Dosing Recommendations Research Articles

Analytical Validation of Aptamer-Based Serum Vancomycin Monitoring Relative to Automated Immunoassays.

The practice of monitoring therapeutic drug concentrations in patient biofluids can significantly improve clinical outcomes while simultaneously minimizing adverse side effects. A model example of this practice is vancomycin dosing in intensive care units. If dosed correctly, vancomycin can effectively treat methicillin-resistant streptococcus aureus (MRSA) infections. However, it can also induce nephrotoxicity or fail to kill the bacteria if dosed too high or too low, respectively. Although undeniably important to achieve effectiveness, therapeutic drug monitoring remains inconvenient in practice due primarily to the lengthy process of sample collection, transport to a centralized facility, and analysis using costly instrumentation. Adding to this workflow is the possibility of backlogs at centralized clinical laboratories, which is not uncommon and may result in additional delays between biofluid sampling and concentration measurement, which can negatively affect clinical outcomes. Here, we explore the possibility of using point-of-care electrochemical aptamer-based (E-AB) sensors to minimize the time delay between biofluid sampling and drug measurement. Specifically, we conducted a clinical agreement study comparing the measurement outcomes of E-AB sensors to the benchmark automated competitive immunoassays for vancomycin monitoring in serum. Our results demonstrate that E-ABs are selective for free vancomycin─the active form of the drug, over total vancomycin. In contrast, competitive immunoassays measure total vancomycin, including both protein-bound and free drug. Accounting for these differences in a pilot study consisting of 85 clinical samples, we demonstrate that the E-AB vancomycin measurement achieved a 95% positive correlation rate with the benchmark immunoassays. Therefore, we conclude that E-AB sensors could provide clinically useful stratification of patient samples at trough sampling to guide effective vancomycin dose recommendations.

Evaluation of Soil Fertility for Crop Production in Beel Chiroil, Pabna, Bangladesh

The study area is at Beel, Chiroil, Chatmohar, Pabna, Bangladesh. Ten soil sampling locations were selected from this area. Based on soil type and existing cropping patterns, soil samples were collected after harvesting the crops from each selected location of the study area. All soil samples (ten) were collected as per Soil Samples Collection Method of Soil Resources Development Institute (SRDI). The collected soil samples were submitted to the Central Laboratory of SRDI. The test results of the soil samples found that, the soil of the study area contained neutral soil pH (6.87), medium organic matter (3.58%), nitrogen (0.198 Meq/100g), potassium (0.256 Meq/100g) and zinc (1.15 μg/g), low phosphorus (13.503μg/g), sulfur (19.83 μg/g) and boron (0.28 μg/g) and very high iron (53.14 μg/g), calcium (20.288 Meq/100g) and magnesium (10.167 Meq/100g) on average. Interpretation of the soil test results indicate that, fertility condition of the research field will provides a good basis of fertilizer recommendation for the study area farmers. A recommendation of fertilizer doses is prepared according to Fertilizer Recommendation Guide, 2018 of Bangladesh Agricultural Research Council (BARC). The research also helps to suggest some suitable cropping patterns for the study area.

Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children.

Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups. We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters. Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM. Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.

Anakinra Removal by Continuous Renal Replacement Therapy: An Ex Vivo Analysis.

Patients with sepsis are at significant risk for multiple organ dysfunction, including the lungs and kidneys. To manage the morbidity associated with kidney impairment, continuous renal replacement therapy (CRRT) may be required. The extent of anakinra pharmacokinetics in CRRT remains unknown. The objectives of this study were to investigate the anakinra-circuit interaction and quantify the rate of removal from plasma. The anakinra-circuit interaction was evaluated using a closed-loop ex vivo CRRT circuit. CRRT was performed in three phases based on the method of solute removal: 1) hemofiltration, 2) hemodialysis, and 3) hemodiafiltration. Standard control samples of anakinra were included to assess drug degradation. University research laboratory. None. Anakinra was administered to the CRRT circuit and serial prefilter blood samples were collected along with time-matched control and hemofiltrate samples. Each circuit was run in triplicate to assess inter-run variability. Concentrations of anakinra in each reference fluid were measured by enzyme-linked immunosorbent assay. Transmembrane filter clearance was estimated by the product of the sieving coefficient/dialysate saturation constant and circuit flow rates. Removal of anakinra from plasma occurred within minutes for each CRRT modality. Average drug remaining (%) in plasma following anakinra administration was lowest with hemodiafiltration (34.9%). The average sieving coefficient was 0.34, 0.37, and 0.41 for hemodiafiltration, hemofiltration, and hemodialysis, respectively. Transmembrane clearance was fairly consistent across each modality with the highest during hemodialysis (5.53 mL/min), followed by hemodiafiltration (4.99 mL/min), and hemofiltration (3.94 mL/min). Percent drug remaining within the control samples (93.1%) remained consistent across each experiment, indicating negligible degradation within the blood. The results of this analysis are the first to demonstrate that large molecule therapeutic proteins such as anakinra, are removed from plasma with modern CRRT technology. Current dosing recommendations for patients with severe renal impairment may result in subtherapeutic anakinra concentrations in those receiving CRRT.

