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The anticancer drug, Lenvima (lenvatinib), has severe side effects. Therapeutic drug monitoring helps ensure its efficacy and safety. Regular and optimally timed blood sampling is tough, especially when lenvatinib is self-medicated. Microsampling using the easy to handle Microsampling Wing (MSW) may help circumvent this problem. However, current lenvatinib detection methods are not sensitive enough to detect its concentrations in microsamples (50-250 μL). Thus, the aim of this study was 2-fold (1) develop an analytic method to estimate plasma lenvatinib concentrations in microsamples and (2) verify whether this method works on micro (5.6 μL) blood plasma samples obtained clinically through MSW from patients with unresectable hepatocellular carcinoma (HCC).A simple, highly sensitive, and specific liquid chromatography-electrospray ionization tandem mass spectrometry method was developed. Using this novel protocol, the trough blood plasma concentration of lenvatinib was measured for both blood sampled conventionally and that using MSW. Thirty-five venous whole blood samples were obtained from 11 patients with HCC. Furthermore, the stability of lenvatinib in MSW samples during storage was evaluated.The mean plasma lenvatinib concentration estimates were not significantly different between the MSW and conventional venous blood samples. CV for interday and intraday assays was low. Up to day 5, the lenvatinib concentration in the MSW samples was 85%-115% of the initial day concentration (when stored at 25°C or 4°C). The interference of endogenous matrix components in the human plasma was low.These results indicate that the novel mass spectrometry protocol accurately measures lenvatinib in human plasma and is reproducible. Thus, MSW could be a useful microsampling device for lenvatinib therapeutic drug monitoring in patients with HCC when used in combination with this novel liquid chromatography-electrospray ionization tandem mass spectrometry detection method.

As Niemann-Pick disease type C (NPC) is difficult to diagnose owing to its various clinical symptoms; biomarker tests have been developed. Previously, we revealed urinary sulfated cholesterol metabolites as noninvasive biomarkers for NPC. However, LC/tandem mass spectrometry (LC/MS/MS) requires long separation time and large urine volumes. Recently, a basic mobile phase was reported to increase the MS intensity. Thus, we developed a highly sensitive and rapid LC/MS/MS method for analyzing urinary cholesterol metabolites using a basic mobile phase additive. 3β-Sulfooxy-7β-N-acetylglucosaminyl-5-cholenic acid, its glycine and taurine conjugates, 3β-sulfooxy-7β-hydroxy-5-cholenic acid, and 7-oxo form were measured, with selected reaction monitoring in negative ion mode. Oasis HLB and L-column 3 were used for column-switching LC/MS/MS and urine diluted 10-fold was employed as the sample. After trapping, gradient separation was performed using solutions containing 1% (v/v) ammonium solution. On average, a 16-fold increase in peak areas was observed compared to that obtained at pH 5.5 with the mobile phases. Although the previous method needed 60 min for separation from interference peaks, we succeeded to separate them in 7 min with optimized LC condition. Further, all compounds showed good linearity from 0.3-1000 ng/mL, with satisfactory intra- and inter-day reproducibility. The developed method was applied to the urinalysis of healthy participants and NPC patients. Overall, the concentrations of metabolites correlated with those obtained using the previous method. Therefore, we succeeded to increasing MS intensity and shorten LC running time; and the method is useful for the noninvasive diagnostic screening of patients with NPC.

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 mm and 50 mm were used for method 1 and 2, respectively. 2H3-labeled PPCS (PPCS-2H3_ 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 min 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.

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.

Sintering of zirconia usually takes a long time. In recent years, new products with extremely short sintering time have been released. Therefore, it is useful to study in detail the effect of sintering temperature and time on translucency of zirconia. The prepared discs were sintered under four conditions; 30 minutes, 40 minutes, 50 minutes and 60 minutes as firing temperature rising time up to 1500°C. Samples were measured with a spectrophotometer and translucency parameter (TP), opalescence parameter (OP) and contrast ratio (CR) were calculated. In this study, there were no statistically significant differences between TP, OP and CR due to the differences in heating rates. There is a possibility that a heating time up to the sintering temperature does not affect translucency of zirconia.

