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Rigorous dose adjustment by therapeutic drug monitoring (TDM) is recommended when everolimus (EVR) is administered for immunosuppression. In this study, the authors developed a highly sensitive ultrahigh-performance liquid chromatography coupled with the tandem mass spectrometry (UHPLC-MS/MS) method for measuring EVR concentrations in whole blood using a high-throughput solid-phase extraction method for sample pretreatment. Furthermore, the blood EVR concentrations in routine TDM samples from patients who underwent renal transplantation measured using the established UHPLC-MS/MS method were compared with those measured using the latex agglutination turbidimetric immunoassay (LTIA).Blood samples were pretreated by solid-phase extraction using a 96-well HLB µElution plate. The clinical application of the newly developed method was evaluated using 87 blood samples from 19 patients who underwent kidney transplant.The calibration curve showed good linearity over a wide range of 0.1-50 ng/mL, with relative error ≤15% obtained from the back calculation of calibrators, and ≤20% for the lower limit of quantification. Within-batch and batch-to-batch accuracies and precisions fulfilled the acceptance criteria of the US Food and Drug Administration guidelines for bioanalytical method validation. The extraction recovery rates were good (≥65.2%), and almost no matrix effects were found in any of the quality control samples. Blood EVR concentrations measured by UHPLC-MS/MS were positively correlated with those measured by LTIA. A Bland-Altman plot indicated that the UHPLC-MS/MS method yielded better measurements than the LTIA method, regardless of the concentration.Therefore, the authors succeeded in developing a novel high-sensitivity and high-throughput method for measuring blood EVR concentration by UHPLC-MS/MS using a µElution plate for sample pretreatment.

The pharmacokinetics of voriconazole shows large intra-individual and inter-individual variability and is affected by various factors. Recently, inflammation has been focused as a significant factor affecting the variability. This study aimed to compare the influence of C-reactive protein (CRP) and other clinical laboratory parameters on intra-individual variability in trough voriconazole concentration and examine the impact of inflammation in patients with hematological malignancies. We conducted a retrospective, single-center, observational cohort study. Forty-two patients with hematological malignancy who received oral voriconazole for prophylaxis against deep mycosis and underwent multiple measurements of trough plasma voriconazole concentration were recruited. Quantitative changes in pharmacological and clinical laboratory parameters (Δ) were calculated as the difference between the current and preceding measurements. Voriconazole concentration/maintenance dose per weight (C/D) was found to correlate positively with CRP level (n = 202, rs = 0.314, p 0.001). Furthermore, ΔC/D correlated positively with ΔCRP level (n = 160, rs = 0.442, p 0.001), and ΔCRP showed the highest correlation coefficient among the laboratory parameters. Univariate and multivariate analyses identified ΔCRP (p 0.001) and Δgamma-glutamyl transpeptidase (γGTP) (p = 0.019) as independent factors associated with ΔC/D. Partial R

Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC-MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti-MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples.Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate.The method showed good linearity over wide ranges. Within-batch and batch-to-batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations.This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.

What is known and objective Clinical cases of attenuation of opioid analgesic effect by administration of immune checkpoint inhibitors has not been reported. We present a case of head and neck cancer under pain management with opioids, in which cancer pain was exacerbated after administration of nivolumab. Case summary A male patient with head and neck cancer was hospitalized for the second-line treatment of nivolumab. He had complained of head and neck pain after admission, but the pain was especially worse after nivolumab administration. The dose of opioids was eventually increased by approximately 320% (morphine equivalent dose) compared to before administering nivolumab. What is new and conclusion When administering immune checkpoint inhibitors such as nivolumab in clinical practice, the possibility of attenuation of opioid analgesic effect should be considered.

Background Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future. Methods After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode. Results The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2-1000 ng/mL concentration range. The average recovery rate was 98.63 ± 4.55% (mean ± SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib. Conclusions A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting.

Cyclosporin A (CyA) has potent inhibitory activity on organic anion transporting polypeptide 1B (OATP1B), causing drug-drug interactions with its substrate drugs. 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a uraemic toxin, has also been suggested to inhibit OATP1B activity. Recent study has identified coproporphyrin-I (CP-I) as a specific endogenous substrate for OATP1B, which is useful to indicate OATP1B activity. We investigated the relationship of CP-I with CyA and CMPF concentrations in patients taking CyA.In total, 121 blood samples from 74 patients who took CyA and underwent routine therapeutic drug monitoring were divided into trough and peak samples.CyA and CP-I concentrations were significantly higher in peak samples than in trough samples. A positive correlation between CP-I and CyA concentrations was found in all samples and in trough and peak samples, while no correlation was observed between CP-I and CMPF concentrations. Multiple regression analysis identified CyA and C-reactive protein concentrations as independent factors affecting CP-I concentration, with blood CyA concentration having markedly greater contribution to plasma CP-I concentration.The present study suggests that CyA inhibits OATP1B activity in a concentration-dependent manner in clinical setting, and that dose adjustment of OATP1B substrate drugs coadministered with CyA according to plasma CMPF concentration may not be necessary.

