Trough Serum Concentrations Research Articles

Linezolid-Associated Neuropathy in Patients with MDR/XDR Tuberculosis in Shenzhen, China.

ObjectiveLinezolid is one of the key drugs for the treatment of multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB). We aimed to describe the incorporation of the Michigan Neuropathy Screening Instrument (MNSI) and serum trough concentration as screening tools for neurotoxicity in the management of MDR/XDR-TB patients receiving a linezolid-based treatment regimen in Shenzhen, China.MethodsA total of 73 patients on a linezolid-containing anti–MDR/XDR-TB regimen were prospectively enrolled. The MNSI was used for peripheral neuropathy screening. Optic neuropathy was diagnosed by ophthalmologists. Serum trough concentration was recorded and its relationship with neuropathy analyzed.ResultsOf all patients, neuropathy was observed in 40% (29) during anti-TB treatment. Of these, 20 (69%) had peripheral neuritis, seven (24%) optic neuritis, and two (7%) both. Serum trough concentration >2 mg/L was observed in 17 (59%) patients with neuropathy and 13 (30%) patients without neuropathy. There was a significant statistical difference between the two groups (P=0.013). Time to onset of neuropathy from initiation of the linezolid-containing regimen was within 2 months for eight (28%) patients, 2–6 months for 18 (62%) patients, and >6 months for three (10%) patients. Sixteen (55%) patients were adjusted to a lower dose of 300 mg linezolid daily. Four (14%) patients had linezolid permanently removed from their regimen.ConclusionNeuropathy is a commonly reported adverse event associated with long-term use of linezolid. MNSI and serum trough–concentration monitoring can be adopted as simple screening tools for early detection of neuropathy to balance linezolid efficacy and tolerability.

Intérêt du suivi immunologique des biothérapies anti-TNF

AbstractUtility of therapeutic drug monitoring of anti-TNF biologicsDespite a good clinical efficacy, treatments targeting the tumor necrosis factor alpha (anti-TNF) are frequently confronted with primary non-response or secondary loss of response most often due to a poor choice of the therapeutic target, a suboptimal dosing of the drug or the appearance of anti-drug antibodies (ADAbs). In order to help the clinician in managing these primary or secondary resistances, algorithms have been developed based on therapeutic drug monitoring (TDM) with measurement of the serum trough concentration and detection of anti-drug antibodies. The reactive use of these algorithms during a disease flare allows restoration of the therapeutic efficacy at a lower cost compared to an empirical optimization approach. However, the clinical benefit remains more controversial, as well as the proactive use of TDM in order to prevent relapses by maintaining the serum concentration of the biologic within a therapeutic range. Despite these limitations, TDM of anti-TNF is now proposed in several international guidelines, particularly for the management of inflammatory bowel disease.

Population Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Flomoxef in the Serum and Liver Tissue of Patients Undergoing Hepatic Resection.

The purpose of this study was to investigate the population pharmacokinetics of prophylactic flomoxef based on serum and liver tissue concentrations and to demonstrate a pharmacodynamic target concentration in the serum and liver tissue exceeding the MIC in order to design an effective dosing regimen. Serum samples (n = 210) and liver tissue samples (n = 29) from 43 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index target value was regarded as the probability of maintaining flomoxef serum trough and liver tissue concentrations exceeding the MIC90 values, 0.5 mg/L and 1.0 mg/L, for Escherichia coli and methicillin-susceptible Staphylococcus aureus, respectively. The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance (CLCR) was identified as a significant covariate influencing total clearance when CLCR was less than 60 mL/min. The probability of achieving concentrations in the serum and liver tissue exceeding the MIC90 for E. coli or methicillin-susceptible S. aureus for a 1 g bolus dose was above 90% at 2 h after the initial dose. Our findings suggest that population pharmacokinetic parameters are helpful for evaluating flomoxef pharmacokinetics and determining intraoperative flomoxef redosing intervals.

