Search

• For elexacaftor-tezacaftor-ivacaftor (ETI) it is unclear whether drug exposure should be monitored by assessment of C min levels or AUC. • A correlation between C min and AUC was found, with correlation coefficients of 0.963, 0.908 and 0.860 for ETI, respectively. • Exposure of ETI may be monitored by assessment of C min levels. Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (C min) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured C min concentration and AUC was evaluated. Serial plasma samples, including C min , were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between C min and AUC 0–24h was found, with Pearson's r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of C min levels. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the clinical benefits of a vancomycin dosage strategy based on a serum trough concentration model in elderly patients. This prospective single-center, open-label, randomized controlled trial categorized 66 elderly patients with severe pneumonia into study and control groups. The control group received vancomycin using a regimen decided by the attending physician. Meanwhile, the study group received individualized vancomycin therapy with a dosing strategy based on a serum trough concentration model. The primary endpoint was the proportion of patients with serum trough concentrations reaching the target values. The secondary endpoints were clinical response, vancomycin treatment duration, and vancomycin-associated acute kidney injury (VA-AKI) occurrence. All patients were at least 60 years old (median age = 81 years). The proportion of patients with target trough concentration achievement (≥ 15 mg/L) with the initial vancomycin regimen was significantly higher in the study group compared to the control group (75.8% vs. 42.4%, P = 0.006). Forty-five patients (68.2%) achieved clinical success, the median duration of vancomycin therapy was 10.0 days, and VA-AKI occurred in eight patients (12.1%). However, there were no significant differences in these parameters between the two groups. The model for predicting vancomycin trough concentrations was upgraded to: serum trough concentration (mg/L) = 17.194 − 0.104 × creatinine clearance rate (mL/min) + 0.313 × vancomycin daily dose [(mg/(kg·d)]. A vancomycin dosage strategy based on a serum trough concentration model can improve the proportion of patients achieving target trough concentrations in elderly patients with severe pneumonia. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effectiveness of an antimicrobial guideline for vancomycin prescribing deployed using electronic prescribing aid and web/phone-based app. To define factors associated with guideline compliance and drug levels, and to investigate if antimicrobial dosing recommendations can be refined using routinely collected electronic healthcare record data.Methods: We used data from Oxford University Hospitals between 01-January-2016 and 01-June-2021 and multivariable regression models to investigate factors associated with dosing compliance, drug levels and acute kidney injury (AKI).Results: 3767 patients received intravenous vancomycin for ≥24 h. Compliance with recommended loading and initial maintenance doses reached 84% and 70% respectively; 72% of subsequent maintenance doses were correctly adjusted. However, only 26% first and 32% subsequent levels reached the target range, and for patients with ongoing vancomycin treatment, 55-63% achieved target levels at 5 days. Drug levels were independently higher in older patients. Incidence of AKI was low (5.7%). Model estimates were used to propose updated age, weight and eGFR specific guidelines.Conclusion: Despite good compliance with guidelines for vancomycin dosing, the proportion of drug levels achieving the target range remained suboptimal. Routinely collected electronic data can be used at scale to inform pharmacokinetic studies and could improve vancomycin dosing. [ABSTRACT FROM AUTHOR]

While the revised 2020 consensus guideline recommends the use of area under the concentration–time curve (AUC)-guided vancomycin monitoring, collecting multiple vancomycin serum samples to calculate the AUC may cause clinical complications. The aim of the present retrospective study was to evaluate whether AUC-guided vancomycin monitoring, in which AUC was calculated based on a single trough concentration, is a better predictor of nephrotoxicity than trough-guided monitoring in patients receiving vancomycin therapy. A single-center, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous vancomycin for a documented or suspected infection and had their serum vancomycin trough concentration monitored between October 1, 2016 and September 30, 2020 were enrolled in the present study. Multivariate Cox proportional hazard analysis indicated that AUC (>600 μg•h/mL) was a significant risk factor for the incidence of acute kidney injury (AKI), while trough concentration (≥15 μg/mL) was not. Moreover, the AUC (>600 μg•h/mL) showed higher specificity and similar sensitivity to the trough concentration (≥15 μg/mL). Kaplan-Meier plots of the cumulative incidence of the AKI-free rate in patients indicated that the onset of AKI was significantly longer in patients with AUC ≤600 μg•h/mL than in patients with AUC >600 μg•h/mL (HR, 16.1; 95% CI, 6.3–41.2; p < 0.001). AUC based on a single trough concentration was a better predictor of nephrotoxicity than trough concentration. [ABSTRACT FROM AUTHOR]