For intensive care unit (ICU) patients, injectable voriconazole (VRCZ) is difficult to use because the patients often develop acute kidney injury. Since many ICU patients have consciousness disturbance, oral ingestion of tablet formulation is also difficult, and administration of a suspension via enteral feeding tube is required when using VRCZ. In this study, we investigated the in vitro adsorption property of oral VRCZ to feeding tube and performed pharmacokinetic analysis of VRCZ prepared by powdering and simple suspension for ICU patients. VRCZ was tube-administered to five ICU patients at a loading dose of 300 mg and plasma VRCZ concentrations before and at 1, 2, 4, 8, 12 h after the first dose were measured using HPLC. Pharmacokinetic parameters were calculated by non-compartmental model analysis. The recovery rate of VRCZ after infusion of the suspension through feeding tube was 89.8 ± 8.3%, but the cumulative rates after the first and second re-infusion were 102.7 ± 20.7 and 99.3 ± 10.3%, respectively, suggesting almost no residual drug in the tube after re-infusion. Metabolic phenotype was extensive metabolizer (EM) in two patients and intermediate metabolizer (IM) in three patients. The values of total clearance (CLtot/F) calculated by moment analysis were 0.51 and 0.55 L/h/kg in two EM patients, and 0.09, 0.29 and 0.31 L/h/kg in three IM patients. The CLtot/F was apparently lower in IM patients compared to EM. In conclusion, powdered and suspended VRCZ administered via enteral feeding tube showed pharmacokinetics depending on CYP2C19 gene polymorphism, similar to that observed in usual oral administration.

Objectives Critically ill patients in intensive care unit (ICU) are susceptible to infectious diseases, thus empirical therapy is recommended. However, the therapeutic effect in ICU patients is difficult to predict due to fluctuation in pharmacokinetics because of various factors. This problem can be solved by developing personalized medicine through therapeutic drug monitoring. However, when different measurement systems are used for various drugs, measurements are complicated and time consuming in clinical practice. In this study, we aimed to develop an assay using ultra-high performance liquid chromatography coupled with tandem mass spectrometry for simultaneous quantification of 12 antimicrobial agents commonly used in ICU: doripenem, meropenem, linezolid, tedizolid, daptomycin, ciprofloxacin, levofloxacin, pazufloxacin, fluconazole, voriconazole, voriconazole N-oxide which is a major metabolite of voriconazole, and posaconazole. Design & methods Plasma protein was precipitated by adding acetonitrile and 50% MeOH containing standard and labeled IS. The analytes were separated with an ACQUITY UHPLC CSH C18 column, under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. Results The method fulfilled the criteria of US Food and Drug Administration for assay validation. The recovery rate was more than 84.8%. Matrix effect ranged from 79.1% to 119.3%. All the calibration curves showed good linearity (back calculation of calibrators: relative error ≤ 15%) over wide concentration ranges, which allowed determination of Cmax and Ctrough. Clinical applicability of the novel method was confirmed. Conclusions We have developed an assay for simultaneous quantification of 12 antimicrobial agents using a small sample volume of 50 μL with a short assay time of 7 min. Our novel method may contribute to simultaneous calculation of pharmacokinetic and pharmacodynamic parameters.

Drug‐drug interaction of fluorinated pyrimidine anticancer agents with phenytoin is well known, but interaction with phenobarbital is limited. We describe a case showing increases in plasma phenobarbital as well as phenytoin concentrations during preoperative S‐1 (tegafur/gimeracil/oteracil) and radiation therapy for rectal cancer., When used in combination with a fluorinated pyrimidine anticancer drug such as S‐1, the blood level of PB as well as PHT may increase. In order to avoid adverse events due to this interaction, confirmation for the blood levels of PHT and PB by TDM is essential.

Free itraconazole and hydroxyitraconazole concentrations were markedly elevated despite almost no changes in total concentrations when itraconazole was discontinued due to adverse effects. Elevated free itraconazole concentration may have a causal relationship with the development of adverse effects.

