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Background Teicoplanin is a glycopeptide antibiotic used for the treatment of methicillin-resistant Staphylococcus aureus infections. To ensure successful target attainment, therapeutic drug monitoring-informed dosage adjustment is recommended. However, it relies on the experience of the clinician and the frequency of drug measurements. This study aimed to design a new optimal dosing regimen of teicoplanin with a maintenance dosing strategy for neonates and children based on their physiological characteristics. Methods Data from teicoplanin-treated patients (n = 214) were collected from electronic medical records. Covariate analyses were performed using population pharmacokinetic (PK) modeling with 399 serum teicoplanin concentrations from 48 neonates and 166 children. Multiple PK simulations were conducted to explore optimal dosing regimens that would allow control of the trough concentration to the target of 15-30 mg/L quicker than the current standard regimen. Results Allometrically scaled body weight, postmenstrual age (PMA), renal function, and serum albumin were implemented as substantial covariates for teicoplanin clearance in a two-compartment PK model. Covariate analyses and comprehensive simulation assessments recommended the following modifications to the current regimen: 1) decreased dose for premature babies (PMA ≤ 28 weeks), 2) decreased dose for children with renal dysfunction, and 3) increased dose for children (0.5-11 years) with an estimated glomerular filtration rate of ≥90 mL/min/1.73 m2. Conclusions This study leverages real-world clinical information and proposes new optimal dosing regimens for teicoplanin in neonates and children through PK modeling and simulation analyses, taking into account the age, including PMA, and renal function of patients.

Vancomycin is a glycopeptide antibiotic that has been used primarily in the treatment of methicillin-resistantStaphylococcus aureusinfections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended.Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician’s experience and expertise.In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. The target trough concentration was attained at comparable rates with the model- and expert-recommended dosing regimens, suggesting that the ML model successfully incorporated the experts’ knowledge. The predictive model developed here will contribute to improved decision making for initial vancomycin dosing and early attainment of therapeutic windows.

Introduction 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 (Cmin) of ≥20 μg/mL remains unclear in patients on CVVHDF using the low flow rate adopted in Japan. Methods The study was conducted in patients undergoing CVVHDF with a flow rate of Results Overall, 60 patients were eligible for study inclusion. The proportion of patients achieving the Cmin 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 Cmin ≥ 20 μg/mL. Conclusions 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.

Background: Vancomycin treatment failure against vancomycin-susceptible gram-positive cocci is not rare in the intensive care unit (ICU). One of the reasons for this is the substandard drug trough concentration. We aimed to examine the hypothesis that the target serum concentration could be reached earlier with a loading dose of vancomycin. Methods: This retrospective cohort study was conducted at our ICU between June 2018 and June 2020 and involved patients who were suspected of having, or confirmed to have, gram-positive cocci infection and treated with vancomycin. One group of the patients was administered a loading dose of vancomycin (loading group) and compared with the group that did not receive a loading dose (control group). The baseline characteristics, vancomycin serum concentrations, and clinical outcomes were collected and analyzed. Results: Fifty-five patients were finally included, of which 29 received a loading dose of vancomycin. The serum concentration of vancomycin before the second dose was significantly higher for the loading group than for the control group (10.3 ± 6.1 mg/L vs. 5.7 ± 4.4 mg/L, P = 0.002). The results for both groups were similar before the fifth dose (12.4 ± 7.3 mg/L vs. 10.3 ± 6.3 mg/L in the loading and the control groups, respectively; P = 0.251). The 28-day mortality was lower for the loading group than for the control group (6.7% vs. 34.6% in the loading and control groups, respectively; P = 0.026). No significant differences were observed in serum creatinine (Cr) concentrations of the two groups. Conclusion: With the loading dose of vancomycin, the target serum concentration of vancomycin may be reached earlier without increasing the risk of acute kidney injury. Trial registration: https://www.chictr.org.cn; ChiCTR2000035369

WHAT IS KNOWN AND OBJECTIVE Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.

AIM The new guidelines in Japan do not recommend a vancomycin (VCM) loading dose for patients with an estimated glomerular filtration rate (eGFR) 30 < and ≤ 80 mL×min-1×1.73m-2 (moderate renal dysfunction) or administration to those with the eGFR < 30 mL×min-1×1.73m-2 (severe renal dysfunction). We investigated the safety and efficiency of VCM in patients with moderate and severe renal dysfunction based on the new guidelines. MATERIALS AND METHODS The study involved patients admitted to our hospital between April 2014 and March 2018 with an eGFR < 80 mL×min-1×1.73m-2 and treated with VCM. VCM trough concentration and pre- and post-administration renal function were investigated retrospectively. The primary endpoints were the proportion of patients who achieved an effective trough concentration of 10 - 20 µg/mL and rate of acute kidney injury (AKI). RESULTS We included 64 patients (32 moderate, 32 severe). The mean VCM trough concentration achieved for the first time was 9.3 and 11.6 µg/mL in the moderate and severe renal dysfunction groups, respectively (p = 0.91). The effective trough concentration endpoint was achieved by 50% and 43% of the patients in the severe and moderate renal dysfunction groups, respectively, and no significant difference was found in the AKI rate. The serum creatinine change was significantly different between the groups - the moderate group showed a slight deterioration and the severe renal dysfunction group an improvement. CONCLUSION It may be necessary to increase the dose for these patients with severe renal dysfunction while implementing a VCM loading dose and monitoring trough concentrations and adverse effects.

Background To explore the clinical application of a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases and neutropenia. Methods Patients with hematological diseases and neutropenia were included in the PPK model study. Nonlinear mixed effect modeling approach (NONMEM) was used for model establishment. Monte Carlo simulation was carried out. A total of 74 patients were divided into model group and non-model group for clinical application research. The model group was given the initial dose of 1g q8h, and the non-model group was given 1g q12h as an empiric initial dosage.the follow-up dose adjustments were made according to the concentration results. Results This two-compartment model showed good stability and accuracy. The first trough concentration(C0 ) and the compliance rate of the first C0 were much higher in the model group than that in the non-model group(14.30 ± 4.73 μg/ml and 59.38% vs. 8.02 ± 2.61 μg/ml, 35.71% ). Less patients needed dose adjustments and fewer adjustment times in the model group than those in the non-model group(12.50% and 0.13 ± 0.34times vs 50.00% and 0.61 ± 0.66times). This suggested that for those patients who had a CLCR≥90 ml/min/1.73m2 , the initial dose of 1g q8h may help to reach the target C0 (10∼20μg/ml) quickly. It also helped to reduce the times and number of patients who need dose adjustments. Conclusions Our PPK model of vancomycin in patients with hematologic diseases and neutropenia can be used to shorten the time to reach the target concentration anddn reduce the number of dose adjustments. This article is protected by copyright. All rights reserved.