Because of its lower risk of renal toxicity than vancomycin, teicoplanin is the preferred treatment for methicillin-resistant Staphylococcus aureus infection in patients undergoing continuous venovenous haemodiafiltration (CVVHDF) in whom renal function is expected to recover. The dosing regimen for achieving a trough concentration (C min) of ≥20 μg/mL remains unclear in patients on CVVHDF using the low flow rate adopted in Japan. The study was conducted in patients undergoing CVVHDF with a flow rate of <20 mg/kg/h who were treated with teicoplanin. We adopted three loading dose regimens for the initial 3 days: the conventional regimen, a high-dose regimen (four doses of 10 mg/kg), and an enhanced regimen (four doses of 12 mg/kg). The initial C min was obtained at 72 h after the first dose. Overall, 60 patients were eligible for study inclusion. The proportion of patients achieving the C min target was significantly higher for the enhanced regimen than for the high-dose regimen (52.9% versus 8.3%, p = 0.003). In multivariate analysis, the enhanced regimen (odds ratio [OR] = 39.93, 95% confidence interval [CI] = 5.03–317.17) and hypoalbuminaemia (OR = 0.04, 95% CI = 0.01–0.44) were independent predictors of the achievement of C min ≥ 20 μg/mL. An enhanced teicoplanin regimen was proposed to treat complicated or invasive infections by methicillin-resistant Staphylococcus aureus in patients receiving CVVHDF even with a low flow rate. [ABSTRACT FROM AUTHOR]

This study was designed to investigate the characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia. Fifty-seven cancer patients complicated with severe pneumonia were included in this research. Vancomycin serum trough concentrations were measured using the fluorescence polarization immunoassay (FPIA) method. The Bayesian estimator was used to calculate the pharmacokinetic parameters. The average initial therapeutic dose of vancomycin was 15.18 ± 3.29 mg/kg (q12 h). Our study shows that vancomycin initial trough concentrations measured in cancer patients are significantly reduced (6.54 ± 3.11 mg/L; p < 0.0001) compared with the recommended standard vancomycin trough concentration (10–15 or 15–20 mg/L). Meanwhile, the clearance (CL) and volume of distribution (Vd) of vancomycin was increased significantly in cancer patients. Multivariate linear regression analysis revealed that Cys-C was the most important variable for vancomycin trough concentration (r2 = 0.439). The relationships between vancomycin trough concentrations and Cys-C were further evaluated after the 57 patients were grouped by cut-off point (1.44 mg/L) of the serum Cys- C levels before vancomycin was administered. Compared with group Early group (Cys-C>1.44 mg/L), Delayed group (Cys-C≤1.44 mg/L) had much lower trough concentrations. Meanwhile, CL and CLcr were significantly increased in Delayed group (Cys-C≤1.44 mg/L). Although the clinical outcomes were similar between two groups, the duration of vasoactive agent in Early group was considerably shorter compared with Delayed group (χ2 = 4.213; p < 0.05). The serum trough concentration of vancomycin was significantly reduced in cancer patients complicated with severe pneumonia. Higher dosage regimen is needed to ensure clinical effectiveness. The Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether vancomycin trough concentration is up to standard dosage. Especially for patients with baseline Cys-c less than 1.44 mg/L, it is more likely to need higher dosage algorithm. [ABSTRACT FROM AUTHOR]

• We characterized vancomycin pharmacokinetics on the first dose for the early detection of target attainment. • Correlation between vancomycin Ctrough and AUC 24 values in children has been observed. • Ctrough that correlates with the target AUC 24 >400 in children are lower than the values observed and targeted in adults. • The vancomycin dosage regimen of 80 mg/kg/day provides the highest probability to produce AUC 24 in the range of 400–800 mg-h/L. Vancomycin is a common drug used in children with severe infection. In adults, at least 15 mg/L of the optimal vancomycin trough concentration (C trough) is needed to generate the target 24-h area under the concentration-time curve (AUC 24) to the minimum inhibitory concentration (MIC) of 400 for a pathogen with the MIC ≤1 mg/L. To determine vancomycin PK in children with severe infection and to explore the correlation between vancomycin C trough and AUC 24 in children, as well as to propose the appropriate vancomycin dosages using Monte Carlo simulation. Children aged 2–18 years who were admitted to Chiang Mai University Hospital and received intravenous vancomycin for severe infection were included in the study. Serum samples for vancomycin PK were obtained before and serially after the administration of the first dose according to the protocol. Pharmacokinetic analyses were performed using Phoenix WinNonlin® 7.0 and NLME™7.0. Fourteen children with 64% males and age range from 2 to 13 years were included in this study. Non-compartmental analysis revealed the median volume of distribution, clearance, and elimination half-life of 0.58 L/kg, 2.82 mL/kg/min and 2.33 h, respectively. Vancomycin serum concentrations were best described by a two-compartmental model with first-order elimination.The observed C trough at 6 h correlated well with the AUC 24. The median vancomycin C trough at steady state that correlated with the AUC 24 ≥ 400 and <800 were 11.18, 9.50, 7.91 and 6.55 mg/L in simulated children receiving vancomycin 40, 60, 80 and 100 mg/kg/day, respectively. Correlation between vancomycin C trough and AUC 24 values in children has been observed. However, the values of C trough that correlate with the target AUC 24 ≥400 in children are lower than the values observed and targeted in adults. [ABSTRACT FROM AUTHOR]