Botulinum neurotoxin type A in the interdisciplinary treatment of sialorrhea in adults and children-update and practice recommendations.

Sialorrhea is defined as a chronic excessive flow of saliva from the mouth, often with adverse consequences for health and quality of life of patients. In addition to currently used non-drug treatment and systemic drugs, intraglandular Botulinum Neurotoxin A (BoNT/A) injections have been examined in case studies, controlled trials and clinical practice. Two pivotal Phase III trials recently led to market approval in the USA and EU for IncobotulinumtoxinA [Xeomin®, IncoBoNT/A, Clostridium botulinum neurotoxin type A (150 kD), free from complexing proteins, Merz Pharmaceuticals GmbH] for treatment of chronic sialorrhea in adults and pediatric patients. This review provides a multidisciplinary approach to discuss the current state of sialorrhea therapy as well as benefits and current limitations of BoNT/A injections. A consensus regarding treatment recommendations made available to physicians in Germany in 2022 has now been updated here for presentation to an international audience. This review provides a framework including a flow chart for patient selection, recommendations for dosing and the injection process, as well as a discussion of therapeutic goals, long-term benefits and safety aspects. This review is aimed at supporting physicians in developing multidisciplinary and individualized treatment approaches to achieve optimal benefits for patients.

The Dose-Response Relationship of Atomoxetine for the Treatment of Children With ADHD: A Systematic Review and Dose-Response Meta-Analysis of Double-Blind Randomized Placebo-Controlled Trials

Objectives: The present study aimed to meta-analytically estimate the dose-response relationship of atomoxetine for treating children with ADHD. Methods: We systematically searched double-blind randomized placebo-controlled trials that evaluated the effectiveness of atomoxetine for treating ADHD in children. The search was carried out in PubMed, Cochrane Library, CINHAL, and ClinicalTrials.gov databases, covering articles from their inception until January 20, 2023. In addition, a dose-response meta-analysis was conducted. Results: In this dose-response meta-analysis, 12 double-blind randomized placebo-controlled trials involving 2,250 patients were included. The efficacy of atomoxetine increased up to a dosage of 1.4 mg/kg, after which it reached a plateau. Conclusions: The first dose-response meta-analysis of atomoxetine dosing for children with ADHD conducted here enhances the robustness of the Food and Drug Administration and the European Medicines Agency dose recommendations.

Medication patterns and dosing guidance in pediatric patients supported with intermittent hemodialysis or continuous kidney replacement therapy.

Hemodialysis is a life-saving technology used during periods of acute or chronic kidney failure to remove toxins, and maintain fluid, electrolyte and metabolic balance. While this technology plays an important role for pediatric patients with kidney dysfunction, it can alter the pharmacokinetic behavior of medications placing patients at risk for suboptimal dosing and drug toxicity. The ability to directly translate pharmacokinetic alterations into dosing recommendations has thus far been limited and dosing guidance specific to pediatric hemodialysis patients is rare. Despite differences in dialysis prescription and patient populations, intermittent (iHD) and continuous kidney replacement therapy (CKRT) patients are often pooled together. In order to develop evidence-based dosing guidelines, it is important to first prioritize drugs for study in each modality. Here we aim to identify priority drugs in two hemodialysis modalities, through: 1) Identification of hospitalized, pediatric patients who received CKRT or intermittent hemodialysis (iHD) using a machine learning-based predictive model based on medications; 2) Identification of medication administration patterns in these patient cohorts; and 3) Identification of the most commonly prescribed drugs that lack published dosing guidance. Notable differences were found in the pattern of medications and drug dosing guidance between iHD and CKRT patients. Antibiotics, diuretics and sedatives were more common in CKRT patients. Out of the 50 most commonly administered medications in the two modalities, only 34% and 28% had dosing guidance present for iHD and CKRT, respectively. Our results add to the understanding of the differences between iHD and CKRT patient populations by identifying commonly used medications that lack dosing guidance for each hemodialysis modality, helping to pinpoint priority medications for further study. Overall, this study provides an overview of the current limitations in medication use in this at-risk population, and provides a framework for future studies by identifying commonly used medications in pediatric CKRT and iHD patients.