Objective The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Methods The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM® version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis–Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods. Results The maximum elimination rate (Vmax) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1–5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone. Conclusions The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00365-0.

BACKGROUND Adrenocortical carcinoma is an orphan but aggressive malignancy with limited treatment options. Cabozantinib (CAB), a tyrosine kinase inhibitor, has emerged as a new potential treatment. However, no data are available on whether and how CAB can be administered to patients undergoing hemodialysis. METHODS An liquid chromatography with tandem mass spectrometry detection method was developed and validated according to the European Medicines Agency and United States Food and Drug Administration guidelines for bioanalytical method validation. The samples were prepared using protein precipitation and online solid-phase extraction. The method was applied to clinical samples of an adrenocortical carcinoma patient receiving CAB treatment (80 mg daily). During the 10 days of observation, the patient received periodic hemodialysis on 7 days. Pharmacokinetic (PK) simulations were performed using Bayesian forecasting according to an existing population PK model for CAB. RESULTS Based on the PK simulation, a mean plasma trough concentration of 1375 ng/mL [90% prediction interval (PI), 601-2602 ng/mL] in the steady state at a daily dose of 80 mg was expected for CAB. However, an individual simulation involving the measured plasma levels of the patient resulted in a mean trough concentration of 348 ng/mL (90% PI, 278-430 ng/mL). The model based on individual PK parameters estimated accessible plasma levels of 521, 625, and 834 ng/mL by dose adjustment to 100, 120, and 160 mg, respectively. CONCLUSIONS After establishing an liquid chromatography with tandem mass spectrometry detection method for therapeutic drug monitoring of CAB, our analyses involving a single patient undergoing hemodialysis indicated that higher than expected doses of CAB were required to achieve reasonable plasma concentrations. Our study demonstrates the usefulness of therapeutic drug monitoring for the evaluation of "new" drugs in patients with renal impairment.

Background Pharmacokinetic-pharmacodynamic (PK/PD) targets of vancomycin therapy have been recognized for methicillin-resistant Staphylococcus aureus infections but not for other gram-positive bacterial infections. Therefore, we investigated whether vancomycin concentration targets such as the trough level and ratio of the area under the curve to minimum inhibitory concentration (AUC/MIC) are associated with the treatment outcome in enterococcal bacteremia. Methods A retrospective cohort analysis enrolled patients with bacteremia caused by vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis who were treated with vancomycin from January 2007 to December 2017 at a tertiary hospital located in Seoul, South Korea. Patients without vancomycin concentrations were excluded from the study. The primary outcome was 28-day all-cause mortality. Results A total of 37 patients were enrolled—26 with E. faecium infection and 11 with E. faecalis infection. The 28-day all-cause mortality rate was 21.6 %. In univariate analysis, vancomycin trough level (≤ 15 µg/mL; p = 0.042), age (p = 0.044), and septic shock (p = 0.049) were associated with 28-day mortality but not AUC24/MIC (> 389; p = 0.479). In multivariate analysis, vancomycin trough concentration (≤ 15 µg/mL; p = 0.041) and younger age (p = 0.031) were associated with 28-day mortality in patients with enterococcal bacteremia. Conclusions In this study, a vancomycin trough level of 15 µg/mL or lower was associated with 28-day mortality in enterococcal bacteremia. However, relatively large prospective studies are needed to examine the efficacy of vancomycin PK/PD parameters in patients with enterococcal bacteremia.

Objectives To investigate the population pharmacokinetics of posaconazole gastroresistant tablets in children with cystic fibrosis (CF) and perform simulations to recommend optimal doses. Patients and methods Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from pharmacy records. Relevant clinical data were collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A stepwise covariate model-building exercise evaluated the influence of interacting medicines and liver function. Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7–17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77%–83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 h for two doses then 300 mg once daily (OD) in children aged 6–11 years; and 86%–88% with a dose of 400 mg every 12 h for two doses then 400 mg OD in adolescents aged 12–17 years. This dose scheme also yielded a 90% probability of achieving an AUC of 30 mg·h/L. AUC and trough concentration were highly correlated (r2 = 0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30 mg·h/L in 90% of patients. Conclusions A starting dose of 300 mg OD in those aged 6–11 years and 400 mg OD in those aged 12–17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg·h/L.

Key messages Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Abstract Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1–2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Purpose: We aimed to evaluate the blood concentration of levetiracetam (LEV), as a second-line drug, in patients with status epilepticus (SE) in an emergency clinical setting. Methods: We prospectively evaluated 20 consecutive patients with SE admitted to our department between July 2017 and July 2019. LEV (2500 mg) was administered via bolus infusion after diazepam infusion, followed by 500 mg every 12 h for 48 h and then 500 mg orally. The primary outcomes were LEV blood concentration 15 min, 12 h, 48 h, and 96 h after administration and the proportion of patients showing trough LEV concentration within the therapeutic range. The secondary outcomes were the discontinuation of apparent convulsive seizure, epileptic wave on electroencephalogram, tracheal intubation, adverse events related to blood parameters, and abnormal findings in vital signs examination. Results: Median blood LEV (2500 mg) concentration at 15 min after administration was 81.6 μg/mL. The median trough concentration after 12, 48, and 96 h was 28.8, 10.5, and 9.1 μg/mL, respectively. Moreover, 95% of patients had trough concentration above the lower limit of the therapeutic blood concentration (>12 μg/mL) after 12 h. Regarding secondary outcomes, endotracheal intubation, seizure suppression, and abnormal electroencephalogram findings were observed in approximately 40%, 90%–95%, and 41% of patients, respectively. No abnormal findings were noted in blood tests and vital sign examination, although the AST/ALT levels increased in 10% of the patients. Conclusion: After bolus administration of 2500 mg, the blood LEV concentration reached the therapeutic window in patients with early-stage SE.