Adalimumab with Methotrexate vs. Adalimumab Monotherapy in Psoriasis: First-Year Results of a Single-Blind Randomized Controlled Trial

Adalimumab is normally prescribed with methotrexate (MTX) in rheumatoid arthritis given the enhanced treatment effect and reduced antidrug antibody formation compared with adalimumab monotherapy (ADL). In psoriasis, the long-term treatment effects and pharmacokinetic profile have not been investigated extensively. We conducted a randomized controlled trial to assess the efficacy, safety, pharmacokinetics, and immunogenicity of adalimumab combined with MTX 10 mg per week (ADL-MTX group) compared with that of ADL (ADL group) in chronic plaque psoriasis. A total of 31 patients in the ADL-MTX group and 30 in the ADL group were analyzed. After 1 year, a (nonsignificant) better drug survival was found in the ADL-MTX group (74.2 vs. 58.6%, P= 0.15). The PASI 75 response in week 49 was 58.1 versus 36.7% (P= 0.13), and the median (interquartile range) serum-trough concentrations were 6.8 (5.5‒9.2) versus 5.9 (3.5‒8.8) mg/l (P= 0.26) in the ADL-MTX group and ADL group, respectively. Fewer patients showed antidrug antibodies in the ADL-MTX group (22.6 vs. 60.0%, P < 0.01). No serious adverse events occurred. Combination therapy of adalimumab and MTX results in fewer patients showing antidrug antibodies, with a trend toward a better PASI 75 response, drug survival, and higher serum-trough concentrations than ADL. Patient-reported outcomes and adverse events were comparable between the groups.

Infliximab: a single-centre, prospective, observational evaluation of TDM data in patients with IBD

ObjectivesTherapeutic drug monitoring of infliximab (IFX) is important to optimise treatment of inflammatory bowel disease (IBD). A recent IBD consensus statement recommends targeting trough serum concentrations of >3 μg/mL, higher...

Population Pharmacokinetic and Exposure–Response Model Simulations: Predicted Exposure and Efficacy for Maintenance Doses of Intravenous Golimumab Every 6 or 8 Weeks in Patients With Moderately to Severely Active Rheumatoid Arthritis

Golimumab is approved to treat moderate-to-severe active rheumatoid arthritis when given intravenously at weeks 0 and 4, then every 8 weeks (Q8W) with concomitant methotrexate. These analyses assessed whether a shorter dosing interval could ameliorate diminished efficacy experienced by a small proportion of patients toward the end of the dosing interval. Population pharmacokinetic and exposure-response modeling simulations were performed for intravenous golimumab 2 mg/kg at weeks 0 and 4, then Q8W or every 6 weeks (Q6W) through 1 year. A 2-compartment pharmacokinetic model with linear clearance developed based on GO-FURTHER (A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, an Anti-TNFα Monoclonal Antibody, Administered Intravenously, in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy) study data was used for pharmacokinetic simulations. A latent-variable indirect exposure-response model developed based on GO-FURTHER American College of Rheumatology (ACR) 20%/50%/70% improvement (ACR20, ACR50, and ACR70, respectively) data was used to predict clinical endpoints of ACR20/ACR50/ACR70 response rates. For Q6W and Q8W dosing, respectively, predicted median golimumab steady-state trough (Ctrough,ss) concentrations were 0.57 and 0.24 µg/mL, and Cmax at steady state values were 33.1 and 32.9µg/mL. Predicted peak median ACR20 steady-state response rates were 76.7% (Q6W) and 75.6% (Q8W). Predicted median ACR20 response rates at Ctrough,ss increased by 4.7 percentage points with Q6W (73.7%) versus Q8W (69.0%) dosing. Greater improvement in ACR20 response rates at trough time points was predicted in patients with lower golimumab trough serum concentrations. Consistent findings were observed for ACR50/ACR70 response rates. These simulations suggest that intravenous golimumab Q6W dosing increases golimumab Ctrough,ss, which may improve clinical response in the small proportion of patients with rheumatoid arthritis with waning efficacy at the end of the standard dosing interval. gov identifier: NCT00973479. Clinicaltrialsregister.eu: EudraCT 2008-006064-11.