Comparison of the therapeutic effects of 15 mg and 30 mg initial daily prednisolone doses in patients with subacute thyroiditis: a multicenter, randomized, open-label, parallel-controlled trial

Introduction Current guidelines recommendations for the initial dose of prednisolone (PSL) in the treatment of subacute thyroiditis (SAT) are based on low-quality studies. We designed a randomized controlled trial (RCT) to compare the efficacy and safety of using a low initial dose of PSL with a standard initial dose of PSL in SAT patients. Patients and methods This open-label RCT was conducted at five hospitals in China from June 2019 to January 2022. SAT patients with moderate-to-severe pain or a poor response to non-steroidal anti-inflammatory drugs (NSAIDs) were randomly assigned in a 1:1 ratio to the experimental and control groups. The initial dose of PSL was 15 mg/d in the experimental group and 30 mg/d in the control group. The primary outcome was the total duration of PSL treatment, with non-inferiority prespecified with a margin of 7 days. Clinical trial registration number: ChiCTR1900023884. Results The full analysis set included 60 patients (30 in each group). The mean duration of PSL treatment in the experimental and control group was 34.62 ± 14.12 and 41.18 ± 16.89 days, respectively, meeting the non-inferiority criterion (pnon-inferiority = 0.0006). The total dose of PSL used in the experimental group was lower than in the control groups (330 vs 595 mg, p < 0.0001). There were no differences in the mean time to pain relief and complete resolution, the occurrence of recurrence, hypothyroidism, or adverse events between the groups. Conclusions The initial dose of 15 mg/d of PSL was not inferior to the dose of 30 mg/d in terms of efficacy and showed a similar safety profile. A low initial dose of PSL could be recommended for Chinese adult SAT patients who have a suboptimal response using NSAIDs or experience moderate-to-severe pain. KEY MESSAGES Low initial dose (15 mg/d) of prednisolone was non-inferior to the standard initial dose of prednisolone (30 mg/d) in treatment duration, time to pain relief, or the prevalence of hypothyroidism, recurrence, and adverse reactions in the treatment of subacute thyroiditis. Patients with subacute thyroiditis administered a low initial dose of prednisolone had a lower total dose of prednisolone compared to those receiving the standard dose of prednisolone.

Design of a Smart Application (Limbekfeed) Using the Profile Matching Method in Determining the Dosage of Catfish Feeding

In catfish farming, providing the right feed is crucial for optimal growth and health. However, determining the accurate dosage of feed that is suitable for individual catfish can be complex and time-consuming. To address this challenge, we have developed an intelligent application called "Limbekfeed" using the Profile Matching method for determining the dosage of catfish livestock feed. The prototype of this application leverages the Profile Matching method, which connects the profile of the catfish with the feed profiles available in the database. Users input data such as size, weight, age, and water quality. The prototype application then compares this data with the predefined feed profiles in the system and provides recommendations for the most suitable feed dosage. Test results indicate that the "Limbekfeed" application prototype is expected to provide feed dosage recommendations to help farmers avoid the risks of overfeeding or underfeeding.

The public-health significance of far-UVC-induced indoor ozone and its associated secondary chemistry.

There has been much recent interest in whole-room far-UVC (wavelength around 222 nm) to markedly and safely reduce overall levels of airborne pathogens in occupied indoor locations. Far-UVC light produces very low levels of ozone-in real-world scenarios induced ozone levels of less than 10 ppb, and much less in moderately or well-ventilated rooms compliant with US far-UVC dose recommendations, and very much less in rooms compliant with international far-UVC dose standards. At these very low ozone levels, there is no epidemiological evidence of increased health risks from any of the very large outdoor ozone studies, whether from ozone alone or from ozone plus associated pollutants. Indoors, at the low ozone concentrations of relevance here, ozone does not react rapidly enough with preexisting airborne volatile organic compounds to compete with even extremely low levels of room ventilation, so significant ozone-induced ultrafine particle production is very unlikely. Direct measurements in real-life room scenarios are consistent with these conclusions. A potential exception is the cleaning material limonene, which has an unusually high ozone interaction cross-section; in the far-UVC context, turning off far-UVC lights during cleaning with limonene products would be reasonable.

Promise: Investigation into the Combination of a Potent Beti with Ruxolitinib in Patients with High or Intermediate-2 Risk Myelofibrosis Not Receiving an Adequate Response with Ruxolitinib Alone