Purpose: Therapeutic drug monitoring (TDM) is widely used in clinical practice to maximize drug efficacy and minimize toxicities. Currently, it is also practiced in the use of oral molecular targeted drugs. The objective of this study was to assess the clinical importance of measuring the systemic concentration of oral molecular targeted drugs used to treat renal cell carcinoma (RCC). Methods: The systemic concentrations of the oral molecular targeted drugs sorafenib, sunitinib, axitinib, pazopanib, and everolimus used for RCC were useful for therapeutic interventions, and clinical outcomes were evaluated retrospectively. Results: The interventional use of systemic drug concentration was confirmed in 26 of 87, and their categories are presented. The systemic concentration of sunitinib was useful in dose reduction and/or discontinuation (n = 10), dose escalation (n = 3), and adherence monitoring (n = 2). Nine of the 10 patients whose dose was reduced showed reduced adverse event. Two patients who were intervened in adherence monitor showed improved adherence. For axitinib, dose reduction and/or discontinuation (n = 1) and dose escalation (n = 6) were confirmed. For pazopanib, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, both of them were confirmed to have reduced adverse events. For everolimus, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, a patient with reduced dose recovered from adverse events. Interventions for sorafenib were not identified. Conclusions: This study demonstrated that systemic concentrations of oral molecular targeted drugs for RCC were considered to be clinically useful for dose adjustment, monitoring of treatment adherence, and the detection of drug interactions. Moreover, this information could be successfully used to guide individualized therapy to maximize the antitumor effects of these drugs.

Background The current standard immunosuppressive regimens, calcineurin inhibitors, have diabetogeneic and anti-vascularization effects on islet grafts. KRP-203, a sphyngosine-1-phosphate functional antagonist, exerts its immunomodulatory function through lymphocyte sequestration. However, the effect of this antagonist on islets is unclear. We examined the effect of KRP-203 on the islet function and vascularization and sought a calcineurin-free regimen for islet allotransplantation. Methods KRP-203 was administered for 14 days to mice, then diabetogenic effect was evaluated by blood glucose levels and a glucose tolerance test. Static glucose stimulation, the breathing index, and insulin/DNA were examined using isolated islets. Islet neovascularization was evaluated using a multi-photon laser scanning microscope (MPLSM). After islet allotransplantation with either KRP-203 alone, Sirolimus alone, or both in combination, the graft survival was evaluated by blood glucose levels and immunohistochemical analyses. A mixed lymphocyte reaction was also performed to investigate the immunological characteristics of KRP-203 and Sirolimus. Results No significant differences in the blood glucose levels or glucose tolerance were observed between the control and KRP-203 groups. Functional assays after islet isolation were also comparable. The MPLSM showed no inhibitory effect of KRP-203 on islet neovascularization. Although allogeneic rejection was effectively inhibited by KRP-203 monotherapy (44%), combination therapy prevented rejection in most transplanted mice (83%). Conclusions KRP-203 is a desirable immunomodulator for islet transplantation due to the preservation of the endocrine function and lack of interference with islet neovascularization. The combination of KRP-203 with low-dose Sirolimus may be promising as a calcineurin-free regimen for islet allotransplantation.

Background Renal function and use of concomitant medications should be carefully monitored in patients subjected to treatment with direct oral anticoagulants (DOACs); the dose should be individually designed for each patient. Owing to the complex therapeutic indications and dose reduction criteria, pharmacists exercise caution when determining the optimal dose for each patient. A DOAC check sheet has been developed that is automatically printed in the dispensing room at the same time as the prescription and can be used by pharmacists to dispense DOACs promptly and correctly. The purpose of this study was to evaluate the system for dispensing DOACs using a check sheet. Methods The study was conducted at Tohoku University Hospital in Japan; prescriptions containing DOACs dispensed by the hospital pharmacists were evaluated. The DOAC check sheet described indications, dosage regimens, dose reduction criteria, and contraindications for each drug and included the patient’s information. The check sheet was set to print automatically in the dispensing room at the same time as the prescription when an inpatient was prescribed DOACs. This check sheet was evaluated using a prescription survey and a questionnaire for pharmacists. Results The usefulness of this check sheet for the correct use of DOACs was evaluated. There were four inquiries out of 642 (0.6%) prescriptions from pharmacists to physicians regarding DOAC prescriptions, such as the dose introduced before DOAC check sheet utilization, and there were 21 out of 905 (2.3%) prescriptions when the DOAC check sheet was used it, showing a significant increase (p = 0.0089). After the introduction of this sheet, overdoses of DOACs were identified at the time of dispensing. Of the 52 pharmacists who responded to the questionnaire, 51 (98%) stated that the check sheet was useful. Conclusion The use of the DOAC check sheet is likely to render safety to DOAC drug therapy for individual patients.