Population pharmacokinetic analysis and dosage recommendations for digoxin in Japanese patients with atrial fibrillation and heart failure using real-world data

BackgroundDigoxin is an important treatment option for reducing the ventricular rate in patients with atrial fibrillation (AF) and heart failure (HF). Digoxin has a narrow therapeutic window and large interindividual variability. A low target blood concentration, especially ≤0.9 ng/mL, is recommended for patients with HF who are taking digoxin. This study aimed to develop a population pharmacokinetic model and to identify clinical factors that affect digoxin exposure and an optimal digoxin dosing regimen in Japanese patients with AF and HF.MethodsA population pharmacokinetic analysis was performed by using a nonlinear mixed effects model based on 3465 concentration points from 391 patients (>18 years) who were receiving oral digoxin. Using trough serum digoxin concentrations and clinical data, a population pharmacokinetic model was developed for determining covariates of clearance. A 1-compartment model was used to examine the interindividual variability of the oral clearance (CL/F) of digoxin. An appropriate dosage of digoxin was identified using Monte Carlo simulation.ResultsThe final model demonstrated that creatinine clearance (CLCR) and the use of amiodarone were factors that contributed to the CL/F of digoxin. Monte Carlo simulation results showed that with a daily maintenance dose of 0.25 mg, the intoxication risk window of a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients regardless of renal function category or concurrent use of amiodarone. The appropriate maintenance dosage was 0.125 mg daily for most Japanese patients with AF and HF. However, with a daily dose of 0.125 mg, a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients with renal impairments (CLCR 30 mL/min) or concurrent use of amiodarone. A daily maintenance dose of 0.0625 mg was acceptable for these patients.ConclusionsCLCR and the use of amiodaron were found to contribute to digoxin clearance using a population pharmacokinetic methodology. For Japanese patients with AF and HF, 0.125 mg is an appropriate daily digoxin maintenance dose, but a dose reduction is required for patients with CLCR <30 mL/min or concurrent amiodarone use.

Suivi thérapeutique pharmacologique de la cyamémazine : comment interpréter une concentration ? Une revue de la littérature

Cyamemazine is the most prescribed antipsychotic drug in France, often in combination with another antipsychotic, for its sedative and anxiolytic component. Providing to physicians serum concentrations of cyamemazine in different contexts (compliance checking, ineffectiveness, adverse effects, intoxication, modification of pharmacokinetic parameters…) requires to interpret them correctly. This article presents an update on how to interpret a concentration of cyamemazine, wich remains poorly documented. The anxiolysis occurs at steady-state serum trough concentrations of 4 to 5μg/L; the antipsychotic effect from 18-20μg/L. Cyamemazine is not a drug with a narrow therapeutic window and concentrations up to 400μg/L may be sought in cases of partial efficacy; concentrations of 1800μg/L might be fatal; lower concentrations might be fatal if association with high others concentrations of drugs.

Magnitude of Lamotrigine Exposure Through Breastfeeding.

Importance: Lamotrigine use during breastfeeding has significantly increased in the recent years, whereas breast milk lamotrigine pharmacokinetics data are still sparse. Objectives: To assess lamotrigine exposure in breastfed infants by monitoring maternal serum and breast milk concentrations. Methods: Breastfeeding women treated with lamotrigine were recruited to this study. Maternal trough breast milk and serum samples were collected, and additional breast milk samples were collected 1, 3, 6, 9, 12 hours after lamotrigine consumption. Trough breast milk/serum ratios (M/S ratio) and breast milk area under the curve (AUC) values were calculated. Results: Twenty-one breastfeeding women were recruited to this study, and the final dataset was based on the samples collected from 17 women. Lamotrigine trough serum and mother's milk concentrations were 5.1 ± 3.3 mg/L and 3.1 ± 1.9 mg/L, respectively (mean ± standard deviation). The trough M/S ratio of lamotrigine was 0.66 ± 0.22. The lamotrigine breast milk average AUC was 41.7 ± 24.6 mg·h/L. The estimated infant dose of lamotrigine was 0.52 ± 0.31 mg/kg/day and 0.26 ± 0.15 mg/kg/day for fully and partially breastfed infants, respectively. Significant correlation was found between the maternal lamotrigine serum trough concentrations and the breast milk parameters: trough breast milk concentrations (Spearman's rho = 0.986, p < 0.0001) and breast milk AUC values (Spearman's rho = 0.941, p < 0.0001). No significant correlation was found between the maternal lamotrigine daily dose and serum trough concentrations, breast milk trough concentrations, and breast milk AUC values (Spearman's rho = 0.294, 0.285, and 0.438, p = 0.252, 0.396, and 0.078, respectively). Conclusion and Relevance: High correlation between the maternal lamotrigine trough serum concentrations and the breast milk AUC values was found, implying that monitoring the maternal lamotrigine serum concentrations can be useful for prediction of exposure of infants to lamotrigine through the breast milk. The trial was registered in the Israeli trials registry MOH_2021-09-05_010243 at September 5, 2021 Retrospectively registered https://my.health.gov.il/CliniTrials.