ISRCTN: 12451433 Background: Myelofibrosis (MF), a chronic myeloproliferative neoplasm (MPN), often results in progressive splenomegaly and cytopenia (1). Acute myeloid leukaemia develops in 10-20% of patients, and median survival with intermediate-2 disease is four years (2). Stem cell transplant can be curative, but is only suitable for younger, comorbidity-free patients (median MF diagnosis is 73.6 years) (3). Janus Kinase 2 (JAK2) mutation is common in MPN, and the JAK1/2 inhibitor ruxolitinib was approved in 2011 (4). However, patients still experience high disease burden, with a clear need for further treatments. Research has now focused on bromodomain and extra terminal (BET) inhibitors (5), in particular the role these have in disease associated inflammation (6). Preclinical data suggests BETi disrupts this inflammation leading to anti-fibrotic activity within MPN models. BETi with ruxolitinib eliminates fibrosis in MF mouse models thus overcoming a limitation of ruxolitinib monotherapy (7). OPN-2853 (previously PLX2853) is potent against isolated bromodomains from multiple BET proteins with rapid drug absorption, high Cmax, and short half-life differentiating it from other BETi. Preclinical efficacy has been demonstrated across a range of hematologic malignancies. PROMise is evaluating OPN-2853 in combination with ruxolitinib to identify the recommended phase 2 dose (RP2D). Methods: Primary Objectives: To assess the RP2D of OPN-2853 in combination with ruxolitinib that is safe and tolerableTo assess the efficacy of the combination of OPN-2853 and ruxolitinib for reduction in spleen size PROMise is a single country (UK) multicentre study, recruiting up to 60 patients with high or intermediate-2 risk MF who are not receiving an adequate response on ruxolitinib alone. Patients must have been treated with ruxolitinib for at least 24 weeks, on a stable dose for at least 4 weeks, and have ongoing splenomegaly. PROMise is split into three ruxolitinib dose categories based on platelet count which are assessed independently, Low Dose (5mg-20mg daily), Mid Dose (25mg-45mg daily) and High Dose (≥50mg daily). These are evaluated in combination with three OPN-2853 dose levels, Level 1 (20mg OD Decreased Dose), Level 2 (40mg OD Starting Dose) and Level 3 (80mg OD Increased Dose). Cohorts of patients (n=2-4) receive up to eight 21-day cycles of OPN-2853 and ruxolitinib. Patients are closely monitored for Dose Limiting Toxicities in cycle 1. The Trial Safety Committee (TSC) meets following cycle 1 to establish the dose recommendations of OPN-2853 for each dose category using the continual reassessment method (CRM). The CRM is utilised independently for each dose category, as such it is possible for the low, mid and high doses to be allocated to different OPN-2853 doses. Following cycle 8, patients may continue to receive OPN-2853 if experiencing clinical benefit and are followed up annually. Peripheral blood, bone marrow aspirate and bone marrow trephine samples are taken from all patients to measure the proportion who achieve a molecular response, and to determine the on target transcriptional response in myeloid cells. Additionally, pharmacokinetic samples are taken at specified timepoints pre and post dose to establish PK properties of OPN-2853 in combination with ruxolitinib. Current Status: To date PROMise has recruited 14 patients across all dose categories, and two TSC meetings have taken place.

How Much Furosemide Should be Administered to Prevent Transfusion-Associated Circulatory Overload? Results of a Dose-Finding Study

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a common but under-reported complication of transfusion therapy, and results in significant morbidity and mortality. Pre-transfusion furosemide has been proposed as a mitigating strategy but has not received widespread endorsement, in part due to uncertainty regarding safe and effective dosing. An observational study was therefore conducted with the goal of creating a reliable dose-response curve in patients at high risk of TACO, using the statistical technique of Multiple Comparisons Procedure with Modelling (MCP-MOD). METHODS: Eligible patients were identified by screening bolus intravenous (IV) furosemide orders at two large academic hospitals. Eligibility criteria were selected to mimic those of a planned randomized controlled trial (RCT) of pre-transfusion furosemide for the prevention of TACO. Inclusion criteria were inpatients 50 years of age or older. Exclusion criteria were active bleeding, hemodynamic instability, glomerular filtration rate (GFR) &amp;lt; 30mL/min or need for dialysis, diuretic therapy (other than furosemide) administered less than 24 hours, furosemide (either IV or PO) administered less than 12 hours, or exogenous albumin administered less than 8 hours prior to index furosemide therapy. The primary outcome measure was the total volume of urine output in the six hours following IV furosemide administration. MCP-MOD analysis was performed after every 50 patients and continued until a weight-adjusted dose-response curve could be established with 100 mL precision, using the following covariates: age, sex, mean arterial pressure (MAP), serum albumin, GFR and history of chronic furosemide use. RESULTS: A total of 149 participants (53 female and 96 male) were enrolled over 2 years. As too few patients received doses exceeding 0.6 mg/kg to allow for a precise dose-response curve, only 132 patients receiving weight-adjusted doses ranging from 0.1 to 0.6 mg/kg were included in the MCP-MOD analysis. The characteristics of these patients are shown in Table 1. The dose-response curve formula that was derived from these patients was: Urine Output at 6 hours (mL) = 717.21 + 191.33 ln(dose (mg)/weight (kg)) + 0.73 × Age (years) + 103.37 × Sex (M=1/F=0) + 1.63 × GFR (ml/min) + 5.45 × MAP (mmHg) - 9.56 × albumin (g/L) - 62.31 × chronic diuretic use (Y=1/N-0) The curve with accompanying 95% confidence intervals is shown in Figure 1 This formula suggests that in an 80 kg patient with a GFR of 75 mL/min, a MAP of 85 mmHg, albumin of 40 g/L and no history of chronic diuretic use, 10 mg of IV furosemide should produce a diuresis of approximately 600 mL, sufficient to prevent circulatory overload from the transfusion of 1 unit of RBCs. A dose of 20 mg would be required to achieve a similar diuresis in patients with either a MAP &amp;lt; 60 mmHg, or a combination of both a GFR &amp;lt; 45 mL/min and a history of chronic diuretic use. CONCLUSIONS: A statistically precise dose-response curve for IV furosemide is possible with the inclusion of relevant clinical covariates, and can be used to guide dosing decisions in patients at risk of transfusion-associated circulatory overload. This formula derived from this study will inform the dosing recommendations of a planned RCT: Transfusion-Associated Circulatory Overload: Best Eliminated by Lasix® (TACO-BEL).