What is known and objective Thrombocytopenia is one of the typical adverse events caused by linezolid (LZD). Recently, some cases of severe hyponatraemia occurring while receiving LZD have been reported. This study investigated a possible relationship between LZD-induced hyponatraemia and thrombocytopenia and identified the risk factors for hyponatraemia and/or thrombocytopenia. Methods In this retrospective, single-centre, observational cohort study, 63 hospitalized patients aged over 18 years who received intravenous injection of LZD for more than seven consecutive days in Oita University Hospital between April 2015 and March 2018 were analysed. Results Thrombocytopenia occurred in 25 (39.7%) patients and hyponatraemia in 11 (17.5%) patients. Seven of 11 patients with hyponatraemia had concurrent thrombocytopenia. Although both serum sodium level and platelet count declined in most patients who developed hyponatraemia, no significant association between thrombocytopenia and hyponatraemia was found. Creatinine clearance level (Ccr) was significantly lower not only in the thrombocytopenia (vs no-thrombocytopenia) but also in the hyponatraemia group (vs no-hyponatraemia group). Univariate and multivariate logistic regression analyses identified different risk factors for thrombocytopenia and/or hyponatraemia (thrombocytopenia: Ccr and administration period; hyponatraemia: serum albumin; thrombocytopenia and hyponatraemia: administration period and serum albumin). What is new and conclusion In conclusion, this study found no significant relationship between LZD-induced thrombocytopenia and hyponatraemia and identified some possible risk factors associated with onset of the two adverse events. These require further validation.

WHAT IS KNOWN AND OBJECTIVE Cystatin C (Cys-C) is a useful diagnostic marker for early renal dysfunction, but has the disadvantage of giving false-positive results when corticosteroids are administered. In this study, we aimed to evaluate the dose-dependent effect of corticosteroids on the divergence between estimated glomerular filtration rates based on Cys-C (eGFRcys) and creatinine (eGFRcreat) and calculate the cut-off value of corticosteroid dose having an impact on eGFRcys/eGFRcreat ratio. METHODS This retrospective study included 305 patients (1318 therapies) treated with oral or injectable corticosteroids between June 2014 and May 2018, who did not meet the exclusion criteria. All corticosteroid doses were converted to prednisolone equivalent. RESULTS Steroid dose correlated significantly with eGFRcys/eGFRcreat ratio for all corticosteroids and for prednisolone (rs = -.150 and -.273, respectively), whereas no correlation was observed for methylprednisolone and hydrocortisone. The cut-off value of prednisolone dose for eGFRcys/eGFRcreat ratio

Objectives Cardiovascular disease is one of the major causes of death in patients with end-stage kidney disease who have undergone kidney transplantation. Since the complication of cardiovascular disease in patients with chronic kidney disease is strongly linked to oxidative stress, understanding the oxidative stress condition after kidney transplantation would be of great importance for the prevention of cardiovascular disease. This study examined whether improvement of renal function after kidney transplantation has an impact on the redox state of the Cys34 residue of albumin that reflects the level of oxidative stress in blood. Design & methods We enrolled 23 patients with end-stage renal failure who received kidney transplantation. All patients were followed for 180 days after transplantation. The fractions of albumin isoforms were determined by the electrospray ionization time-of-flight mass spectrometry (ESI-TOFMS) method. Results Serum creatinine decreased significantly immediately after kidney transplantation, suggesting successful transplantations. The ESI-TOFMS method identified three albumin isoforms cysteinylated at the Cys34 residue (Cys-Cys34-albumin) and the three corresponding albumin isoforms without Cys34 cysteinylation. The fraction of total Cys-Cys34-albumin decreased transiently after kidney transplantation, and was followed by an elevation at day 7 and gradual decrease thereafter until day 180. Meanwhile, reduced albumin concentration did not change until day 14 after kidney transplantation, then showed a significant increase compared to pre-transplant level at day 30 and remained stably elevated until day 180. Conclusions Actual reduced albumin levels were found to exceed pre-transplant levels on or after day 30 following kidney transplantation unlike immediate restoration of renal function. Renal function was recovered immediately following kidney transplantation, but reduced albumen concentration increased above the pre-transplant levels only from day 30 after transplantation.

Indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid are uremic toxins that accumulate in renal failure and have been reported to decrease the activities of the drug-metabolizing enzyme cytochrome P450 3A and the drug transporter organic anion transporting polypeptides 1B, respectively. In this study, we established and validated an assay for simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma. The samples were pretreated by solid-phase extraction, and measured by ultra-high-performance liquid chromatography-tandem mass spectrometry. The validation results for this assay were within the acceptable limits recommended by the US Food and Drug Administration, with a lower limit of quantitation of 0.05 μg/mL for both indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. Recovery rates of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 100.7-101.9 and 100.2-101.3%, respectively. Matrix effects of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 101.1-105.5 and 97.0-103.8%, respectively. The validated assay was used to analyze indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations in the plasma samples of healthy volunteers and patients with chronic kidney disease. All the measured plasma indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations were within the calibration ranges. This novel method may contribute to predicting the activities of drug-metabolizing enzymes and drug transporters in individual patients.

Fixed dose regimen is currently the standard administration method for TKI. However, this case report indicated that TDM may by a useful approach to individualized dosing of TKI for the treatment of CML when initiating dialysis.

Chemotherapy after hepatectomy for colorectal liver metastasis has not been established, due to the toxic side effects, which are likely related to impaired drug clearance during liver regeneration. We investigated the pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil (5-FU) during liver regeneration after major hepatectomy in a rat model. Thirty-six male Wistar rats were divided into control (C), control with chemotherapy (CC), hepatectomy (H), and hepatectomy with chemotherapy (HC) groups. The CC and HC groups were administered 5-FU for 4 days. Plasma 5-FU, liver weight, and liver dihydropyrimidine dehydrogenase (DPD) were measured. The ileal villous height was measured to determine adverse effects. The area under the curve and maximum plasma concentration of 5-FU increased by up to 51% and 32%, respectively, in the HC group compared to the CC group. The liver regeneration rate was significantly lower in the HC group than in the H group (67.3 ± 7.4 vs 33.0 ± 5.7%, p

The use of a drug administration plan and therapeutic drug monitoring (TDM) based on pharmacokinetic-pharmacodynamic (PK-PD) analysis is important for the effective use of antimicrobial agents to treat infections. We focused on the use of beta-lactam agents, anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, and an antifungal agent as antimicrobial agents and examined their efficacy in patients under special clinical conditions from the viewpoint of safety and TDM. Our PK-PD analysis of the use of an administration plan to set an optimum serum level for beta-lactam agents or anti-MRSA drugs for the treatment of pneumonia, acute renal failure during continuous hemodialysis filtration, febrile neutropenia, or malignant tumors confirmed the necessity of managing the optimal serum level. PK-PD analysis was also useful for TDM of voriconazole and intubation administration in long-term use from the viewpoint of preventing the onset of side effects. PK-PD analysis appears to be a useful tool in antibiotic therapy and TDM for developing a pharmacokinetic "individual difference" for "individualization therapy" under special clinical conditions. PK-PD analysis utilizes the restrictive information that is obtained by a clinic to the maximum and allows coordination with the mission of hospital pharmacists to provide adequate antibiotic therapy.

Recently, several studies on pharmacokinetics parameters of daptomycin reported that plasma trough concentration was linked to efficacy and adverse effects, suggesting the usefulness of therapeutic drug monitoring. Although some methods for determining total daptomycin concentration using liquid chromatography coupled to tandem mass spectrometry were established previously, no sensitive quantification method for free drug concentration was established. In this study, we aimed to develop a quantitative method of measuring both total and free daptomycin concentrations using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), by which both trough and maximum concentrations can be measured. Plasma samples were prepared by solid phase extraction. Free fractions were obtained by ultrafiltration. The assay fulfilled the requirements of US Food and Drug Administration and the European Medicines Agency for assay validation. The methods for total and free drug showed good fit over wide ranges of 0.5–200 and 0.04–40 μg/mL, with lower limits of quantitation of 0.5 and 0.04 μg/mL, respectively. Recovery rate of free daptomycin from ultrafiltration was approximately 100%. Extraction recovery rates of total and free drug measurements ranged from 57.1 to 67.4% and 54.6 to 62.3%, while matrix effect varied between 111.9 and 118.7% and 104.0 and 127.1%, respectively. The maximum and trough concentrations of total and free daptomycin in plasma from two patients in intensive care unit were successfully determined, demonstrating the feasibility of clinical application of the novel methods for determining plasma total and free daptomycin concentrations. In conclusion, we succeeded to develop a sensitive and selective method using UPLC-MS/MS for quantitative measurement of total and free daptomycin concentrations in plasma.