• Hepatic impairment increases the risk of drug overexposure in septic patients. • Up to now there has been a lack of effective indicators to predict linezolid overexposure risk. • ICG-PDR is an independent predictor of linezolid overexposure. • First pilot application of the ICG test demonstrating its potential to predict linezolid overexposure in septic patients. Hepatic impairment increases the risk of drug overexposure in septic patients. However, there is a lack of effective indicators to predict overexposure risk. The indocyanine green (ICG) clearance test is a helpful method for dynamically assessing hepatic function and perfusion. This study aimed to investigate whether the ICG test could serve as a potential predictor of linezolid trough concentration (C min) and to compare its efficacy with that of conventional liver function markers. A total of 35 consecutive septic patients treated with linezolid were grouped into either linezolid C min of ≤7 µg/mL or >7 µg/mL. Correlations between linezolid C min and ICG-PDR (plasma disappearance rate), ICG-R15 (retention ratio after 15 min) and other traditional indicators were analysed by Spearman's rank test. A multivariable regression model was employed to discern factors contributing independently to overexposure. Statistical differences were observed between groups for APACHE II score (P = 0.031), SOFA score (P = 0.018), creatinine clearance (CL Cr) (P = 0.003), thrombocytes (P = 0.039), lactate (P = 0.003), ICG-PDR (P < 0.001) and ICG-R15 (P < 0.001). Moreover, linezolid C min was correlated with ICG-PDR (ρ = –0.628, P < 0.001), ICG-R15 (ρ = 0.676, P < 0.001) and CL Cr (ρ = –0.503, P = 0.002). ICG-PDR was identified as an independent predictor of linezolid overexposure, with an optimal cut-off value of 17.70%/min (93.3% sensitivity, 85.0% specificity; P < 0.001). This pilot clinical trial represents the first investigation of potential of the ICG test to predict linezolid overexposure in septic patients. [ABSTRACT FROM AUTHOR]

Determination of appropriate pharmacokinetic end point to bridge different dosing regimens is often a challenge when developing a new route of administration. Trough concentrations (C trough) are often considered the most relevant PK end point to predict efficacy (ACR20/DAS28) in the treatment of rheumatoid arthritis for biologics. However, no systematic research has been conducted to evaluate this approach. We developed a novel strategy to predict the most relevant PK variables that may be used to support a change in the route of administration for biological products. Our analysis indicated that matching only C trough when switching from intravenous dosing to subcutaneous dosing with decreasing dosing interval may result in a lower treatment response. If only average concentration (C ave) is considered as the relevant variable, our analysis showed that treatment response may be worsened when switching from subcutaneous dosing to intravenous dosing with increasing dosing interval. The study results demonstrated that matching a single pharmacokinetic end point (C trough or C ave) may not be sufficient to ensure efficacy when switching between intravenous dosing and subcutaneous dosing. A practical novel pharmacokinetic bridging approach is provided to support a change in the route of administration for biological products. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this study was to investigate the pharmacokinetic profile and safety of voriconazole treatment in patients with Child–Pugh class B and C cirrhosis. Methods Liver cirrhosis patients who had received the recommended voriconazole maintenance dose (group A) or halved maintenance dose (group B), orally or intravenously, were included. Voriconazole-related adverse events (AEs) were defined according to the Common Terminology Criteria for Adverse Events. Results A total of 110 trough plasma concentrations of voriconazole ( C min ) were measured in 78 patients. There was a significant difference in voriconazole C min between group A and group B ( C min , 6.95 ± 3.42 mg/l vs. 4.02 ± 2.00 mg/l; p < 0.001). No significant difference in voriconazole C min between Child–Pugh class B and C cirrhosis patients was observed in either of the two groups. The international normalized ratio and co-medication with a CYP2C19 inhibitor had a significant effect on voriconazole C min in group B. The incidence of AEs in group A was 26.5% and in group B was 15.9%, and 87.5% of AEs developed within 7 days after starting voriconazole treatment. Conclusions These results suggest that the recommended dose and halved maintenance dose may be inappropriate in patients with Child–Pugh class B and C cirrhosis due to the high C min , and that voriconazole C min should be monitored earlier to avoid AEs. [ABSTRACT FROM AUTHOR]