Clinical Factors Associated with Cytokine Release Syndrome and Dosing Recommendations for Restarting Elranatamab Following an Interruption

BACKGROUND In the MagnetisMM-3 (NCT04649359) study, elranatamab (ELRA) administered at a dose of 76 mg once-weekly (QW) with 2 step-up priming doses of 12 mg on day 1 and 32 mg on day 4 had a manageable safety profile, with 56.3% of patients developing cytokine release syndrome (CRS) and 98.8% of events occurring with the first 3 doses. Here, we report clinical factors associated with CRS and dosing recommendations for restarting treatment after dose interruptions in patients with relapsed or refractory multiple myeloma (RRMM) undergoing treatment with ELRA. METHODS Eligible patients received ELRA subcutaneously in step-up priming doses of 12 and 32 mg on days 1 and 4 of cycle 1, respectively, followed by 76 mg of ELRA QW. CRS events were graded according to the criteria of the American Society for Transplantation and Cellular Therapy and managed according to published guidelines. Multivariable analyses were performed to identify clinical factors associated with CRS. Baseline factors (extramedullary disease by BICR, prior antibody-drug conjugate, prior CAR-T, number of prior lines of therapy [≤5, &amp;gt;5], sex, and age [continuous variable]) were included in the model for CRS after the initial dose, and only post-baseline factors (time to previous CRS and time to initial tocilizumab use) were included in the model for CRS after the second dose. A previously described population pharmacokinetic (PK) model was used to simulate different interruption scenarios and determine how long it takes for ELRA exposure to drop below the threshold associated with CRS events (Hibma J, et al. Poster presented at PAGE 31 2023 [abstract 10648]). The data used to develop this model was collected from the following open-label elranatamab trials: MagnetisMM-1 (NCT03269136; phase 1), MagnetisMM-2 (NCT04798586; phase 1), MagnetisMM-3 (NCT04649359; phase 2), and MagnetisMM-9 (NCT05014412; phase 1/2). Of 183 patients who were treated in MagnetisMM-3 with the 2 step-up priming dosing, 106 patients (57.9%) experienced CRS, 43.7% grade 1, 13.7% grade 2, and 0.5% grade 3. Tocilizumab was used to manage CRS. Of the 130 CRS events, 37 (28.5%; 20 grade 1 and 17 grade ≥2) were treated with tocilizumab, and 93 (71.5%; 82 grade 1 and 11 grade ≥2) were not. After the initial elranatamab dose, 79/183 patients had CRS. The presence of extramedullary disease was predictive of a decreased risk of CRS after the initial dose. Of the 180 who received a second elranatamab dose, 35 had CRS afterwards. In a multivariable model also adjusting for CRS after the initial dose, prior tocilizumab use was predictive of a decreased risk of CRS after the second dose. After receiving doses of 76 mg of ELRA, 16 instances of dose delays lasting &amp;gt;6 to ≤12 weeks were observed. In most of these instances (11/16; 68.8%), patients did not repeat the 32-mg step-up dose. In 5 instances, patients restarted treatment with 32 mg of ELRA. No patients experienced CRS after retreatment. For the 4 instances of dose delays lasting &amp;gt;12 weeks after a 76-mg dose, patients repeated the 32-mg step-up dose in 2 instances, and patients received &amp;gt;32 mg ELRA after the interruption in the other 2 instances, with none experiencing CRS after retreatment. With dose delays of 6-12 weeks, ELRA exposure decreases below the C max after a 32-mg dose but not less than that for the 12-mg dose. With dose delays &amp;gt;12 weeks, ELRA exposure decreases below the C max after a 12-mg dose. To minimize the risk of CRS events after dose interruptions, clinical and PK data and modeling were used to develop recommendations for restarting therapy (Figure). CONCLUSIONS Extramedullary disease and use of tocilizumab were associated with a decreased risk of CRS. Based on clinical and PK data and modeling, it is recommended that patients receiving 76 mg ELRA who then experience dose delays lasting 6-12 or &amp;gt;12 weeks should restart treatment at doses of 32 or 12 mg, respectively.