Assessment of Anti-Xa activity in patients receiving concomitant apixaban with strong p-glycoprotein inhibitors and statins.

What is known and objectivesAlthough the apixaban Food and Drug Administration (FDA) package insert recommends dose reduction in patients administered dual strong inhibitors of p‐glycoprotein (P‐gp) and cytochrome P‐450 (CYP) 3A4, there are limited published data regarding potential drug‐drug interactions between apixaban (Eliquis) and common p‐glycoprotein (P‐gp) and CYP3A4 inhibitors co‐administered with statins. The aim of this study was to investigate the degree of elevation relative to apixaban serum peak and trough concentration after the co‐administration of amiodarone, diltiazem and statins (atorvastatin, rosuvastatin and simvastatin).MethodsPatients prescribed apixaban 5mg twice daily for at least one week were identified from the anticoagulation clinic database and contacted for potential enrolment. A total of 117 volunteers were enrolled with eight excluded due to discontinued use, resulting in 109 volunteers (44 females and 65 males delineated into age groups 40–64 and ≥65 years old) completing the observational study. Fifty‐five volunteers were administered apixaban without the P‐gp inhibitors amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin and simvastatin). Fifty‐four volunteers were administered apixaban with either amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin or simvastatin). Peak and trough concentrations were assessed for each patient utilizing an apixaban anti‐Xa assay.ResultsOf the combinations studied, the mean apixaban trough concentration upon co‐administration of amiodarone without a statin was elevated compared to apixaban alone (experimental 156.83 +/− 79.59 ng/ml vs. control 104.09 +/− 44.56 ng/ml; p = 0.04). The co‐administration of diltiazem and rosuvastatin, and the administration of amiodarone without a statin led to greater than 1.5‐fold increase in apixaban concentrations (peak experimental 315.19 +/− 157.53 ng/ml vs control 207.6 +/− 83.38 ng/ml; p = 0.08 and trough experimental 182.03 +/− 95.93 ng/ml vs control 112.32 +/− 37.78 ng/ml; p = 0.17) suggesting the need to assess dose adjustment for patients per the FDA package insert. In addition, the aggregated mean peak (p = 0.0056) and trough (p = 0.0089) elevation of CYP3A4 experimental groups (atorvastatin and simvastatin) co‐administered apixaban and diltiazem were statistically significant compared with the aggregated non‐CYP3A4 control groups (no statin and rosuvastatin).What is new and conclusionHerein, we report novel data regarding peak and trough apixaban concentrations after concomitant administration of P‐gp and CYP3A4 inhibitors (amiodarone or diltiazem) co‐administered with statins (atorvastatin, rosuvastatin or simvastatin). Providers should consider utilizing the apixaban anti‐Xa assay or comparative heparin anti‐Xa assay to determine if patients require dose reduction to decrease adverse events in high‐risk patients prescribed apixaban and concomitant p‐glycoprotein and CYP3A4 inhibitors amiodarone or diltiazem with and without a CYP3A4 or non‐3A4 statin.

Therapeutic drug monitoring for biological medications in inflammatory bowel disease.