This report summarizes a totality-of-evidence approach supporting recommendation of a 320-mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

BackgroundThe role of favipiravir as a treatment for COVID-19 is unclear, with discrepant activity against SARS-CoV-2in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. In Vero-E6 cells, high concentrations are needed to inhibit SARS-CoV-2 replication. The purpose of this analysis was to use available data to simulate intracellular pharmacokinetics of favipiravir ribofuranosyl-5⍰-triphosphate (FAVI-RTP) to better understand the putative applicability as a COVID-19 intervention.MethodsPreviously publishedin vitrodata for the intracellular production and elimination of FAVI- RTP in MDCK cells incubated with parent favipiravir was fitted with a mathematical model to describe the time course of intracellular FAVI-RTP concentrations as a function of incubation concentration of parent favipiravir. Parameter estimates from this model fitting were then combined with a previously published population PK model for the plasma exposure of parent favipiravir in Chinese patients with severe influenza (the modelled free plasma concentration of favipiravir substituting forin vitroincubation concentration) to predict the human intracellular FAVI-RTP pharmacokinetics.ResultsIn vitroFAVI-RTP data was adequately described as a function ofin vitroincubation media concentrations of parent favipiravir with an empirical model, noting that the model simplifies and consolidates various processes and is used under various assumptions and within certain limits. Parameter estimates from the fittings toin vitrodata predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP when driven by a predicted free plasma concentration profile.ConclusionThis modelling approach has several important limitations that are discussed in the main text of the manuscript. However, the simulations indicate that despite rapid clearance of the parent drug from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. Population average intracellular FAVI-RTP concentrations are estimated to maintain the Km for the SARS-CoV-2 polymerase for 3 days following 800 mg BID dosing and 9 days following 1200 mg BID dosing after a 1600 mg BID loading dose on day 1. Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.

What is known and objective The revised vancomycin monitoring guidelines recommend targeting an area under the curve (AUC) of 400–600 mg*hr/L for serious methicillin‐resistant Staphylococcus aureus (MRSA) infections. An AUC can be measured by checking a peak and trough concentration at steady state; however, this requires obtaining an additional blood sample. The most practical way to perform AUC‐guided dosing is by estimating an AUC from a steady‐state trough. The purpose of this study was to compare AUCs estimated from trough‐only data to AUCs calculated from peak and trough concentrations. Methods Steady‐state peak and trough data were collected from an open‐access clinical calculator VancoPK.com. Patients were included who had (1) peaks drawn ≥60 min after the end of infusion, (2) peak and trough levels drawn ≥4 h apart and (3) troughs drawn ≤4 h early or late. The population was randomized and divided into a model group and test group. A population equation for vancomycin volume of distribution (Vd) was derived and compared to other general adult Vd models. Accuracy and precision of estimated AUCs were measured with bias, root mean square error (RMSE) and Lin's concordance correlation. Results and discussion A total of 2,500 adult patients were included in the model group and 1,843 were included in the test group. The derived Vd equation, Vd (L) = 0.29(age) +0.33(total BW in kg) +11, produced accurate and precise AUC estimates from trough‐only data. The mean actual AUC and estimated AUC were 504 and 503, respectively, with a correlation of 0.926. The RMSE between estimated and actual AUCs was 47.7, meaning that over 95% of estimated AUCs were within 100 points of actual AUCs with the study's Vd model. Other Vd models performed well for certain types of patients, depending on their body weight and age. What is new and conclusion There is limited evidence from large, robust populations regarding how to estimate Vd for general adult patients. Accuracy and precision of estimated AUCs depend on the applied population Vd model. The Vd model from the present study can be used for AUC‐guided dosing with trough‐only data which requires less blood work than peak‐trough monitoring. AUC calculations are practical with the use of open‐access websites., Vancomycin area under the curves (AUCs) measured from peak and trough concentrations were compared to AUCs estimated from trough‐only data. A population model for vancomycin volume of distribution derived in the present study produced accurate and precise AUC estimates for general adult patients. AUC‐guided dosing with trough‐only data requires less blood work than peak‐trough monitoring and the calculations are practical with open‐access clinical calculators.

Purpose:We aimed to evaluate exposure-toxicity/efficacy relationship of lenvatinib by determining its target trough concentration for patients with hepatocellular carcinoma (HCC)., Methods:In this retrospective, observational study, 28 HCC patients who had been treated with lenvatinib were enrolled between August 2018 and April 2020. We evaluated the association between the trough lenvatinib concentration and occurrence of grade ≥ 3 toxicities. Additionally, we estimated the association of the trough lenvatinib concentration with responder status (disease control; complete response, partial response, or stable disease), and progression-free survival (PFS)., Results:The mean trough lenvatinib concentration was significantly higher in the group with grade ≥ 3 toxicity (n = 15) than in the group with grade ≤ 2 toxicity (n = 13). Based on the receiver operating characteristic curve, the threshold values of the trough lenvatinib concentrations for predicting grade ≥ 3 toxicities and responder status were 71.4 ng/mL [area under the curve (AUC) 0.86, 95% confidence interval (CI) 0.71-1.00; p < 0.05] and 36.8 ng/mL (AUC 0.95, 95% CI 0.85-1.00; p < 0.05), respectively. Lenvatinib concentrations of 36.8-71.4 ng/mL resulted in longer PFS than concentrations < 36.8 ng/mL and ≥ 71.4 ng /mL [median 13.3 months (36.8-71.4 ng/mL) vs. 3.5 months (< 36.8 ng/mL) and 7.8 months (≥ 71.4 ng /mL), respectively]., Conclusions:Considering these results, we propose that the target trough concentration of lenvatinib could be 36.8-71.4 ng/mL for maintaining disease control status and reducing grade ≥ 3 toxicity in the treatment of HCC.

