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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.

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.

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.

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.

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.

Background: Although lenvatinib treatment has a favorable efficacy for unresectable hepatocellular carcinoma (HCC), it is associated with adverse events (AEs) that must be closely monitored and managed. Thrombocytopenia is one of the major AEs. The aim of this study was to clarify whether thrombocytopenia can be predicted by the plasma concentration of lenvatinib. Methods: This was a single-center retrospective observational study. Twenty-three patients with unresectable HCC and pharmacokinetics data at the initial lenvatinib administration between May 2018 and September 2020 at Oita University Hospital were enrolled. The AEs during the 4 weeks after the initiation of treatment were evaluated, and the correlations between the thrombocytopenia and the plasma concentration of lenvatinib were examined. Spearman’s correlation was used to evaluate the correlation between two continuous variables. Results: The rate of platelet count decrease correlated with the maximum plasma concentration (C max ) (r = 0.65, P = 0.001), whereas it did not with the minimum plasma concentration (C min ) (r = 0.29, P = 0.206). After stepwise multiple linear regression analysis, the starting dose of lenvatinib and the serum albumin concentration were identified as independent explanatory variables. Next, a formula for predicting the C max using these two variables was created. The predicted C max was strongly correlated with the C max (r = 0.87, P < 0.0001) and the rate of platelet count decrease (r = 0.67, P = 0.001). Conclusions: This study identified the usefulness of the drug C max to predict the rate of platelet count decrease within 4 weeks after the initiation of treatment. Although it is difficult to measure the plasma concentration of lenvatinib in community hospitals, the predicted C max is useful for predicting the rate of platelet count decrease with this treatment. World J Oncol. 2021;12(5):165-172 doi: https://doi.org/10.14740/wjon1399

4β-Hydroxycholesterol (4β-OHC) is formed by Cytochrome P450 (CYP)3A and has drawn attention as an endogenous phenotyping probe for CYP3A activity. However, 4β-OHC is also increased by cholesterol autooxidation occurring in vitro due to dysregulated storage and in vivo by oxidative stress or inflammation, independent of CYP3A activity. 4α-hydroxycholesterol (4α-OHC), a stereoisomer of 4β-OHC, is also formed via autooxidation of cholesterol, not by CYP3A, and thus may have clinical potential in reflecting the state of cholesterol autooxidation. In this study, we establish a sensitive method for simultaneous quantification of 4β-OHC and 4α-OHC in human plasma using ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Plasma samples were prepared by saponification, two-step liquid-liquid extraction, and derivatization using picolinic acid. Intense [M+H]+ signals for 4β-OHC and 4α-OHC di-picolinyl esters were monitored using electrospray ionization. The assay fulfilled the requirements of the US Food and Drug Administration guidance for bioanalytical method validation, with a lower limit of quantification of 0.5 ng/ml for both 4β-OHC and 4α-OHC. Apparent recovery rates from human plasma ranged from 88.2% to 101.5% for 4β-OHC, and 91.8% to 114.9% for 4α-OHC. Additionally, matrix effects varied between 86.2% and 117.6% for 4β-OHC and between 89.5% and 116.9% for 4α-OHC. Plasma 4β-OHC and 4α-OHC concentrations in healthy volunteers, stage 3-5 chronic kidney disease (CKD) patients, and stage 5D CKD patients as measured by the validated assay were within the calibration ranges in all samples. We propose this novel quantification method may contribute to accurate evaluation of in vivo CYP3A activity.

Combination therapy of tegafur/uracil (UFT) and leucovorin (LV) is widely used to treat colorectal cancers. Although this therapy has a significant therapeutic effect, severe adverse effects occur frequently. Therapeutic drug monitoring (TDM) may help to prevent adverse effects. A useful assay that can quantitate plasma levels of 5-FU, uracil, and tegafur simultaneously for TDM has been desired, but such a method is not currently available. In this study, we aimed to develop a sensitive method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). After preparing plasma samples by protein precipitation and liquid extraction, 5-FU, uracil, and tegafur were analyzed by UPLC-MS/MS in negative electrospray ionization mode. Validation was performed according to US Food and Drugs Administration guidance. The calibration curves were linear over concentration ranges of 2–500 ng/mL for 5-FU, 20–5000 ng/mL for uracil, and 200–50,000 ng/mL for tegafur. The corresponding average recovery rates were 79.9, 80.9, and 87.8%. The method provides accuracy within 11.6% and precision below 13.3% for all three analytes. Matrix effects of 5-FU, uracil, and tegafur were higher than 43.5, 84.9, and 100.2%, respectively. This assay was successfully applied to assess the time courses of plasma 5-FU, uracil, and tegafur concentrations in two patients with colorectal liver metastasis who received UFT/LV therapy after hepatectomy. In conclusion, we succeeded to develop a sensitive and robust UPLC-MS/MS method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma. This method is potentially useful for TDM in patients receiving UFT/LV combination therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Imatinib is used as first-line treatment for chronic myeloid leukemia (CML) even in patients with impaired renal function. We successfully used therapeutic drug monitoring to determine the dose for re-administration of imatinib in a CML patient who initiated dialysis for acute renal dysfunction associated with the initial imatinib therapy.