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.

The aim of this study was to clarify the temperature dependence of color, i.e. the thermochromism of restorative composite resins at typical intraoral temperatures. Five brands of restorative composite resins were used. The CIE L*a*b* color values were measured using a spectrophotometer at specimen temperatures of 4, 23, 37, 60, and 80ºC. The temperature dependence of the refractive index of the materials at 4-80ºC were also determined using a refractometer. The values of L* for all materials decreased, and those of a* and b* for most of the materials increased, with increasing temperature. The color difference (ΔE*) for all materials increased with increasing specimen temperatures. The refractive index of the A4 shade of the materials consistently decreased with increasing temperatures. Most of the materials exhibited perceptible thermochromism related to intraoral thermal conditions. Optical properties that change in response to temperature could help explain the thermochromism of materials.

Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high-performance LC/electrospray ionization-tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR-ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000-fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in-source collision-induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment. The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high-throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice.

Clozapine (CLZ) is a key drug in treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N-desmethylclozapine and clozapine N-oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in-source collision-induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra- and inter-assay accuracy was 84.6%-114.8%, and the intra- and inter-assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment-resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in-source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice.

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.

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.

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.

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). 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. 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

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

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.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.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.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.

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 (AUC 0-12 ) 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 AUC 0-12 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 AUC 0-12 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·C 1 + 3.08·C 4 + 5.17·C 8 for MPA, and -0.13 + 3.01·C 1 + 3.51·C 4 + 5.74·C 8 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 AUC 0-12 within ± 15% of the observed AUC 0-12 was 77.27% for MPA and 81.82% for AcMPAG. Conclusion: LSS using three time-point (C 1 , C 4 , and C 8 ) provides the most reliable and accurate simultaneous estimation of the AUC 0-12 of MPA and AcMPAG in Japanese lung transplant patients.

Oral molecular-targeted agents are used clinically for the treatment of various types of cancer. However, even when treatment is started at the dosage indicated in the medical package insert, we have experienced many cases in which treatment had to be stopped early owing to the occurrence of serious side effects or an insufficient therapeutic effect. In recent years, a wide range of studies has been conducted on the therapeutic drug monitoring (TDM) of oral molecular-targeted therapeutic agents to prevent serious side effects and maximize the therapeutic effect. In Japan, the TDM of imatinib has been covered by insurance since 2012, and the TDM of sunitinib has been covered since 2018. In contrast, tyrosine kinase inhibitors may have severe side effects, but their TDM is not covered by medical insurance. We aimed to identify a safe, highly effective chemotherapy regimen based on scientific evidence gathered from Japanese patients. We examined the relationship between the plasma concentration of drugs and clinical findings, such as side effects and treatment effects, at our hospital. In this symposium review, we introduce our results based on the treatment of patients with renal cell carcinoma.

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.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, and ribociclib) are used to treat human epithelial growth factor receptor (HER)-2 negative and hormone receptor (HR) positive advanced breast cancer in combination with aromatase inhibitors (letrozole, anastrozole) or an estrogen receptor antagonist (fulvestrant). Administration of these drugs frequently causes severe side effects, such as neutropenia and diarrhea. Therefore, therapeutic drug monitoring (TDM) of CDK4/6 inhibitors, aromatase inhibitors, and the estrogen receptor antagonist is considered important for ensuring the efficacy and safety of these drugs. In this study, we describe a simple, highly sensitive, and specific liquid chromatography/electrospray ionization tandem mass spectrometry method for simultaneous quantitation of the concentrations of palbociclib, abemaciclib, ribociclib, letrozole, anastrozole, and fulvestrant. In addition, we analyzed plasma samples from patients with HER2-negative and HR-positive advanced breast cancer treated with these compounds using this novel method. In our method, the intra-assay relative error (RE) values ranged from -12.8% to 12.9%, the inter-assay RE values ranged from -4.8% to 6.2%, and the coefficient of variation (CV) values for intra- and inter-assay were ≤8.6% and ≤13.3%, respectively. The analytes showed good stability with RE values ranging from -13.5% to 13.6% and CV values