Intravenous (IV) atezolizumab is approved for non–small cell lung and other cancers. Subcutaneous (SC) atezolizumab coformulated with recombinant human hyaluronidase, a permeation enhancer for SC dispersion and absorption, is being developed to improve treatment options, reduce burden, and increase efficiency for patients and practitioners. IMscin001 (NCT03735121), a 2‐part, open‐label, global, multicenter, phase 1b/3 study, is evaluating the pharmacokinetics (PK), safety, and efficacy of SC atezolizumab. The part 1 (phase 1b) objective was determination of an SC atezolizumab dose yielding a serum trough concentration (Ctrough) comparable with IV. Patients enrolled in 3 cohorts received SC atezolizumab 1800 mg (thigh) once (cohort 1), 1200 mg (thigh) every 2 weeks for 3 cycles (cohort 2), or 1800 mg (abdomen) every 3 weeks cycle 1, then cycles 2 and 3 (thigh) every 3 weeks (cohort 3). In subsequent cycles, IV atezolizumab 1200 mg every 3 weeks was administered until loss of clinical benefit. SC atezolizumab 1800 mg every 3 weeks and 1200 mg every 2 weeks provided similar Ctrough and area under the curve values in cycle 1 to the corresponding IV atezolizumab reference, was well tolerated, and exhibited a safety profile consistent with the established IV formulation. Exposure following SC injection in the abdomen was lower (20%, 28%, and 27% for Ctrough, maximum concentration, and area under the concentration‐time curve from time 0 to day 21, respectively) than in the thigh. Part 1 SC and IV PK data were analyzed using a population PK modeling approach, followed by simulations. Part 2 (phase 3) will now be initiated to demonstrate that SC atezolizumab PK exposure is not lower than that of IV.

Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation. PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUCPAT) was evaluated against the reference AUC (AUCREF) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUCBM-P) calculated using an evaluated available software with clinical data. Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept −15.57, median AUCPAT/AUCREF 0.93 [range 0.81–1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8–1.2. Employment of only a trough concentration was more biased (AUCPAT/AUCREF range 0.73–1.30 for 11 h, AUCPAT/AUCREF range 0.62–1.40 for 23 h). In comparison with the evaluated software, AUCPAT was not biased against the AUCBM-P (slope 1.04, intercept −15.80, median AUCPAT/AUCBM-P 1.00 [range 0.86–1.10]). The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin.

Vancomycin (VCM) is useful for treating methicillin-resistant Staphylococcus aureus. In infants, calibrating the initial VCM dose is difficult, and many regimens have been proposed. For instance, our center uses the VCM regimen recommended for infants in the 2012-13 Nelson's Pediatric Antimicrobial Therapy. Nonetheless, our experience has shown that the initial VCM trough concentrations were frequently off target. We therefore analyzed the data on the initial VCM trough concentration in infant patients at our center.The study subjects were inborn infants born between July 2014 and June 2019 who were given VCM at earlier than day 60 in the neonatal intensive care unit. The primary outcome was the initial VCM trough concentration. The patients were divided into three groups by VCM trough concentration:10, 10-15, and15 mg/L. We also estimated VCM trough concentration by one method using Monte Carlo simulation, based on Nelson regimen dosage.Thirty-three patients were analyzed. The number of patients with10, 10-15, and15 mg/L was 24, 4, and 5, respectively. There was no significant difference in clinical characteristics between10 versus 10-15 and 10-15 versus15 mg/L. The numbers of patients with10, 10-15, and15 mg/L in the simulation were 26, 6, and 1, respectively.Most initial VCM trough concentrations were below the target. We could not find any significant clinical characteristics, which affected VCM trough concentration. Increasing the VCM dosage of the Nelson regimen with simulation should therefore be considered.

Persistent inflammation, immunosuppression and catabolism syndrome (PICS) in critically ill patients are associated with unreliable creatinine (Cr)-based estimated glomerular filtration rate (eGFR) and alteration in vancomycin clearance (CL) due to ongoing muscle wasting and renal dysfunction (RD). Currently, cystatin C (Cys) is of great interest for eGFR due to its muscle independence. Patients receiving intravenous vancomycin with trough concentration monitoring after intensive care unit stay ≥ 14 days were retrospectively enrolled. Those with C-reactive protein > 30.0 mg/L, lymphocytes count 10% were diagnosed with PICS. Impact of PICS on vancomycin trough achievement was analyzed. Plasma Cys and Cr levels with their eGFRs in RD were compared in patients with and without PICS. Furthermore, the performance of eGFRs in predicting vancomycin CL was quantificationally evaluated by population pharmacokinetics (PPK) analysis using the Phoenix NLME software. Of 69 enrolled patients, 32 (46.4%) were PICS. PICS was predictive of Cr-guided vancomycin supratherapeutic trough concentrations (OR = 5.26, P = 0.013). Significant elevation of Cys, not of Cr, was observed in patients with PICS suffering from RD (P = 0.022), causing substantial differences among eGFRs. Fifty-two and 17 patients were enrolled for the modeling group and validation group, respectively. A one-compartment PPK model with first-order elimination adequately described the data of 126 Ctrough. Prediction of vancomycin CL with Cys and Cr-based eGFR (CKD-EPIcys-cr) significantly reduced the interindividual variability of CL (from 75.6 to 28.5%). External validation with 34 Ctrough showed the robustness and accuracy of this model. This study showed the negative impact of PICS on Cr-guided vancomycin trough achievement. PPK model with CKD-EPIcys-cr can be used to optimize vancomycin dosage in patients with PICS.

Patients with rheumatoid arthritis (RA) are eligible for treatment with therapeutic monoclonal antibodies (mAbs) that target tumor necrosis factor α (TNFα), as well as others, such as rituximab (RTX) and tocilizumab (TCZ). Although pharmacokinetic variability and the link between concentration-clinical response of anti-TNFα mAbs have been well-described, little is known about RTX and TCZ. We aimed to evaluate the variability of RTX and TCZ serum concentrations in RA patients treated in second-line and the relationship between RTX/TCZ concentrations and the clinical response. Serum mAb trough concentrations of RA patients treated with RTX (n = 35) or TCZ (n = 46) were determined at week 24 by liquid chromatography-tandem mass spectrometry. The clinical response was assessed at week 24 by the change in the disease activity score in the 28 joints-erythrocyte sedimentation rate from baseline (ΔDAS28-Erythrocyte Sedimentation Rate) and according to the European League Against Rheumatism (EULAR) recommendations. RTX and TCZ trough concentrations were highly variable, with a coefficient of variation of 171.3% for RTX (median [10th-90th percentiles]

Herein, we describe a case of an elderly patient with muscular dystrophy for whom control of the plasma vancomycin (VCM) concentration proved difficult when he developed a catheter-related bloodstream infection. The pharmacist initially carried out therapeutic drug monitoring using an estimate of the creatinine clearance (CLcr) level, which was based on the serum creatinine (SCr) and serum cystatin-C (CysC) levels, but was ultimately unable to control the plasma VCM concentration. Therefore, the plasma VCM concentration was predicted ex post facto using population pharmacokinetic parameters as a covariate; that is, directly including the glomerular filtration rate (GFRCysC) estimated from the CysC level, which is not affected by the muscle mass. As a result, the estimated VCM concentration was closer to the actual concentration than that predicted using CLcr. Furthermore, the results of examining the predictive accuracy according to the assessment of renal function at the time of initial VCM administration suggested that estimation of the trough concentration using GFRCysC might be useful in elderly patients with muscular dystrophy.