We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h−1) = CLbody(non-CRRT) = 3.65 × (Ccr/62.25)0.64 in the absence of CRRT, or = CLbody(CRRT) + CLCRRT = 2.49 × (Ccr/52.75)0.42 + CLCRRT in the presence of CRRT; CLCRRT = QE × 0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L) = 10.04; V2 (L) = 8.13; and Q (L h−1) = 3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30–40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.

We investigated the potential of mid-regional pro-adrenomedullin (MR-proADM) for use as a novel biomarker for arterial stiffness as the criterion for vascular failure and cardiometabolic disease (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome) compared with high-sensitivity C-reactive protein (hsCRP). Overall, 2169 individuals (702 men and 1467 women) were enrolled. Multiple regression analysis was performed to assess the association of MR-proADM and hsCRP with brachial-ankle pulse wave velocity (baPWV), adjusting for other variables. The diagnostic performance (accuracy) of MR-proADM with regard to the index of vascular failure was tested with the help of receiver operating characteristic curve analysis in the models. MR-proADM was significantly higher in participants with vascular failure, as defined by baPWV and/or its risk factors (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome), than in control groups. Independent of cardiovascular risk factors (age, drinking, smoking, body mass index, systolic blood pressure, lipid and glycol metabolism), MR-proADM was significantly associated with baPWV, and MR-proADM showed higher areas under the curve of baPWV than hsCRP showed. MR-proADM is more suitable for the diagnosis of higher arterial stiffness as the criterion for vascular failure than hsCRP. Because vascular assessment is important to mitigate the most significant modifiable cardiovascular risk factors, MR-proADM may be useful as a novel biomarker on routine blood examination.

Background Rheumatoid arthritis (RA) is one of the causes of secondary osteoporosis, and steroids are often used in combination, therefore osteoporosis is highly associated with RA. Furthermore, joint disorders due to RA cause various degrees of dysfunction and ADL declines. The Steinbrocker classification is often used as the degree of dysfunction. Immobilization progresses with the progress of dysfunction, possibly causing severe osteoporosis. Objectives Of the 2238 cases in Akita Orthopedic Group omn Rheumatoid Arthrotis (AORA) registry 2017, 101 cases simultaneously measuring bone metabolism markers (TARCP-5b, NTX, urinary DPD, BAP, total P1NP) and pentosidine were involved. Methods Patients were divided by Steinbrocker classification into class 1,2 (group A 84 cases) and clss 3, 4 (group B 17 cases). we examined whether there is a difference in bone metabolism markers in each group according to Steinbrocker classification. Results The average age in group B (75.9) was significantly higher than group A (66.9) (p = 0.01). DAS 28 ESR was significantly higher in group B (p Conclusion Immobilization by long-term bed rest is known to enhance bone resorption. In 2002, Wakae reported DPD in urine showed a higher value in the group of not going out in femoral neck fracture cases. Based on the results of this study, urinary DPD showed a high value in RA group with high degree of dysfunction, which possibly reflected immobilization due to progress of functional disorder. Moreover, it is known that pentosidine will be higher in cases with high disease activity, severe osteoporosis will be occurred in the group with progressive functional disorder which is difficult to tight control. Disclosure of Interests None declared