Matching-Adjusted Indirect Comparison of Personalized Prophylaxis with Simoctocog Alfa Versus Standard Prophylaxis with Efanesoctocog Alfa in Adults with Severe Hemophilia a

Background: Personalized factor VIII (FVIII) prophylaxis is currently the gold standard approach for the treatment of patients with severe hemophilia A. Although several FVIII concentrates are available, head-to-head comparative studies of their relative efficacy are not feasible in rare diseases such as hemophilia A. In such situation, the use of validated indirect comparison methods such as matching-adjusted indirect comparison (MAIC) methodology can be used to indirectly compare outcomes from separate clinical studies. MAIC can be used to adjust for differences in patient characteristics between studies, with the goal to reduce bias in the treatment effect estimates which can occur with comparison of efficacy data across clinical trials. Aims: To indirectly compare the efficacy of a pharmacokinetic (PK)-guided personalized prophylaxis regimen with simoctocog alfa (Nuwiq ®; a 4 th-generation recombinant FVIII [rFVIII] concentrate with no chemical modifications of fusion proteins) against a standard prophylaxis regimen with efanesoctocog alfa (Altuviiio ®; an Fc-fusion rFVIII concentrate with chemical modifications including Von Willebrand factor independent-XTEN fusion protein), in previously-treated patients (PTPs) with severe hemophilia A. Methods: After matching study populations by accounting for clinically important baseline characteristics,individual patient-level data (IPD) from 65 patients treated with simoctocog alfa from the NuPreviq study were compared against aggregate data from the once-weekly efanesoctocog alfa arm of the XTEND-1 study (n=133). All patients enrolled in both studies were male, with the exception of one female in XTEND-1. Baseline age and body weight were used to re-weight the simoctocog alfa IPD to match the aggregate data reported for efanesoctocog alfa from the XTEND-1 study. Unanchored indirect treatment comparisons were performed for various clinical outcomes using the re-weighted data for simoctocog alfa and the published comparator study data. The endpoints analysed were annualized bleeding rates (ABRs), percentage of patients with zero bleeds, and weekly consumption of FVIII. All efficacy endpoints reported here consider treated and untreated bleeds. Results: After matching populations, the effective sample size for simoctocog alfa was 35.3. Although, the percentage of patients with zero bleeds was higher with simoctocog alfa versus efanesoctocog alfa (64.1% vs 55.5%), this difference was not statistically significant (Table 1). The mean total ABRs were similar between the two products: 1.5 for simoctocog alfa and 1.1 for efanesoctocog alfa (Table 1). The mean weekly dose was significantly higher in patients treated with simoctocog alfa versus efanesoctocog alfa (98.3 IU/kg vs 52.2 IU/kg, respectively; p&amp;lt;0.0001). Conclusion: An indirect comparison analysis demonstrated that a PK-guided, personalized prophylaxis with simoctocog alfa in adult PTPs resulted in zero bleed rates and ABRs that are not statistically different from those with efanesoctocog alfa. The higher total weekly dose observed with simoctocog alfa is to be expected based on the dosing recommendations for each respective FVIII replacement product. This MAIC analysis provides important comparative efficacy and utilization data, which can help guide patients and physicians in making decisions regarding product choice for prophylaxis regimens.

Tumor Lysis Syndrome in Patients with AML Initiated on Venetoclax-Based Treatment without a Dose Ramp-up