Valproic acid(VPA) is a classic drug that used to treat epilepsy in monotherapy or combination with other anticonvulsant drugs such as lamotrigine (LTG). Although it was reported that VPA could increase lamotrigine trough concentration in clinical practice, there was no report about the effect of LTG on the trough concentration of VPA and its main metabolites, such as 4-ene-VPA, 3-OH-VPA, 4-OH-VPA, 3-keto-VPA, 2-PGA which are related to the therapeutic and toxic effects of VPA. In this study, a simple and rapid method for the simultaneous determination of VPA and its five metabolites in human plasma using HPLC–MS/MS was developed for the first time. Benzoic acid was used as an internal standard (IS). Separation was performed on a Hypersil GOLD C 18 column by isocratic elution using acetonitrile: 10 mM ammonium acetate solution (90:10, v/v) as mobile phase at a flow rate of 0.3 mL/min. A triple quadrupole mass spectrometer operating in the negative ion-switching, electron spray ionization mode with selection reaction monitoring (SRM) was employed to determine transitions of m/z 143.183 → 143.183, 157.033 → 113.165, 173.017 → 129.074, 159.058 → 101.082, 140.870 → 140. 870, 159.049 → 123.076, 121.035 → 77.136 for VPA, 2-PGA, 3-keto-VPA, 3-OH-VPA, 4-ene-VPA, 4-OH-VPA and IS, respectively. The method also afforded satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-batch), accuracy, recovery, matrix effect and stability. This method was successfully applied to evaluate the effect of LTG on the trough concentration of VPA, 2-PGA, 3-keto-VPA, 3-OH-VPA, 4-ene-VPA, 4-OH-VPA in Chinese epilepsy patients. The result showed that there was no significant difference in the concentration of VPA and its five metabolites between patients in VPA monotherapy and patients in therapy combining VPA with LTG. [ABSTRACT FROM AUTHOR]

• GS-441524 trough ≥70 ng/mL leads to symptom improvement in COVID-19 pneumonia. • Probability of GS-441524 trough ≥70 ng/mL was associated with eGFR and BMI. • An individualised remdesivir dosing schedule may optimise its efficacy. Remdesivir (RDV) is the cornerstone for treating coronavirus disease 2019 (COVID-19). The active metabolite of RDV, GS-441524 (a nucleoside analogue), has high interindividual variability in plasma concentrations; however, its concentration–response relationship is still unclear. This study investigated the target GS-441524 trough concentration for symptom improvement in COVID-19 pneumonia. This single-center, retrospective, observational study included Japanese patients (age ≥15 years) with COVID-19 pneumonia who were administered RDV for ≥3 days from May 2020 to August 2021. To determine the cut-off value of GS-441524 trough concentration on Day 3, achievement of the National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) ≤3 after RDV administration was evaluated using the cumulative incidence function (CIF) with the Gray test and time-dependent receiver operating characteristic (ROC) analysis. Multivariate logistic regression analysis was performed to determine factors influencing GS-441524 target trough concentrations. The analysis comprised 59 patients. The CIF revealed that GS-441524 trough concentration ≥70 ng/mL was associated with the achievement of NIAID-OS ≤3 (P = 0.047), which was significant based on the time-dependent ROC analysis. Factors influencing GS-441524 trough concentration ≥70 ng/mL included a decrease in estimated glomerular filtration rate (eGFR) [adjusted odds ratio (aOR) = 0.96, 95% confidence interval (CI) 0.92–0.99; P = 0.027] and BMI ≥25 kg/m2 (aOR = 0.26, 95% CI 0.07–0.86; P = 0.031). GS-441524 trough concentration ≥70 ng/mL is a predictor of efficacy in COVID-19 pneumonia. The presence of lower eGFR or BMI ≥25 kg/m2 was associated with achieving GS-441524 trough concentration ≥70 ng/mL. [ABSTRACT FROM AUTHOR]