Background Treatment outcomes for rheumatoid arthritis (RA) have been improved by advances in drugs. In daily clinical practice, treatment outcomes are assessed with both inflammatory findings and based on swollen joints (SJ), tender joints (TJ), a patient’s global assessment on visual analogue scale (GVAS) score, a physician’s GVAS score, etc. Although composite measures indicate suppressed inflammatory or articular symptoms, many patients show no improvement in GVAS scores. The reported residual symptoms include morning stiffness (MS), pain (P), and dullness (D). Objectives We investigated the residual symptoms of patients achieving low disease activity (LDA) or complete remission (CR). Methods His study included 111 RA patients who received outpatient treatment at our department (31 men and 80 women). The mean age was 65.1 (range, 27–89) years. The disease stages were distributed as follows: 36 patients with Stage 1, 23 patients with Stage 2, 20 patients with Stage 3, and 32 patients with Stage 4. The severity of dysfunction was distributed as follows: Class 1 in 73 patients, Class 2 in 25 patients, Class 3 in 11 patients, and Class 4 in 2 patients (Steinbrocker classification). Based on the disease activity score in 28 joints using the erythrocyte sedimentation rate, disease activity was graded as CR in 54 patients, LDA in 19, moderate disease activity in 37, and high disease activity in 1. Questionnaire forms were used to assess the presence or absence and duration of MS and the presence or absence and severity of P (Pain VAS) and of D (Dullness VAS). These variables were assessed to determine how they were associated with clinical outcome measures, drugs, and surgery. Results The following residual symptoms were observed in 73 patients who achieved the treatment target of LDA or CR: MS in 34 patients (46.6%), P in 48 (65.6%), and D in 38 (52.8%). In the LDA+CR group, the Pain VAS (P Conclusion Residual symptoms were frequently observed even in patients achieving LDA or CR, which is regarded as the treatment target. Because P and D were significantly correlated with the GVAS, relief of these residual symptoms is expected to improve treatment effects. Although D was relieved by bDMARDs, further studies on the treatment of residual P in patients achieving LDA or CR are necessary. Disclosure of Interests None declared

Background While the number of rheumatoid arthritis (RA) surgeries has been declining due to advances in pharmacotherapies for RA, forefoot surgeries are on the rise. In recent years, the common use of joint ultrasonography in RA consultations has led to the early detection of synovitis. However, little is known about how much forefoot deformities such as hallux valgus and metatarsophalangeal (MTP) joint dislocation are affected by synovitis in the forefoot of RA patients. Objectives The present study examined factors involved in forefoot deformity among patients with foot synovitis identified on joint ultrasound. Methods Subjects (71 patients, 91 feet) were RA patients who had undergone foot joint ultrasonography more than 2 years earlier and underwent standing X-rays of the feet before and after ultrasonography. Surgery cases were excluded. Mean age was 64.9 years (range, 15-90 years). Disease stage was Stage 1 in 14 patients, Stage 2 in 14 patients, Stage 3 in 16 patients, and Stage 4 in 27 patients. According to the Steinbrocker functional classification, RA was Class 1 in 45 patients, Class 2 in 19 patients, Class 3 in 6 patients and Class 4 in 1 patient. Twenty-five patients had been administered biological drugs. At the time of joint ultrasonography, patients were questioned regarding whether they had any complaints involving the forefoot, midfoot or hindfoot (noted separately). The following scans were performed: forefoot (MTP joints 1-5); midfoot (calcaneocuboid, calcaneocuboid and cuneonavicular joints) and hindfoot (peroneal muscle tendon, talocrural joint, talocalcaneal joint and posterior tibial muscle tendon). Foot deformity score (FDS) (hallux valgus angle + first-second intermetatarsal angle [M1M2 angle] + first-fifth intermetatarsal angle [M1M5 angle]) was used as the benchmark for forefoot deformity, and an increase >5° was considered to indicate worsening deformity. Results Forefoot deformity had progressed in 25 patients. Mid- and hindfoot synovitis and the presence of complaints were not associated with deformity. However, significant worsening of FDS was observed in patients with forefoot synovitis or forefoot complaints. While no difference in age, disease activity, biologic disease-modifying antirheumatic drug usage or health assessment questionnaire results were seen in the advanced deformity group, duration of disease was significantly shorter in this group. Conclusion Mid- and hindfoot synovitis was unrelated to forefoot deformity. MTP joint synovitis in the forefoot was related to forefoot deformity. Continuous synovitis in the forefoot must damage the articular capsule and ligament structure, leading to progression of deformity. As shown by the short duration of the disease in the advanced deformity group, deformity may progress in the early stages among patients with forefoot deformity. Disclosure of Interests None declared

Breast cancer has been suggested to have two distinct driving mechanisms: the hormone receptor and the growth factor receptor pathways. We hypothesized that each driving system produces a different expression pattern of estrogen-regulated genes, such as progesterone receptor, in proliferating cells. Progesterone receptor and Ki67 expressions were assessed by dual-fluorescence immunohistochemistry in estrogen-receptor-positive breast cancer tissues. Two distinct proliferating cell populations were observed: progesterone-receptor-positive and progesterone-receptor-negative. In the training cohort, tissues with progesterone-receptor-positive proliferating cells were associated with lower grade and better disease-free survival (p = 0.0055 and 0.0026, respectively). These associations were confirmed in the validation cohort from the neoadjuvant endocrine trial JFMC34 (p = 0.033 and 0.0003, respectively). In the validation cohort, patients with progesterone-receptor-positive proliferating cells responded better to endocrine therapy and had a lower Oncotype DX Recurrence Score. In the multivariate analysis, progesterone receptor status of proliferating cells, but not progesterone receptor or Ki67 alone, was an independent predictor of disease-free survival in both cohorts (p = 0.0043 and 0.0026). In conclusion, the progesterone receptor status of proliferating cancer cells was associated with histological grade and Recurrence Score, and a potent prognostic factor in estrogen-receptor-positive breast cancers. Results suggest that different driving systems generate different expression patterns of progesterone receptor in proliferating cancer cells. Further studies are warranted to validate the findings.