Introduction Treatment with the combination of a hypomethylating agent (HMA) and venetoclax (VEN) is the standard of care for older patients (pts) with acute myeloid leukemia (AML). Venetoclax, an oral BCL-2 inhibitor, was initially approved for the treatment of chronic lymphocytic leukemia (CLL). In the early, pivotal studies assessing VEN safety, tumor lysis syndrome (TLS) was found to be a dose-limiting, potentially fatal toxicity. Dosing modifications were made to allow for safer initiation of the drug and, ultimately, a dose ramp-up was included in the dosing recommendation for CLL. Given the risk for TLS with VEN initiation for CLL, it was hypothesized that the risk would be the same, or potentially greater, when treating pts with AML. Therefore, studies of VEN in AML have included a dose ramp-up. Although reported rates of tumor lysis syndrome in these studies have been much lower than expected, a dose ramp-up for pts with AML is included in the package insert for VEN and continues to be utilized in clinical trials. Methods We conducted a retrospective analysis of pts ≥18 years of age with newly diagnosed or relapsed/refractory AML treated with a standard dose hypomethylating agent (HMA), either azacitidine or decitabine, and VEN without a dose ramp-up (initiated at 400mg daily or 100mg daily if on concomitant voriconazole or posaconazole) at Thomas Jefferson University Hospital from January 1, 2018- August 1, 2021. The primary objective of this study was to determine the rate of laboratory and clinical TLS within 72 hours after chemotherapy initiation, as defined by the Cairo-Bishop criteria (Table 1). The secondary objectives were (1) to identify clinical and laboratory risk factors for the development of TLS in pts with AML who were treated with HMA-VEN without a VEN dose ramp-up and (2) to compare rates of TLS in pts with AML who were treated with HMA-VEN without a VEN dose ramp-up to historical rates of TLS in pts who underwent a VEN dose ramp-up. In the Phase 3 study of azacitidine and venetoclax the rate of TLS during the VEN dose ramp-up period (days 1-3 of treatment) was 1% (DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.). Results Ninety pts were included in the analysis. Seventy-one pts had newly diagnosed AML and 19 had relapsed/refractory disease. The majority of pts (58/90, 64%) had adverse risk disease by 2017 European LeukemiaNet Criteria. Median baseline white blood cell count at the time of therapy initiation was 3.25 (range 0.5-161.4). Sixty-one pts (68%) were receiving allopurinol prophylaxis at the time of HMA-VEN administration. Eighteen pts (20%) had a history of underlying renal disease. Fifteen pts (17%) were on medications, such as thiazide diuretics, aspirin, or levodopa, that can increase the risk of TLS at the time of treatment. Zero pts met the defined criteria for laboratory or clinical TLS. One pt developed acute kidney injury and one pt developed a cardiac arrhythmia (atrial fibrillation) but neither had concomitant evidence of laboratory TLS. Discussion In this retrospective study of 90 pts with newly diagnosed or relapsed/refractory AML who were treated with HMA-VEN without a VEN dose ramp-up no pts developed clinical or laboratory tumor lysis syndrome. This is comparable to the rate of TLS (1%) seen in the registration trial of HMA-VEN where pts were treated with VEN 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and thereafter. Starting pts with AML on full dose VEN on day 1, regardless of white blood cell count, renal function, or concomitant medications, appears safe and could be implemented in clinical practice and clinical trials moving forward. This would simplify dosing for pts, pharmacists, and providers and allow for easier initiation of therapy.

2551. Assessing Meropenem Concentrations in Children with Septic Shock: Population-Based Pharmacokinetic (PK) Modeling of Meropenem Demonstrates Variability from Acute Kidney (AKI) to Augmented Renal Clearance (ARC)

Abstract Background The primary objective of this study was to characterize meropenem (MERO) pharmacokinetics (PK) in critically ill infants and children with septic shock to develop dosing recommendations to achieve therapeutic drug exposure in this complex population with a spectrum of renal function from augmented renal clearance (ARC) to acute kidney injury (AKI). Methods Children ≥4 weeks old hospitalized with septic shock requiring fluid resuscitation and pressors, receiving MERO 20 mg/kg IV every 8 hr as standard-of-care, were enrolled and studied prospectively from 2019 to 2023. Population PK modeling was used to derive Bayesian post-hoc PK parameters (NONMEM 7.3). Renal biomarkers (serum creatinine [SCr], cystatin C [CYS], serum neutrophil gelatinase-associated lipocalin [NGAL]) were evaluated as covariates. Estimated glomerular filtration rate (e-GFR) was calculated by the modified Schwartz equation. Results A total of 304 MERO serum concentrations were included from 26 participants. Median age was 12.6 yr (range 1.2-19.6); weight 38.4 kg (10-98); SCr 0.36 mg/dL (0.09-2.57); CYS 448.9 mg/d (178.3-1824.1), and NGAL 176.05 ng/mL (29.3-1000). Median MERO serum concentration was 11 mcg/mL (range 0.033-217, interquartile range [IQR] 1.873-37.85). A two-compartment model with allometrically scaled weight on clearance (0.75) best described the data. Significant covariates (final model) were e-GFR, CYS, NGAL, age, diagnosis of appendicitis and albumin. Using the final model, the median CL was 0.15 (range 0.05-0.51, interquartile range [IQR] 0.06-0.25) L/hr/kg and V1 0.20 (0.07-0.57, IQR 0.12-0.31) L/kg, with GFR 139 (23-364, IQR 93-204) mL/min/1.73 m2 (Figure). The distribution of MERO concentrations, CL and GFR across quartiles documents wide variations in renal function observed in septic shock, from AKI to ARC (Figure). Meropenem Serum Concentration, Meropenem Renal Clearance, and Glomerular Filtration Rate, by Quartiles Conclusion Wide variation in MERO plasma exposure was documented in children with septic shock across the spectrum of renal function. GFR-based dosing recommendations may optimize MERO dosing and improve outcomes in this population. This work was supported by NICHD grant 1 R01 HD095547-01 Disclosures Edmund Capparelli, PharmD, Melinta: Advisor/Consultant

189. Outcomes of High-dose Oral Beta-lactam Step-down Therapy Compared to Alternative Oral Therapy for Bacteremic Urinary Tract Infections