• This study examined vancomycin trough concentrations for critically ill adults without dialysis. • Trough concentrations are good markers of area under the curve in these patients. • Therapeutic drug monitoring of vancomycin is beneficial in clinical practice, especially for source-limited centers. There are conflicts in guideline recommendations about the value and range of vancomycin trough concentration during therapeutic drug monitoring (TDM). This multicentre, retrospective study was conducted to explore the usefulness of trough concentration in specific patients who were critically ill and without any form of dialysis. Patient information from five centres was retrospectively collected and the 24-hour area under the curve (AUC) was estimated by a Bayesian method. Patients were categorised into four groups according to trough concentration: < 10, 10–15, 15–20 and > 20 mg/L, and the corresponding AUC was analysed. A multivariable logistic regression model was used to investigate the relationship between trough concentration and AUC. Overall, 645 trough concentrations available from 416 patients were included in this study. The results indicated that the AUC was always < 400 mg/L∙h or > 600 mg/L∙h in the < 10 or > 20 mg/L groups, whereas the ratios of vancomycin AUC target attainment (400–600 mg/L∙h) were 48.8% and 92.3% in the 10–15 mg/L and 15–20 mg/L groups, respectively. Augmented renal clearance, low daily dose and non-q12h administration were found to be independent risk factors associated with AUC target non-attainment for patients with trough concentrations of 10–15 mg/L. Vancomycin trough concentration is a good marker of AUC for critically ill adults without any form of dialysis. However, AUC-guided TDM may be needed for patients with trough concentrations of 10–15 mg/L, especially for those with risk factors. [ABSTRACT FROM AUTHOR]

Background Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. Patients and methods This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI C min ) and 3-month PSA response. Results From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50–78]). In univariate analysis, ABI C min was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4–15.6) versus 8.0 ng/mL (CI 95% 5.8–11.6; P = 0.0015). In multivariate analysis, only ABI C min was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01–1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI C min was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI C min above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31–0.99], 12.2 [CI 95% 9.2–19.5] versus 7.4 [CI 95% 5.5–14.7] months otherwise, P = 0.044). Conclusions We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients. [ABSTRACT FROM AUTHOR]

A two-stage photovoltaic thermal system based on solar trough concentration is proposed, in which the metal cavity heating stage is added on the basis of the PV/T stage, and thermal energy with higher temperature is output while electric energy is output. With the 1.8 m² mirror PV/T system, the characteristic parameters of the space solar cell under non-concentrating solar radiation and concentrating solar radiation are respectively tested experimentally, and the solar cell output characteristics at different opening widths of concentrating mirror of the PV/T stage under condensation are also tested experimentally. When the mirror opening width was 57 cm, the solar cell efficiency reached maximum value of 5.21%. The experimental platform of the two-stage photovoltaic thermal system was established, with a 1.8 m² mirror PV/T stage and a 15 m² mirror heating stage, or a 1.8 m² mirror PV/T stage and a 30 m² mirror heating stage. The results showed that with single cycle, the long metal cavity heating stage would bring lower thermal efficiency, but temperature rise of the working medium is higher, up to 12.06°C with only single cycle. With 30 min closed multiple cycles, the temperature of the working medium in the water tank was 62.8°C, with an increase of 28.7°C, and thermal energy with higher temperature could be output. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver transplant (LT) patients might be overimmunosuppressed as recommendations for tacrolimus trough concentrations (TC) within 4–6weeks after liver transplantation are set too high (10–15ng/ml). Early tacrolimus exposure was evaluated in relation to acute rejection and long-term outcomes. Methods: Four hundred and ninety-three consecutive LT patients receiving tacrolimus as primary immunosuppression (1995–2008) were analyzed. Acute rejection was diagnosed using protocol biopsies at day 6.1±2.5. Median follow-up was 7.3years (IQR 3.9–10.5). Early tacrolimus exposure (<15days) was evaluated against moderate/severe acute rejection, chronic rejection, graft loss, chronic renal impairment and mortality using multiple logistic and Cox regression. Results: Maintenance immunosuppression was tacrolimus monotherapy (48.1%), double therapy combination with antimetabolites or steroids (18%), or triple therapy combination with antimetabolites and steroids (33.9%). Histological grade of acute rejection was moderate in 157 cases (31.8%) and severe in 19 cases (3.9%). Tacrolimus TC>7ng/ml on the day of protocol biopsy was associated with less moderate/severe rejection (23.8%) compared with<7ng/ml (41.2%) (p =0.004). Mean tacrolimus TC 7–10ng/ml within 15days after LT were associated with reduced risk of graft loss (RR=0.46; p =0.014) compared to TC 10–15ng/ml. A peak TC>20ng/ml within this period was independently related to higher mortality (RR=1.67; p =0.005), particularly due to cardiovascular events, infections and malignancy (RR=2.15; p =0.001). Early tacrolimus exposure did not influence chronic rejection (p =0.58), or chronic renal impairment (p =0.25). Conclusions: During the first 2weeks after LT, tacrolimus TC between 7 and 10ng/ml are safe in terms of acute rejection and are associated with longer graft survival. [ABSTRACT FROM AUTHOR]