Background Recently, the Nanopia® TDM Zonisamide reagent using the latex particle‐enhanced turbidimetric immunoassay (LTIA) method was developed. The aim of this study was to compare the differences in serum zonisamide (ZNS) concentrations quantified by the high‐performance liquid chromatography (HPLC) method and the LTIA method using a TBA‐25FR analyzer. Methods A total of 78 samples from 33 patients were quantified by both HPLC and LTIA methods. Deproteinization was used as pretreatment for the HPLC method. The ZNS concentrations quantified by two methods were compared. Results The HPLC method had intra‐ and inter‐day precision lower than 1.86% and 9.00%, and accuracy better than 2.44% and 6.33%, respectively. The LTIA method showed intra‐ and inter‐day precision lower than 2.50% and 5.20%, and accuracy better than 15.80% and 10.60%, respectively. The lower limits of quantification for the HPLC and LTIA methods were 1.0 and 5.0 µg/mL, respectively. The ZNS concentration quantified by the HPLC method correlated strongly with that by the LTIA method (r = 0.953, P

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.

Introduction Different measured values for tacrolimus were obtained with different automated immunoassays. We aimed to examine the differences in the blood tacrolimus concentrations measured by the major immunoassay systems commercially available in Japan. Methods Whole-blood samples from 118 patients were assayed by 3 commercial assays: chemiluminescent enzyme immunoassay (CLIA), affinity column-mediated immunoassay (ACMIA), and enzyme-multiplied immunoassay technique (EMIT). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for reference. Key findings The correlation coefficient of immunoassay vs LC-MS/MS was excellent for ACMIA (.83) and CLIA (.81) and good for EMIT (.71). The mean error was negative for ACMIA and positive for CLIA and EMIT. The mean absolute error and root-mean-square error were almost the same for ACMIA and CLIA and lower than those for EMIT. Conclusions The ACMIA and CLIA yield considerably better results than the EMIT for monitoring blood tacrolimus concentrations.

Background Treatment of rheumatoid arthritis (RA) has improved dramatically with the widespread use of biological disease-modifying antirheumatic drugs. In this context, the number of RA patients who undergo orthopaedic surgery is reportedly decreasing. However, the number of RA patients who undergo foot surgery is increasing. Joint ultrasonography has been used for early diagnosis and disease activity assessment in RA, allowing visualisation of synovitis. However, few detailed studies or evaluations of clinical parameters related to synovitis in the foot have been performed. Objectives This study investigated the association between synovitis in the foot as observed on joint ultrasonography and the degree of disability on the health assessment questionnaire (HAQ) in RA patients. Methods The study included 79 outpatients (101 feet) with RA. Patients who had undergone surgery were excluded. The mean age was 66.0 years (24–92 years), and the mean disease duration was 13 years and 5 months (ranging from 1 month to 49 years). Joint ultrasonography was performed by the same examiner using the same diagnostic instrument in the same room. Synovitis was defined as a power Doppler score of ≥Grade 1. The scanning sites were forefoot (metatarsophalangeal joints of toes 1–5), metatarsus (calcaneocuboid and talonavicular joints), and hindfoot (talocrural and subtalar joints, peroneal tendon, posterior tibial tendon). The presence or absence of synovitis was evaluated at each site, and the association with the HAQ score was examined. Results Synovitis was detected in the forefoot of 40 feet (39.6%), in the metatarsus of 34 feet (33.7%), and in the hindfoot of 63 feet (62.4%). Patients with synovitis in the forefoot (PD+: 0.41±0.1, PD-: 0.80±0.1, p=0.018) and hindfoot (PD+: 0.52±0.1, PD-: 0.86±0.1, p=0.043) had significantly lower HAQ scores. Conclusions Given that assessment of foot impairment is not included in the disease activity index for RA, there may be a delay in diagnosis of foot lesions. Our results showed that patients with synovitis in the forefoot and rearfoot had lower HAQ scores (disability measure), suggesting that increased physical activity may be associated with increasing incidence of synovitis in the foot. The ability of RA patients to perform activities of daily living may have improved with advances in pharmacotherapy, leading to increased physical stimulation, resulting in an increased incidence of synovitis of the foot. References [1] Brown AK. Arthtitis Rheum58(10); 2958–67: 2008 [2] Wakefield RJ. Ann Rheum Dis63; 382–5: 2004 Disclosure of Interest None declared