Therapeutic drug monitoring (TDM) is the measurement of serum drug concentrations and anti-drug-antibodies (ADA) for biologic therapies used to treat inflammatory bowel disease (IBD). The aim of this article is to review the current literature concerning reactive and proactive TDM for both adults and children with IBD. Although optimal trough concentration windows for some of these medications are not well defined, there is mounting evidence to suggest that reactive TDM is associated with favorable therapeutic outcomes, including less immunogenicity, greater drug exposure, and a decreased risk of treatment failure. Moreover, while the exact mechanism of loss of response is not fully elucidated, the vast majority of studies have reported a decreased incidence of nonresponse and secondary loss of response when TDM is implemented. Proactive TDM, while even less understood in the literature, employs a schedule of preemptive analysis of serum trough concentrations to accordingly adjust the patient's biologic dosage. Proactive TDM may decrease the need for IBD-related surgery/hospitalization, and therefore merits future studies of investigation.

Assessment-of-vancomycin-pharmacokinetic-parameters-among-malaysian-adult-patients-in-penang-with-different-kidney-functions

Introduction: Vancomycin is indicated for highly resistant gram-positive systemic infections. The targeted trough and 24-hour area under the concentration-time curve (AUC24) level of vancomycin must be achieved for efficacy and safety. Local population-based pharmacokinetic parameters including the elimination rate constant (Ke), half-life (t1/2), volume of distribution (Vd) and vancomycin clearance (Clvanco) can allow better vancomycin dosing determination. Objective: This study aims to determine the pharmacokinetic parameters in the Malaysian adult patients in Penang based on different kidney functions. Method: This was a retrospective, single-centered study conducted in the Clinical Pharmacokinetics Department, Penang General Hospital from 1 January 2016 to 31 December 2017. This study included adult patients who had been treated with intravenous vancomycin under therapeutic drug monitoring. The patients’ personalised vancomycin pharmacokinetic parameters were determined using a series of pharmacokinetic equations. Result: From the recruited 26 patients, 73.1% were male and 46.2% were above 50 years old. A total of 34.6% patients had the actual body weight / ideal body weight ratio of more than 1.0. The median total daily dose was 34.72 mg / kg. The median for Cmax (peak serum concentration) was 26.0 mg /L while Cmin (trough serum concentration) was 14.20 mg / L. The median for AUC24 is 412.08 mg*hr / L. The overall median for Ke and t1/2 were 0.091 hr-1 and 7.62 hours, respectively. The median Vd was 0.90 L / kg. It was found that with increasing creatinine clearance, the Ke and Vd increased while the t1/2 decreased. Conclusion: The vancomycin pharmacokinetic data from this study varied according to different degree of creatinine clearances.

Comparing two equations for estimation of kidney function (Cockcroft-Gault and Glomerular Filtration Rate Assessment in Liver Disease) for vancomycin dosing in adult liver transplant recipients: a pilot, randomized clinical trial

Background: In the setting of impaired liver function, estimation of glomerular filtration rate (GFR) using common creatinine-based equations is inaccurate. Recently, the Glomerular filtration Rate Assessment In Liver disease (GRAIL) model has been introduced to estimate GFR in liver transplantation. This study was conducted to compare vancomycin dose adjustment in liver transplant patients using Cockcroft-Gault (C-G) versus the GRAIL method. Methods: In this pilot, randomized clinical trial, adult liver transplant recipients who were a candidate to receive intravenous vancomycin were enrolled. The level of kidney function was estimated using the GRAIL model and C-G equation in the intervention and control arms, respectively. Then, vancomycin maintenance doses were accordingly adjusted. At the steady state, peak and trough serum concentrations of vancomycin were collected for area under the concentration-time curve (AUC) calculation and pharmacokinetic comparisons. Results: Fifteen patients were enrolled in each arm of study. The mean daily dose of vancomycin was estimated insignificantly lower for individuals in the GRAIL arm than the C-G group (1550.00±544.45 versus 1750.00± 389.60mg). Compared with the C-G group, a higher rate of patients in the GRAIL arm experienced below-target vancomycin trough concentrations (40.0% versus 13.3%), and a lower rate showed above target trough concentration (40.0% versus 66.7%). These differences did not reach statistical significance. Individuals in the GRAIL arm represented significantly higher rate of below target vancomycin AUC/MIC than patients in the C-G arm (46.7% versus 6.7%) (P=0.049). No differences in clinical outcomes were observed between the two groups. Conclusion: Using the GRAIL model for vancomycin dosing may result in less percent of patients with at target AUC/MIC compared to the C-G method and expose more patients at risk for vancomycin under dosing.