Abstract: The performances of solar cell arrays based on a Trough Concentrating Photovoltaic/Thermal (TCPV/T) system have been studied via both experiment and theoretical calculation. The I–V characteristics of the solar cell arrays and the output performances of the TCPV/T system demonstrated that among the investigated four types of solar cell arrays, the triple junction GaAs cells possessed good performance characteristics and the polysilicon cells exhibited poor performance characteristics under concentrating conditions. The optimum concentration ratios for the single crystalline silicon cell, the Super cells and the GaAs cells were also studied by experiments. The optimum concentration ratios for the single crystalline silicon cells and Super cells were 4.23 and 8.46 respectively, and the triple junction GaAs cells could work well at higher concentration ratio. Besides, some theoretical calculations and experiments were performed to explore the influences of the series resistances and the working temperature. When the series resistances Rs changed from 0Ω to 1Ω, the maximum power Pm of the single crystalline silicon, the polycrystalline silicon, the Super cell and the GaAs cell arrays decreased by 67.78%, 74.93%, 77.30% and 58.07% respectively. When the cell temperature increased by 1K, the short circuit current of the four types of solar cell arrays decreased by 0.11818A, 0.05364A, 0.01387A and 0.00215A respectively. The research results demonstrated that the output performance of the solar cell arrays with lower series resistance was better and the working temperature had a negative impact on the current under concentration. In addition, solar irradiation intensity had certain effects on the solar cell’s performance. For the crystalline silicon solar cell arrays, when the solar direct radiation exceeded a certain value, the I–V curves almost became a straight line and the output performances decreased due to the high series resistance leading to the high power loss. For the triple junction GaAs solar cell array, its performance was always excellent. [Copyright &y& Elsevier]

Abstract: The electrical and thermal performance of a 2m2 Trough Concentrating Photovoltaic/Thermal (TCPV/T) system with an energy flux ratio 10.27 are characterized by experiments. A single crystalline silicon solar cell array, a polycrystalline silicon cell array, a Super cell array and a GaAs cell array are respectively used in the experiments. The experimental results show that the electrical performance of the system with the GaAs cell array is better than that of crystal silicon solar cell arrays. The superior output performance of the GaAs cell array mainly benefits from its lower series resistance. But the thermal performances of the system using the single crystal silicon solar cell array and the polycrystalline silicon solar cell array are better. It results from the widths of the two types of cells in the system close to that of the focal line. Another 10m2 TCPV/T system with an energy flux ratio of 20 using the GaAs cell array and a concentrating silicon cell array are also constructed and characterized. The experimental results indicate that the photoelectric efficiency of the GaAs cell array is 23.83%, and the instantaneous electrical efficiency and thermal efficiency of the system are 9.88% and 49.84% respectively. While the instantaneous electrical efficiency and thermal efficiency of the system using the low-cost concentrating silicon cell array are 7.51% and 42.4% respectively. The economic performance analysis show the electricity generating cost of the TCPV/T system with the concentrating silicon cell array can catch up with flat-plate PV system, but besides electricity generation, the TCPV/T system supplies extra heat energy to users. [Copyright &y& Elsevier]

Abstract: The overall performances of a 10m2 Trough Concentrating Photovoltaic/Thermal (TCPV/T) system with a Super cell array, a GaAs cell array and a concentrating silicon cell array are investigated. The experimental results show that the average electrical efficiencies of the TCPV/T system with the three types of solar cell arrays are 3.63%, 8.94%, and 3.67% respectively in typical synoptic condition. The thermal efficiencies of the TCPV/T system with the three types of solar cell arrays are 45.17%, 41.69%, and 34.53% respectively after the TCPV/T system runs over 5h. The TCPV/T system with the three types of cell arrays is also evaluated based on the electricity generation costs. From the point of the performance price ratio, the concentrating silicon cell array is preferable for the system with a middle or low concentration ratio. In order to improve the performance of the TCPV/T system, a 2m2 experimental system utilizing the mirrors with a higher reflectivity is built. In concentrating irradiance, when the mirror reflectivity increases from 0.69 to 0.92, even the area of the reflecting mirrors reduce, the maximum powers of the cell arrays increase. The electrical efficiencies of the system using a Super cell array, a GaAs cell array and a concentrating silicon cell array rise by 0.9%, 2.62% and 5.47% respectively. The high reflectivity of the parabolic mirror is pursued. All these works are helpful to the further study on the trough concentrating system. [Copyright &y& Elsevier]