Objectives This systematic review and meta-analysis was designed to determine the optimal trough concentration of voriconazole for children with invasive fungal infections (IFIs). Methods We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Japana Centra Revuo Medicina) for clinical studies describing the voriconazole trough concentration. We used stepwise cut-off values of 1.0–2.0 mg/L for efficacy and 3.0–6.0 mg/L for safety. The efficacy outcomes were treatment success and all-cause mortality, and the safety outcomes were hepatotoxicity, neurotoxicity and all-cause adverse events. Results Nine studies involving 211 patients were included in the analysis. The probability of treatment success against IFIs was significantly increased at cut-off values of ≥1.0 mg/L (odds ratio [OR] = 2.65, 95% confidence interval [CI] = 1.20–5.87). Our analysis did not find any relationship between the trough concentration and survival. Concerning safety, the occurrence of any outcomes did not significantly differ according to the voriconazole trough concentrations at any cut-off value. However, in a subgroup analysis of Asian study locations, a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough cut-off values ≥ 3.0 mg/L (OR = 8.40, 95% CI = 1.36–51.92). Although a significant correlation between the voriconazole concentration and hepatotoxicity was evident in regression curve analysis, (y = 0.1198e0.2298x), no correlation was demonstrated for neurotoxicity (y = 0.3913e−0.008x). Conclusion Our findings suggest that the optimal trough concentration for increasing clinical success and minimizing hepatotoxicity during voriconazole therapy in children with IFIs, particularly for Asian populations, is 1.0–3.0 mg/L.

BACKGROUND: There is a significant correlation between augmented renal clearance (ARC) and lower serum trough concentrations of vancomycin (VCM) during therapy. There is a need to evaluate the predictive performance of the population pharmacokinetic (PPK) model used for individual calculation of dosage regimens in ARC patients. OBJECTIVE: Our study aimed to estimate the predictive performance differences of the reported VCM PPK software JPKD-vancomycin and SmartDose in patients with varying renal function status, especially those with ARC. METHODS: Patients receiving VCM treatment from May 2014 to December 2019 were enrolled, and divided into the ARC group, the normal renal function (NRF) group, and the impaired renal function (IRF) group. VCM dosage, trough concentration, area under the curve (AUC) and pharmacokinetic parameters were compared among the three groups. The predictive performance of PPK software was expressed using absolute prediction error (APE), sensitivity, specificity, and regression coefficient (r(2)) of linear regression analysis between the measured VCM trough concentration and the predicted trough concentration. RESULTS: A total of 388 patients were included: 86 patients in the ARC group, 241 patients in the NRF group, and 61 patients in the IRF group. The daily dose of the adjusted regimen in the ARC group was higher than in the NRF group, but the trough concentration was significantly lower than in the NRF group (2.8±0.6 g vs 1.9±0.6 g, p0.6 for the initial regimen and adjusted regimen of VCM in the ARC and NRF groups, and the r(2) of the adjusted regimen of JPKD was >0.8 in the ARC and NRF groups. In the IRF group, 31.1% of patients had a change in serum creatinine (Scr) level of >50%. The r(2) increased from 0.527 to 0.7347 in SmartDose and from 0.55 to 0.7802 in JPKD when using Scr at the sampling time. The ARC group showed a significant decrease in AUC (p

Objective To evaluate the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after a single subcutaneous injection in the abdomen of 150 or 300 mg Depo-Provera and compare results to two injections of Depo-SubQ Provera 104 given 3 months apart. Design Partially randomized, multicenter, parallel-group study. Setting Research unit. Patient(s) Forty-two women of reproductive age with confirmed ovulatory cycle and body mass index of 18–35 kg/m2. Intervention(s) Women received a single subcutaneous injection of 150 mg (n = 24) or 300 mg (n = 9) of Depo-Provera or two injections of Depo-SubQ Provera 104 (n = 9). Main Outcome Measure(s) Suppression of ovulation as measured by progesterone, serum medroxyprogesterone acetate concentrations, and estimated pharmacokinetics parameters. Result(s) No ovulations were observed during 7 months after a single injection of 150 or 300 mg Depo-Provera. The 150 mg group had a similar Cmax as observed over two injection cycles of Depo-SubQ Provera 104 and a similar 6-month trough concentration as the 3-month trough of Depo-SubQ Provera 104. Conclusion(s) Our pharmacodynamics and pharmacokinetics data provide proof of concept that Depo-Provera (150 mg) may be an effective contraceptive method when injected subcutaneously every 6 months, with up to a 4-week grace period for reinjections. Clinical Trial Registration Number NCT02456584.

Background Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs). Methods A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not. Results We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P Conclusions There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4–6 ng/mL during the immunosuppression maintenance period.

Serum concentrations of voriconazole are difficult to predict, especially in pediatric patients, because of its complex pharmacokinetic characteristics. This study aimed to identify the factors associated with the concentration of voriconazole in pediatric patients.This cohort study was based on retrospective data collection and involved the administration of voriconazole to pediatric patients younger than 18 years, between January 2010 and August 2017. Electronic medical records of the patients were reviewed to collect demographic characteristics, voriconazole treatment regimen, and factors that could potentially influence voriconazole trough concentrations. A voriconazole trough serum concentration of less than 1.0 mcg/mL or greater than 5.5 mcg/mL was defined as outside the therapeutic range and was set as the outcome of this study.Among the 114 patients enrolled, 61 patients were included in the analysis. Oral administration of a maintenance dose of voriconazole and C-reactive protein (CRP) level were significantly and independently associated with a low initial trough concentration of voriconazole (1.0 mcg/mL). Alanine aminotransferase levels were a significant factor associated with a high initial trough concentration of voriconazole (5.5 mcg/mL) after adjusting for sex, age, weight, and serum creatinine (odds ratio 5.42; 95% confidence interval 1.34-21.97).Considering the variability of voriconazole concentrations in pediatric patients, monitoring certain parameters and considering the route of administration could help determine the therapeutic range of voriconazole and subsequently avoid unwanted effects.

Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R 2 = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events.