The mechanical properties -tensile strength, yield strength, elongation after fracture, and Vickers hardness- and alloy phases of the dental cast alloys Ti-6%Nb-4%Cu, Ti-18%Nb-2%Cu, and Ti-24%Nb-1%Cu were investigated. Ti-6%Nb-4%Cu consisted of a single α-phase, while Ti-18%Nb-2%Cu and Ti-24%Nb-1%Cu consisted of α- and β-phases. The tensile strengths, yield strengths, and hardnesses of these alloys were higher than those of Ti-5%Cu and Ti-30%Nb; however, their breaking elongations were smaller. These differences in the mechanical properties are attributable to solid-solution strengthening or to precipitation strengthening by the dual-phase (α+β) structure. Thus, Ti-Nb-Cu alloys are suitable for use in high-strength dental prostheses, such as implantretained superstructures and narrow-diameter implants.

Introduction Miniscrews are frequently used for skeletal anchorage during edgewise treatment, and their clinical use has been verified. However, their disadvantage is an approximately 15% failure rate, which is primarily attributed to the low mechanical stability between the miniscrew and cortical bone and to the miniscrew's close proximity to the dental root. To solve these problems, we developed a novel spike-like auxiliary skeletal anchorage device for use with a miniscrew to increase its stability. Methods The retention force was compared between miniscrews with and without the auxiliary skeletal anchorage device at each displacement of the miniscrew. The combined unit was also implanted into the bones of 2 rabbits in vivo, and implantation was visually assessed at 4 weeks postoperatively while the compression force was applied. Results The retention force of the combined unit was significantly and approximately 3 to 5 times stronger on average than that of the miniscrew alone at each displacement. The spiked portion of the auxiliary anchorage device embedded into the cortical bone of the hind limb at approximately a 0.3-mm depth at 4 weeks postimplantation in both rabbits. Conclusions The auxiliary skeletal anchorage device may increase miniscrew stability, allow a shortened miniscrew, and enable 3-dimensional absolute anchorage. Further evaluation of its clinical application is necessary.

Titanium is difficult to machine because of its intrinsic properties. In a previous study, the machinability of titanium was improved by alloying with silver. This study aimed to evaluate the durability of tungsten carbide burs after the fabrication of frameworks using a Ti-20%Ag alloy and titanium with a computer-aided design and computer-aided manufacturing system. There was a significant difference in attrition area ratio between the two metals. Compared with titanium, the ratio of the area of attrition of machining burs was significantly lower for the experimental Ti-20%Ag alloy. The difference in the area of attrition for titanium and Ti-20%Ag became remarkable with increasing number of machining operations. The results show that the same burs can be used for a longer time with Ti-20%Ag than with pure titanium. Therefore, in terms of tool life, the machinability of the Ti-20%Ag alloy is superior to that of titanium.

The mechanical properties -tensile strength, yield strength, elongation after fracture, Vickers hardness, and Young's modulus-and the phases of Ti-Ag alloys were investigated, as prepared with 22.5, 25, 27.5, and 30 mass% Ag. The tensile strength, yield strength, hardness, and Young's modulus of the alloys increase with their Ag content up to 25 mass%, but their breaking elongation decreases. These changes in the mechanical properties are attributed to solid-solution strengthening of the α-titanium phase, to Ti2Ag precipitation, and to the formation of eutectic structures composed of α+Ti2Ag. The addition of Ag, at 25 mass% in particular, improves the mechanical properties of these alloys, making them suitable for high strength dental prostheses, such as implantretained superstructures and narrow-diameter implants.