Abstract: An initial loading dose of teicoplanin is required to reach the optimal trough concentration (≥10μg/mL) rapidly. To attain the optimal teicoplanin concentration efficiently, an individual loading dose regimen based on population pharmacokinetics, in which the target trough concentration was set to 15μg/mL, was defined. Among 70 patients, 33 patients received the individual loading dose regimen, 33 patients received the conventional loading dose regimen (200mg or 400mg every 12h on Day 1 followed by 200mg once daily) and 4 patients received no loading dose. The proportion of patients showing an optimal plasma concentration was 88% in the individual loading dose regimen but only 33% in the conventional loading dose regimen. No patient without a loading dose showed the optimal concentration. Both total loading dose and plasma concentration were significantly (P <0.001) higher in the individual loading dose group than in the conventional loading dose group. Notably, the trough concentration was almost constant in patients with individual loading doses ranging from 800mg to 1800mg. These findings suggest that individual adjustment of the initial loading dose of teicoplanin is potentially useful to attain the optimal concentration rapidly. [Copyright &y& Elsevier]

• Routine TDM may not be needed in febrile neutropenia patients with preserved renal function. • No breakthrough infections were observed in patients with febrile neutropenia. • Few patients with preserved renal function showed neurotoxicity. • There was a significant trend for higher cefepime trough concentrations with neurotoxicity. • Accounting for renal function reduced the variability in cefepime trough concentrations. Cefepime is a first-line antibiotic for the treatment of febrile neutropenia (FN) in haematological cancer patients. Therapeutic drug monitoring (TDM) of cefepime is frequently advocated. However, it remains unclear what range of concentrations should be targeted for maximal efficacy and minimal toxicity. Therefore, we examined the relationship between cefepime exposure and clinical efficacy or neurotoxicity in FN patients. This prospective, observational, single-centre study included all adult hospitalised patients presenting with FN at the haematology ward and treated with cefepime from August 2019 until October 2020. Primary outcomes were incidence of breakthrough infection and neurotoxicity and their relationship with free cefepime serum trough concentrations. A total of 76 patients were included, contributing 96 cefepime treatment courses. The median (interquartile range) estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR CKD-EPI) and free cefepime trough concentration were 101 (85–112) mL/min/1.73m2 and 8.6 (4.9–16.2) mg/L, respectively. Interpatient and intrapatient variability in cefepime trough concentrations was largely explained by renal function. No cefepime-related breakthrough infections occurred during cefepime treatment. Neurotoxicity, probably induced by cefepime administration, occurred during 6/96 (6.3%) treatment courses. Patients with neurotoxicity showed a significant trend for higher trough concentrations (median 15.4 mg/L vs. 8.6 mg/L; P < 0.001). This study provides real-world clinical data showing that high cefepime dosage is efficacious and safe in FN patients. Routine TDM does not appear to be needed in FN patients with preserved renal function. However, TDM might be reserved for FN patients at high risk of cefepime-induced neurotoxicity or when intended to cover pathogens with a minimum inhibitory concentration >1 mg/L. [ABSTRACT FROM AUTHOR]

We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C 24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 in vivo. Image 1 • (Carbonyl)oxyalkyl-linked amino acid prodrugs serve as effective drug delivery tools to improve the oral bioavailability of the anti-HIV drug atazanavir. • The bioconversion design strategy, formulated to refine previous approaches, allows the derivation of prodrugs directly from the parent, with bioactivation enabled by the linker element. • Prototype prodrugs displayed a proof-of-concept for oral exposure improvement (2-fold) in rats compared to dosing of the parent drug. • Linker refinement resulted in the discovery of prodrug 22 , which improved not only oral AUC (5-fold) but also trough concentrations (67-fold) of the parent drug. • The new prodrugs represent an advancement in the oral delivery of 1 by acting as depots in vivo with slow parent release in a fashion that substantially enhances trough concentrations. [ABSTRACT FROM AUTHOR]