Supplemental Digital Content is available in the text., Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5–10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4–64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5–462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (β1=0.9; P

Contains fulltext : 249113.pdf (Publisher’s version ) (Open Access) Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180 mg QD; the highest tolerable dose tested in clinical trials: 240 mg QD; and two precision dosing strategies targeting the median trough concentrations following 180 mg QD, and 240 mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS) and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240 mg dosing strategy, with only a minor increase in the probability of developing toxicity.

Purpose To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab. Methods Nonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target Ctrough in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma. Results Bemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab Ctrough of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial. Conclusion A projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.

Since December 2019, a novel coronavirus (severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID-19). The antiretroviral drug favipiravir (FPV) has been experimentally used for COVID-19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high-performance liquid chromatography in patients with severe COVID-19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1,600 mg of FPV twice daily on day 1, followed by 600 mg twice daily from day 2 to day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty-nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8-12 hours) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and half-maximal effective concentration (9.7 µg/mL) against SARS-CoV-2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID-19.

Background Direct oral anticoagulants (DOACs) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. Outcomes from DOAC trials included few individuals ≥ 120 kg leading to uncertainty whether high body weight (BW) reduces DOAC concentrations. Objectives This article investigates the relationship between factor Xa (FXa) inhibitor concentrations, BW, and renal function, and compares them in high BW patients with unselected populations. Methods Consecutive patients in two United Kingdom centers, weighing ≥ 120 kg receiving 5 mg twice daily apixaban or 20 mg once daily rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays, expressed in mean or median (5th–95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration. Results One hundred patients were included; age range: 23 to 78 years, 31% were women, 58% had AF, creatinine clearance range: 67 to 474 mL/min. Median BW was 139 kg, and 84% had body mass index (BMI) ≥ 40 kg/m2. DOAC peak and trough concentrations varied from 44 to 727 and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and BW or BMI, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only two trough concentrations were below the expected range, and 109/116 were within the on-therapy range. Conclusion These data indicated that obese or high BW patients generally achieve therapeutic FXa inhibitor concentrations. However, further investigations assessing clinical outcomes are required.

Background A trough concentration (Cmin) ≥20 μg/mL of teicoplanin is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, sufficient clinical evidence to support the efficacy of this target Cmin has not been obtained. Even though the recommended high Cmin of teicoplanin was associated with better clinical outcome, reaching the target concentration is challenging. Methods Pharmacokinetics and adverse events were evaluated in all eligible patients. For clinical efficacy, patients who had bacteremia/complicated MRSA infections were analyzed. The primary endpoint for clinical efficacy was an early clinical response at 72–96 h after the start of therapy. Five dosed of 12 mg/kg or 10 mg/kg was administered as an enhanced or conventional high loading dose regimen, respectively. The Cmin was obtained at 72 h after the first dose. Results Overall, 512 patients were eligible, and 76 patients were analyzed for treatment efficacy. The proportion of patients achieving the target Cmin range (20–40 μg/mL) by the enhanced regimen was significantly higher than for the conventional regimen (75.2% versus 41.0%, p min ≥ 20 μg/mL was an independent factor for an early clinical response (odds ratio 3.95, 95% confidence interval 1.25–12.53). There was no significant difference in the occurrence of adverse events between patients who did or did not achieve a Cmin ≥ 20 μg/mL. Conclusion A target Cmin ≥ 20 μg/mL might improve early clinical responses during the treatment of difficult MRSA infections using 12 mg/kg teicoplanin for five doses within the initial 3 days.

Purpose:Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC)., Methods:This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS)., Results:The median sorafenib concentration was 2.91 μg/mL (range 0.74-8.8 μg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 μg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p, Conclusions:From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 μg/mL in patients with HCC.

What is known and objective We investigated the elimination efficiency and pharmacokinetics (PK) parameters of vancomycin (VCM) in patients undergoing continuous haemodiafiltration (CHDF) using a polyethyleneimine-coated polyacrylonitrile membrane (AN69ST) for dosage adjustment. Methods We conducted a retrospective study of CHDF patients treated with VCM from December 2017 to August 2019. We calculated PK parameters of VCM and determined the 24-hour dose required to maintain the target trough concentration of VCM (VCM_trough ). Results and discussion The average (95% CI) volume of distribution and total clearance of VCM were 75.5 L (63.7-87.3 L) and 1.84 L/h (1.38-2.30 L/h), respectively, and the elimination rate constant and half-life were 0.026/h (0.017-0.034/h) and 31.2 h (22.8-39.5 h), respectively. The average AN69ST clearance of VCM (CL_CHDF ) was 0.69 L/h (0.52-0.86 L/h). The estimated average doses required to maintain VCM_trough of 10, 15 and 20 μg/mL were 623.1 mg (379.8-866.4 mg), 934.6 mg (569.7-1299.5 mg) and 1246.2 mg (759.6-1732.8 mg), respectively. What is new and conclusion The PK of VCM and CL_CHDF of AN69ST were clarified. These results suggest that it is possible to adjust the dose of VCM in using AN69ST, which efficiently removes cytokines, and contributes to improvement of serious infections.

Background The optimal loading dose of teicoplanin in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) has never been determined by therapeutic drug monitoring. This study investigated the appropriateness of proposed loading dose regimens of teicoplanin when administered to patients receiving VA-ECMO by using a previously proposed loading dosage and measuring the teicoplanin trough concentration (Ctrough). Methods Patients who initiated teicoplanin therapy while receiving VA-ECMO were enrolled. Every included patient received four loading doses of teicoplanin at a dose of 12 mg/kg. The first three doses were administered 12 h apart, and the fourth dose was administered 24 h after the third dose. Blood samples were collected before administering the maintenance dose (i.e., the fifth dose), and the teicoplanin Ctrough was measured. Serum teicoplanin levels were determined using an Agilent 1290 ultra-high performance liquid chromatography system. Results The teicoplanin Ctrough was successfully tested in 11 patients. Their median age was 68.2 years, and 81.8% of them were men. The median of each loading dose was 11.6 (range, 10.7–12.8) mg/kg. The median teicoplanin Ctrough was 22.01 (range, 14.85–44.84) mg/L. All patients had a Ctrough of more than 10 mg/L, whereas 90.9% (10/11) of the patients achieved a Ctrough of more than 15 mg/L. Conclusion The loading dosage consisting of four doses of teicoplanin administered within the first 72 h at a dose of 12 mg/kg/dose could achieve an adequate therapeutic Ctrough of teicoplanin in patients receiving VA-ECMO.

