated the equivalency of biosimilar products with their reference product, biosimilar products are not commonly used in clinical practice. One reason is that the structural difference between the reference product and a biosimilar one remains unclear. We analyzed glycoforms and amino acids of an infliximab biosimilar product approved in Japan compared to that of the reference product (Remicade®). By combination of papain digestion and LC/ time-of-flight (TOF)-MS, we established a valuable method to analyze these therapeutic antibodies. Nine glycoforms were detected in infliximab, and a difference in amino acids was observed. In the glycoforms of MMF, MGnF/GnMF, GnGn, GnGnF, AGnF/GnAF, and AAF, the relative intensities were significantly different between the reference and biosimilar product. Furthermore, we elucidated that the content rate of the C-terminal lysine was different among glycoforms. In conclusion, our analytical method can analyze not only amino acids but also carbohydrate chains of therapeutic antibodies, and will provide a useful strategy to evaluate bio-medicines including biosimilar antibodies.

Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. Twenty B cell non-Hodgkin’s lymphoma patients who were treated with rituximab for the first time or after more than one year’s abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420.A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236CT, 2677GT/A, 3435CT), ABCG2 (421CA), and CYP3A5 (6986AG) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated.The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0 levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients (p = 0.62).ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients.

[Purpose]: Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them. [Methods]: We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry. [Results]: The concentration and penetration rate of gefitinib (mean ± standard deviation) in the CSF were 3.7 ± 1.9 ng/mL (8.2 ± 4.3 nM) and 1.13 ± 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 ± 16.8 ng/mL (66.9 ± 39.0 nM) and 2.77 ± 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P = 0.0008 and

Introduction Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC). Method We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8. Results In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response. Conclusion Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

To increase the number of surgical operations and reduce the work of anesthesiologists involved in anesthetic management,a pharmacist started providing pharmaceutical services in the operating theater of Kyoto University Hospital in July 2007.We evaluated the changes in the workload of anesthesiologists and number of surgical operations performed due to the services as well as the medicoeconomic effects.Improvement of narcotic management and the provision of anesthetic sets by the pharmacist reduced the workload of anesthesiologists by approximately 173 hours per month.We found that assigning the pharmacist to the operating theater increased the number of daily operations to 22.3,from 20.3 beforehand.Furthermore,doing this achieved annual savings of \2 million by preventing omissions in the reimbursement of medical fees,saved \10 million by providing drug sets designed for use in surgery for individual patients and \5 million by improving drug inventory management.Thus the total annual medicoeconomic benefit was \17 million.The results of the present study suggest that that the stationing of pharmacists in operating theaters not only helps reduce the workload of anesthesiologists and improves drug management but also increases the number of surgical operations and produces medicoeconomic benefits.

[Purpose] Acute kidney injury (AKI) is a common and serious adverse effect of cisplatin-based chemotherapy. However, traditional markers of kidney function, such as serum creatinine, are suboptimal, because they are not sensitive measures of proximal tubular injury. We aimed to determine whether the new urinary biomarkers such as kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and neutrophil gelatinase-associated lipocalin (NGAL) could detect cisplatin-induced AKI in lung cancer patients in comparison with the conventional urinary proteins such as N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin. [Methods] We measured KIM-1, MCP-1, NGAL, NAG, and β2-microglobulin concentrations in urine samples from 11 lung cancer patients, which were collected the day before cisplatin administration and on days 3, 7, and 14. Subsequently, we evaluated these biomarkers by comparing their concentrations in 30 AKI positive (+) and 12 AKI negative (−) samples and performing receiver operating characteristic (ROC) curve analyses. [Results] The urinary levels normalized with urine creatinine of KIM-1 and MCP-1, but not NGAL, NAG, and β2-microglobulin in AKI (+) samples were significantly higher than those in AKI (−) samples. In addition, ROC curve analyses revealed that KIM-1 and MCP-1, but not NGAL, could detect AKI with high accuracy (area under the curve [AUC] = 0.858, 0.850, and 0.608, respectively). The combination of KIM-1 and MCP-1 outperformed either biomarker alone (AUC = 0.871). [Conclusions] Urinary KIM-1 and MCP-1, either alone or in combination, may represent biomarkers of cisplatin-induced AKI in lung cancer patients., First online: 25 September 2015

Therapeutic monoclonal antibodies (mAbs) have heterogeneities in their structures. Multiple studies have reported that the variety of post-translational modifications could affect the pharmacokinetic profiles or pharmacological potencies of therapeutic mAbs. Taking into the account that the structural modification of mAbs would affect the efficacy, it is worth investigating the structural alteration of therapeutic mAbs in the blood and the relationship between their structures and pharmacological effects. Herein, we have developed the method to isolate rituximab from plasma in which endogenous IgGs interfere the detection of rituximab, and successfully developed the analytical method with a liquid chromatograph time-of-flight mass spectrometer to detect the structure of rituximab in plasma with errors less than 30 parts per millions. Eight types of carbohydrate chains in rituximab were detected by this method. Interestingly, time-dependent changes in carbohydrate chains such as AAF (G2F) and GnGn (G0) were observed in rats, although the amino acids were stable. Additionally, these structural changes were observed via incubation in plasma as in the rat experiment, suggesting that a certain type of enzyme in plasma caused the alterations of the carbohydrate chains. The present analytical methods could clarify the actual pharmacokinetics of therapeutic mAbs, and help to evaluate the interindividual variations in pharmacokinetics and efficacy.

2549 Background: Erlotinib is a potent EGFR tyrosine kinase inhibitor, currently used to treat non-small cell lung cancer (NSCLC). Erlotinib shows a significant pharmacokinetic (PK) variability and...

Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. We describe a Japanese woman with NSCLC and CNS metastases who was resistant to 75 mg daily erlotinib, but the metastases were improved by 150 mg daily erlotinib. We investigated the plasma and CSF concentrations of erlotinib at each dose as well as the correlation between the plasma and CSF concentrations of erlotinib. Including this patient, we administered 150 mg erlotinib daily to nine NSCLC patients with CNS metastases and measured the plasma and CSF concentrations just before administration on day 8. The concentrations were determined using high-performance liquid chromatography with ultraviolet detection. The plasma and CSF concentrations of erlotinib at a dose of 75 mg were 433 and 14 nM, respectively. The plasma and CSF concentrations of erlotinib at a dose of 150 mg were increased to 1,117 and 44 nM, respectively. The mean ± standard deviation of CSF concentrations and penetration rates were 106 ± 59 nM and 4.5 ± 1.5%, respectively. There was a good correlation (R 2 = 0.84) between plasma and CSF concentrations (P = 0.0005). This study indicates that CSF concentrations of erlotinib depend on its plasma concentration. As seen in this patient, high CSF concentrations of erlotinib can be achieved by high-dose administration, and this finding suggests the efficacy of high-dose administration, especially to refractory CNS metastases of NSCLC patients.