Pharmacokinetics (PK) is affected by aging, organ functions, concomitant drugs, etc.; hence, determining the dose and target blood concentration from PK/PD analysis based on pharmacodynamics (PD) that uses effectiveness/safety as an indicator is essential to the implementation of personalized medicine. In the Phase I trials of clinical pharmacology studies, the subjects have normal organ functions and were relatively young patients; hence, there are very few reports of careful administration cases, such as with elderly people and patients with organ dysfunction. Even in Japan, anti-cancer drug PK/PD clinical research has been conducted across the body organs, with reports on the usefulness of PK/PD analysis in the proper use of molecularly-targeted therapy. On the other hand, even though the development of immune checkpoint drugs is progressing rapidly, there is little information on PK/PD analysis, and the search for effective blood concentrations and fluctuation factors can also provide important basic information in the development of combination therapies with other anti-cancer drugs. Though it has been reported that it tends to be less effective in patients with low trough blood levels of nivolumab, with the pharmacokinetic variables being blood albumin levels and the weight of the patient, there are very few of these reports in Japan. Although the association of adverse event occurrences between genetic polymorphisms and pharmacokinetics has been reported, there have been very few reports of careful administration. It is also anticipated that the need for comprehensive analysis as precision medicine will also increase even in genetic polymorphism. There is no guideline for dose adjustment that takes PK/PD and genetic polymorphism into consideration in careful administration cases, and this is a pressing issue in promoting personalized medicine. [ABSTRACT FROM AUTHOR]

Background The risk of venous thromboembolism (VTE) is seven times higher in cancer patients than in non-cancer patients. However, several issues have yet to be addressed: the adoption of low-molecular-weight heparin is limited in Japan; warfarin may promote bleeding, when used with gefitinib and erlotinib (EGFR-tyrosine kinase inhibitors [TKIs]); and data on the pharmacokinetics (PK) of direct oral anticoagulants and the effects of their combination with anticancer drugs for cancer patients are limited. To identify anti-cancer drugs and anticoagulants that can be used safely together, this PK study was conducted. Material and methods: This study was conducted as accompanying research to the observational study of the VTE incidence rate in lung cancer patients (Rising-VTE study). VTE was diagnosed at lung cancer staging. Patients with EFGR-TKI monotherapy and VTE treatment indication were enrolled. First, blood collection for the edoxaban PK study was performed during ingestion of edoxaban alone. Second, blood collection for the edoxaban PK study and EGFR-TKI trough value was performed within 8 to 15 days after starting EGFR-TKI oral administration. The pharmacokinetics of edoxaban was analyzed by a noncompartment and compartment model. Results: Twelve patients were enrolled from May 2016 to August 2018, and the data from 10 were able to be examined. The patients were a median 77 years of age (range: 59-91), male/female: 3/7, PS 0/1/2/3: 4/5/0/1, IIIA/IIIB/IV (TNM 7th edition): 1/2/7, and gefitinib/erlotinib/afatinib (EGFR-TKI): 3/6/1. The PK analysis showed that there were no marked differences before and after combination administration of EGFR-TKI. The mean clearance was as follows: before, 11.79±3.92 mL/min; after, 10.24±2.86 mL/min. The mean half-life was as follows: before, 5.33±1.75 h; after, 6.31±1.07 h. Conclusions: The PK of edoxaban were not markedly influenced by the combined administration with EGFR-TKI. Funding: Daiichi Sankyo Co.Ltd [ABSTRACT FROM AUTHOR]

Summary: Background: The use of a vancomycin dosing nomogram is an alternative and more cost-effective method to conventional dosing; it reliably allows the achievement of trough vancomycin serum concentrations of 5–15mg/l, with a successful clinical response. Recent guidelines have further recommended that the trough concentration be maintained at 15–20mg/l for complicated infections. However, to date no published nomogram has been constructed to achieve the optimal trough of 15–20mg/l in an Asian population. This study aimed to develop two vancomycin nomograms for the achievement of trough concentrations of 5–15mg/l and 15–20mg/l in the Taiwanese population, and to ensure the clinical efficacy and safety of such nomograms. Methods: The estimated concentrations and the real concentrations in our patient population were compared between six pharmacokinetic models to see which was the most precise. As the Ambrose method was the best at predicting the trough, this was used to create two nomograms, one for a target trough at 5–15mg/l and the other for a target trough at 15–20mg/l. We then evaluated the nomograms by analyzing the number of patients with the target vancomycin trough concentration, clinical and microbiological outcomes, and safety. Results: More patients who had dosing according to the nomogram had a vancomycin trough concentration within the desired target range than patients who had conventional dosing (65.1% vs. 32.1%, p = 0.001). These patients also had a higher rate of ‘cure’ as the clinical response (35.7% vs. 27.1%) and ‘eradication’ as the microbiological response (46.4% vs. 29.2%), and a lower rate of nephrotoxicity (14.3% vs. 22.9%). For the patients with a complicated infection, more had a trough between 15 and 20mg/l when vancomycin was dosed with the nomogram than when dosed conventionally (41.2% vs. 12.1%, p = 0.019). Conclusions: We found that when dosing vancomycin with these nomograms, patients tended to have vancomycin trough concentrations within the target range and also to have a better outcome with regard to clinical efficacy and the safety profile. [Copyright &y& Elsevier]