The transdermal bisoprolol patch (TB) was designed to maintain a sustained concentration of bisoprolol in plasma by a higher trough concentration than oral bisoporolol (OB). We compared the efficacy between TB and OB in patients with idiopathic premature ventricular contractions (PVCs) while considering their duration of action.A total of 78 patients with a PVC count of ≥ 3,000 beats/24 hours were divided into groups treated with TB 4 mg (n = 43) or OB 2.5 mg (n = 35). PVCs were divided into positive heart rate (HR) -dependent PVCs (P-PVCs) and non-positive HR-dependent PVCs (NP-PVCs) based on the relationship between the hourly PVC density and hourly mean HR. Twenty-four-hour Holter electrocardiograms were performed before and 1 to 3 months after the initiation of therapy.There were no significant between-group differences in the baseline characteristics. Both the TB (from 14.6 [9.9-19.2] to 7.6 [1.7-15.8]%, P < 0.001) and OB (from 13.2 [7.6-21.9] to 4.6 [0.5-17.0]%, P = 0.0041) significantly decreased the PVC density, and there was no significant difference between the two groups (P = 0.73). Compared to OB, the TB had similar effects in reducing the PVC density for P-PVCs (P = 0.96), and NP-PVCs (P = 0.71). The TB significantly decreased the P-PVC density from baseline not only during day-time (P < 0.001) but also night-time (P = 0.0017), while the OB did not significantly decrease the P-PVC density from baseline during night-time (P = 0.17).Compared to OB, the TB could be used with the same efficacy of reducing idiopathic PVCs. The TB may be a more useful therapeutic agent than OB for P-PVCs during a 24-hour period.

ObjectivesNephrotoxicity represents a major complication of vancomycin administration, leading to high rates of morbidity and treatment failure. The aim of this meta-analysis was to evaluate the association between trough levels and risk of renal impairment, by defining an exposure–toxicity relationship and assessing its accuracy in predicting the development of acute kidney injury (AKI).MethodsMedline, Scopus, CENTRAL, Clinicaltrials.gov and Google Scholar databases were systematically searched from inception. Studies examining the effects of trough levels on nephrotoxicity risk in adult patients were deemed eligible.ResultsThe meta-analysis was based on 60 studies, including 13 304 patients. The development of AKI was significantly linked to both higher initial [standardized mean difference (SMD): 0.82; 95% CI: 0.65–0.98] and maximum (SMD: 1.06; 95% CI: 0.82–1.29) trough levels. Dose–response analysis indicated a curvilinear relationship between trough levels and nephrotoxicity risk (χ2 = 127.1; P value ConclusionsThe present findings suggest that the development of vancomycin-induced AKI is significantly associated with higher initial and maximum trough levels. An exposure–response relationship was defined, indicating that increasing trough levels correlate with a significant rise of nephrotoxicity risk. Future studies should verify the effectiveness of individualized pharmacokinetic tools that would enable the attainment of trough level targets and minimize the risk of renal toxicity.

Objectives Monitoring tacrolimus blood concentrations is important for preventing allograft rejection in transplant patients. Our hospital offers dried blood spot (DBS) sampling, giving patients the opportunity to sample a drop of blood from a fingerprick at home, which can be sent to the laboratory by mail. In this study, both a volumetric absorptive microsampling (VAMS) device and DBS sampling were compared to venous whole blood (WB) sampling. Methods A total of 130 matched fingerprick VAMS, fingerprick DBS and venous WB samples were obtained from 107 different kidney transplant patients by trained phlebotomists for method comparison using Passing-Bablok regression. Bias was assessed using Bland-Altman. A multidisciplinary team pre-defined an acceptance limit requiring >80% of all matched samples within 15% of the mean of both samples. Sampling quality was evaluated for both VAMS and DBS samples. Results 32.3% of the VAMS samples and 6.2% of the DBS samples were of insufficient quality, leading to 88 matched samples fit for analysis. Passing-Bablok regression showed a significant difference between VAMS and WB, with a slope of 0.88 (95% CI 0.81–0.97) but not for DBS (slope 1.00; 95% CI 0.95–1.04). Both VAMS (after correction for the slope) and DBS showed no significant bias in Bland-Altman analysis. For VAMS and DBS, the acceptance limit was met for 83.0% and 96.6% of the samples, respectively. Conclusions VAMS sampling can replace WB sampling for tacrolimus trough concentration monitoring, but VAMS sampling is currently inferior to DBS sampling, both regarding sample quality and agreement with WB tacrolimus concentrations.

Objective This study was designed to investigate the characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia. Methods 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. Results 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 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 Conclusions 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.

Although the superiority of vancomycin dosing based on area under the concentration-time curve (AUC0-24) over that based on trough concentration has been reported, a dosing strategy to achieve the target AUC0-24 has yet to be developed. The objective of this study was to develop a convenient useable nomogram for vancomycin dosing to obtain the target AUC0-24 (400 μg h/mL). The nomogram was pharmacokinetically developed in a retrospective manner. The number of enrolled patients and concentrations was 166 and 309 for development of the nomogram, 99 and 181 for evaluation of the nomogram, respectively. The nomogram was developed as doses per personal body weight corresponding to each range of estimated glomerular filtration rate (eGFR), which was identified to be the covariate for vancomycin clearance by non-linear mixed effect modeling. The nomogram described the surrogate trough concentration for the target AUC0-24 was calculatedly different for each eGFR range (9.3–15.0 μg/mL). The rate of attainment of therapeutic range using surrogate trough concentration to obtain the target AUC0-24 was 63.8% in the evaluation period. We have developed and evaluated the first convenient useable nomogram of vancomycin dosing to obtain the target AUC0-24.

In the hospital, antibiotics are widely used to treat infections. We report a case of acute kidney injury (AKI) caused by an antibiotic drug combination. A 30-year-old Japanese male presented with lung metastases, pneumothorax, empyema, and methicillin-resistant Staphylococcus aureus (MRSA) infection. The patient received a combination of vancomycin and piperacillin/tazobactam, which resulted in elevated vancomycin trough concentration and subsequently in AKI. Renal function was restored upon vancomycin and piperacillin/tazobactam cessation. Though this patient had AKI most likely due to the combined use of two agents as has been reported in many cases, vancomycin trough concentration showed an unexpected abnormal increase when halting vancomycin treatment. This is the first report indicating a drug-drug interaction between vancomycin and piperacillin/tazobactam with unexpected abnormal vancomycin trough concentration, leading to AKI, additionally we think that there was a situation that he stressed against the kidney by a history of medications caused renal dysfunction and co-administration. We suggest that when using vancomycin in combination with piperacillin/tazobactam, the trough concentration of vancomycin must be confirmed simultaneously with renal function and evaluation, and that the combination of these two drugs should be minimized.