609. Implementation of Bayesian Software for Vancomycin Dosing Integrated into an Electronic Medical Record

BackgroundNew vancomycin dosing guidelines recommend using a 24-hour area under the curve (AUC) goal of 400-600mg*h/L rather than a serum trough concentration 10-20 mg/L. This target has the potential to lower troughs and the occurrence of acute kidney injury (AKI). In summer 2020, we were the first to integrate DoseMeRx® Bayesian software into Epic OneChart®, our electronic medical record, to assist with dosing vancomycin. We sought to determine how doses and trough concentrations changed after software implementation. The study also aimed to establish the sample size needed to assess AKI rates.MethodsThis quasi-experimental study evaluated patients receiving ≥3 vancomycin doses before software integration (Q1 2020) and after (Q4 2020). Fifty patients in whom an adult 1-compartment model could be used and a trough concentration was measured were randomly selected from each period. Patients age ≤18 years, ≥200kg, or with pre-existing renal failure were excluded. AKI was defined using AKIN criteria of an increase in Scr of ≥ 0.3 mg/dL over 48 hours. Student’s t-test was used for continuous variables and Fischer exact test for categorical outcomes.ResultsIn Q1, 299 patients had ≥3 vancomycin doses with 107 reviewed to reach 50 meeting inclusion criteria. In Q4, 346 had ≥3 doses and 94 were reviewed to include 50 patients. The primary reason for exclusion was no trough concentration. Demographics and indications for vancomycin were well matched. Skin/soft tissue infection was the most common indication for vancomycin (n=16, both Q1 and Q4). Sixteen patients were in the ICU with 8 on vasopressors before integration. There were 10 patients in the ICU and 6 on vasopressors after. Results in Table 1 were not significantly different (all p >0.05). AKI occurred in 5 (10%) patients before integration and 3 (6%) after. Based on this, a sample of 1442 patients, or approximately 15 months of vancomycin AUC-based dosing, will need to be analyzed to achieve 80% power to detect a significant difference in AKI.Table 1. Results related to vancomycin dosing before and after software integration Values reported as mean and standard deviation (SD) unless notedConclusionVancomycin doses and trough concentrations were similar in the two groups and AKI rates were numerically lower. This serves as an exploratory analysis to inform a larger study on the effects of integrating Bayesian dosing software for vancomycin dosing.Disclosures Bryan Alexander, PharmD, Astellas Pharma (Advisor or Review Panel member) Trevor C. Van Schooneveld, MD, FACP, BioFire (Individual(s) Involved: Self): Consultant, Scientific Research Study Investigator; Insmed (Individual(s) Involved: Self): Scientific Research Study Investigator; Merck (Individual(s) Involved: Self): Scientific Research Study Investigator; Rebiotix (Individual(s) Involved: Self): Scientific Research Study Investigator Scott J. Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP, Merck & Co., Inc (Grant/Research Support) Scott J. Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP, Merck & Co., Inc (Individual(s) Involved: Self): Research Grant or Support

1102. Evaluation of Vancomycin Accumulation in Patients with Obesity

BackgroundCurrent vancomycin guidelines recommend using actual body weight for dosing. However, in patients with obesity, this may result in lower initial vancomycin concentrations that can accumulate with continued doses due to differences in volume of distribution. The objective of this study is to evaluate the incidence of vancomycin accumulation in patients with obesity and identify potential factors associated with accumulation.MethodsThis is a single-center, retrospective, observational study at a tertiary academic medical center. Adult patients with a BMI ≥ 30 kg/m2 and with ≥ 2 vancomycin serum trough concentrations within the same encounter in 2019 were screened. Patients were excluded if they were pregnant, had unstable renal function or severe renal impairment, received < 3 doses before a concentration was drawn, or had inconsistent dosing prior to a concentration draw. Linear kinetics were used to correct for differences in timing of concentration or dose changes. The major endpoint was the incidence of vancomycin accumulation, defined as a 20% increase in trough concentration between the first and any subsequent trough concentrations within the first 10 days of therapy. Minor endpoints included the percentage of supratherapeutic concentrations and the incidence of acute kidney injury (AKI). Descriptive statistics were used to evaluate endpoints and multivariable logistic regression was used to evaluate factors associated with accumulation.ResultsWe screened 543 patients, and 162 were included in our analysis. The median age was 56.5 years (interquartile range [IQR] 43 - 65.3), and 62.3% were male. The median weight was 112.7 kg (IQR 99.8 - 122.6) and the median BMI was 36.8 kg/m2 (IQR 33.1 - 41). The median total daily vancomycin dose at initiation was 28.7 mg/kg/day (IQR 25.4 - 31.2). Vancomycin accumulation occurred in 99 patients (61.1%) within the first 10 days of therapy and AKI occurred in 21 patients (14.9%). No factors studied, including age, gender, obesity class, initial dose, SCr, or frequency were associated with accumulation.ConclusionMost patients with obesity experienced vancomycin accumulation within the first 10 days of therapy. Providers should be cautious when assessing a vancomycin concentration early in the treatment course.Disclosures All Authors: No reported disclosures

Evaluation of Posaconazole Dosing in Children and Young Adults: A Single-Center Review.

Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations. This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason. There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early. The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.

Prospective assessment of breakthrough infections and neurotoxicity and their association with cefepime trough concentrations in patients with febrile neutropenia

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 (eGFRCKD-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.

The relationship between vancomycin AUC/MIC and trough concentration, age, dose, renal function in Chinese critically ill pediatric patients.

To assess the pharmacokinetic parameters of vancomycin in Chinese critically ill pediatric patients, children treated with vancomycin, hospitalized in the intensive care unit were included. Samples to determine peak and trough serum concentrations were obtained on the third day of treatment. Half‐life was significantly longer in neonates and showed a decreasing trend in infants and children. In patients aged ≥1 month, AUC24/MIC ≥400 was achieved in 31.8% at the dose of 40 mg/kg/d, and in 48.7% at the dose of 60 mg/kg/d with an assumed MIC of 1 mg/L. Augmented renal clearance (ARC) was present in 27.3% of children, which was associated with higher vancomycin clearance and lower AUC values. A good correlation was observed between trough concentration and AUC24, and the trough concentration that correlated with AUC24 of 400 were varied according to the dosage regimens, 8.42 mg/L for 6‐hintervals, and 6.63 mg/L for 8‐h intervals. To conclude, vancomycin trough concentration that related to the AUC24 of 400 was much lower in critically ill children than that in adults. The dosage of 60 mg/kg/day did not enough for producing AUC24 in the range of 400–600 mg h/L in critically ill children, especially in those with ARC.

Supratherapeutic Posaconazole Concentration in a Pediatric Transplant Patient With Confirmed Rhizopus Infection.

There are a limited number of studies that guide dosing of posaconazole delayed-release (DR) tablets for the pediatric population. Current FDA-approved doses are only recommended for patients 13 years and older. For younger patients, providers are faced with the challenge of recommending posaconazole doses extrapolated from adult studies or choosing an alternative agent. We report on a case of a 10-year-old patient who experienced a supratherapeutic trough serum concentration and transaminitis after receiving the extrapolated adult dosage of posaconazole DR tablets (300 mg twice daily for the first day, followed by 300 mg daily) for 7 days. In the end, the patient required a smaller dose of 200 mg daily to achieve the desired trough target concentration for the treatment of a Rhizopus neck infection. Our findings highlight the need for additional studies to determine the optimal dosing of posaconazole DR tablets for children.

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice\u2014a prospective single-center trial

PurposeKnowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects.Methods262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed.ResultsMedian of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6–99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05).ConclusionRuxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.