Background Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens. Methods The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (Cavg) and trough concentration (Cmin) at steady state (ss). Safety was bridged by ensuring that concentrations were below those at 10 mg/kg dose every 2 weeks (Q2W), the maximum clinical dose. Results The 400 mg Q6W dose had similar predicted exposure (Cavg,ss, geometric mean ∼1% higher) as the 200 mg Q3W dose. Fewer than 1% of subjects had transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (∼65%) lower than the 10 mg/kg Q2W dose. Conclusions Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types. Clinical trial registration numbers NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.

What is known and objective Vancomycin therapeutic guidelines suggest a loading dose of 25-30 mg/kg for seriously ill patients. However, high-quality data to guide the use of loading doses are lacking. We aimed to evaluate whether a loading dose (a) achieved a target trough concentration at steady state and (b) improved early clinical response. Methods Patients with an estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2 were included. A loading dose of 25 mg/kg vancomycin followed by 15 mg/kg twice daily was compared with traditional dosing. A Cmin sample was obtained before the fifth dose. An early clinical response 48-72 hours after the start of therapy and clinical success at end of therapy (EOT) was evaluated in patients with methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci or Enterococcus faecium. Results There was no significant difference in Cmin between the regimen with and without a loading dose (median: 10.4 and 10.2 µg/mL, P = .54). Proportions of patients achieving 10-20 and 15-20 µg/mL were 56.9% and 5.6%, respectively, in patients with a loading dose. Although there was no significant difference in success rate at EOT between groups, a loading dose was associated with increased early clinical response for all infections (adjusted odds ratio [OR]: 4.588, 95% confidence interval [CI]: 1.373-15.330) and MRSA infections (OR: 12.065, 95% CI: 1.821-79.959). Study limitations included no Cmin measurements within 24 hours and the inclusion of less critically ill patients. What is new and conclusion A loading dose of 25 mg/kg followed by 15 mg/kg twice daily did not achieve the optimal Cmin at steady state in patients with normal renal function. However, more early clinical responses were obtained with a loading dose compared with traditional dosing, possibly because of a prompt albeit temporary achievement of a more effective concentration.

Renal function has an important influence on the pharmacokinetics of vancomycin, and serum cystatin C (CysC) exhibits accurate predictive performance as a marker for renal function. This study aimed to develop a population pharmacokinetics (PopPK) model of vancomycin based on serum CysC in pediatric patients. In addition, vancomycin dosage was optimized with the area under the serum concentration–time curve over 24 h (AUC0–24)/minimum inhibitory concentration (MIC) ratio in the target range of 400–700 and the steady-state trough concentration (Css,trough). Data were retrospectively obtained from pediatric patients aged 2–18 years who received vancomycin treatment for infection from January 2014 to June 2019. PopPK analysis and Monte Carlo simulations were conducted using nonlinear mixed effects model (NONMEM) software. A total of 220 children were included. Serum CysC and age were significant covariates affecting the pharmacokinetics of vancomycin. The final typical value of clearance was 2.25 L/h; the volume of distribution was 8.17 L. The average probability of target attainment values of AUC0–24/MIC ratios within 400–700 in the 2–7, 7–12, and 12–18 years age groups were 66.1%, 68.1% and 66.5%, respectively. The median Css,trough values of vancomycin for the 2–7, 7–12, and 12–18 years age groups were 7.49–11.84, 5.98–11.32, and 5.15–11.39 mg/L, respectively, and were highly correlated with AUC0–24/MIC ratios in the range of 400–700 when the MIC was 1 mg/L. The pharmacokinetic parameters for vancomycin in pediatric patients were estimated using a serum CysC model. The simulated dosages provide a reference for vancomycin therapy.

Background Therapeutic drug monitoring (TDM) is recommended to guide voriconazole therapy. Objectives To determine compliance of hospital-based voriconazole dosing and TDM with the Australian national guidelines and evaluate the predictive performance of a one-compartment population pharmacokinetic voriconazole model available in a commercial dose-prediction software package. Methods A retrospective audit of voriconazole therapy at an Australian public hospital (1 January to 31 December 2016) was undertaken. Data collected included patient demographics, dosing history and plasma concentrations. Concordance of dosing and TDM with Australian guidelines was assessed. Observed concentrations were compared with those predicted by dose-prediction software. Measures of bias (mean prediction error) and precision (mean squared prediction error) were calculated. Results Adherence to dosing guidelines for 110 courses of therapy (41% for prophylaxis and 59% for invasive fungal infections) was poor, unless oral formulation guidelines recommended a 200 mg dose, the most commonly prescribed dose (56% of prescriptions). Plasma voriconazole concentrations were obtained for 82% (90/110) of courses [median of 3 (range: 1–27) obtained per course]. A minority (27%) of plasma concentrations were trough concentrations [median concentration: 1.5 mg/L (range: 5.0 mg/L)]. Of trough concentrations, 57% (58/101) were therapeutic, 37% (37/101) were subtherapeutic and 6% (6/101) were supratherapeutic. The dose-prediction software performed well, with acceptable bias and precision of 0.09 mg/L (95% CI −0.08 to 0.27) and 1.32 (mg/L)2 (95% CI 0.96–1.67), respectively. Conclusions Voriconazole dosing was suboptimal based on published guidelines and TDM results. Dose-prediction software could enhance TDM-guided therapy.

Objectives: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. Methods: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child–Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. Results: There were good correlations between the area under the curve (AUC0–12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child–Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child–Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) μg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2–6 μg/ml). Conclusions: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child–Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child–Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events. Keywords: Voriconazole, Liver dysfunction, Pharmacokinetics, Child–Pugh score

Background The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. Methods We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. Results We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4–8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35–65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9–18.8), piperacillin was 78.6 mg/L (49.5–127.3), tazobactam was 9.5 mg/L (6.3–14.2), and vancomycin was 14.3 mg/L (11.6–21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. Conclusions In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.