Abstract Background Pyelonephritis and associated bacteremia are often treated with intravenous antibiotics followed by oral step-down therapy to a fluoroquinolone (FQ) or trimethoprim/sulfamethoxazole (TMP/SMX). Oral beta-lactams were historically utilized less often due to concern for treatment failure. Literature suggests oral beta-lactams are effective, but there are no preferred oral beta-lactam agents or dosing recommendations. This study evaluates outcomes of high-dose oral beta-lactam therapy for Enterobacterales bacteremia due to a urinary tract infection (UTI) compared to alternative therapy. Methods A retrospective, multicenter, observational cohort study was conducted evaluating patients admitted from February 1, 2020, to October 1, 2022, with gram-negative bacteremia from a urinary source. Adult patients were included if they received empiric intravenous antibiotic active against the bacteria isolated and transitioned to appropriately dosed oral cephalexin, amoxicillin, TMP/SMX, or FQ (Table 1). Excluded were patients who received less than 72 hours of oral therapy, had a diagnosis of renal abscess or lobar nephronia, and those who expired during admission. The primary outcome compared the composite of recurrent bacteremia or mortality within 30 days of completing oral therapy. Secondary outcomes included recurrent UTI, emergency department (ED) or hospital readmission, and Clostridioides difficile infections within 30 days of treatment completion. Results There were 194 patients who met inclusion criteria. The primary outcome occurred in 1/75 (1.3%) patients in the oral beta-lactam group and 2/119 (1.7%) patients in the FQ or TMP/SMX group (p=1.0). Two patients in the FQ or TMP/SMX expired within 30 days and 1 patient in the beta-lactam group had a recurrent bacteremia. There were 16 (21.3%) and 14 (11.8%) patients in the beta-lactam and FQ or TMP/SMX group, respectively, treated for recurrent UTI (p=0.073). Twenty (27%) patients in the beta-lactam group required ED re-evaluation or hospital readmission compared to 30 (25%) patients who received a FQ or TMP/SMX (p=0.74). Zero patients had a Clostridioides difficile infection. Conclusion Oral beta-lactams are as effective as oral FQ and TMP/SMX for the treatment of bacteremia from a urinary source. Disclosures All Authors: No reported disclosures

2526. Ex Vivo Assessment of Sulbactam-Durlobactam (SUL-DUR) Clearance during Continuous Renal Replacement Therapy (CRRT)

Abstract Background Optimal dosing of antibiotics in patients on CRRT is complicated by factors that can influence drug adsorption and clearance including filter type, CRRT mode, effluent rate (ER), and the drug’s properties itself. SUL-DUR is a novel combination antibiotic under development for management of Acinetobacter baumannii infections. We sought to characterize SUL and DUR adsorption and transmembrane clearance (CLTM) in an ex vivo CRRT model. Methods CLTM was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets. One liter of heparinized bovine blood was allowed to circulate in the Prismaflex CRRT system for 10 minutes. SUL and DUR were then added to achieve a plasma concentration of 30 mg/L, the average maximum concentration achieved in humans following SUL-DUR 1g/1g q6h as a 3h infusion. Pre-filter blood, post-filter blood and effluent samples were collected at 0, 10, 30, and 60 minutes to determine SUL and DUR concentrations. Combinations of filters, modes, and replacement fluid were tested in triplicate at effluent rates of 1, 2 and 3 L/h. The sieving coefficient (SC) for CVVH and the saturation coefficient (SA) for CVVHD were calculated to determine CLTM. Adsorption was measured through a closed loop system bypassing effluent elimination. Multiple linear regression was used to determine SUL and DUR CLTM as a function of ER, filter, and mode. Results SUL and DUR adsorption was minimal at 10% for both drugs. Mean ± standard deviation initial SUL and DUR concentrations were 28.6 ± 2.5 and 27.4 ± 1.9 mg/L, respectively. The overall mean SC/SA across different modes, filters, and ERs was 1.0 and 0.9 for SUL and DUR, respectively. Multiple linear regression demonstrated that the ER was the primary driver (p&amp;lt; 0.001) of CLTM for both drugs based on the equations: SUL CLTM (L/h) = -0.0123 + (1 x ER), R2 = 0.998; DUR CLTM (L/h) = 0.0346 + (0.91 x ER), R2 = 0.958. Conclusion SUL and DUR were efficiently cleared by both CVVH and CVVHD through M100 and HF1400 filters. The clearance of both drugs during CRRT was dependent primarily on the ER. When incorporated into established population pharmacokinetic models, these data can be used to estimate CLTM and devise dosing recommendations for SUL-DUR for patients requiring CRRT. Disclosures Xiaoyi Ye, MD, Sanofi Genzyme: Honoraria David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support Joseph L. Kuti, PharmD, bioMeriuex Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Merck &amp; Co, Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria

Characteristics, treatment patterns and retention with extended-release subcutaneous buprenorphine for opioid use disorder: A population-based cohort study in Ontario, Canada

BackgroundUptake and retention for opioid agonist treatment (OAT) remains low. Novel extended-release formulations may improve OAT accessibility by reducing the frequency of healthcare visits. Our aim was to examine uptake, characteristics, treatment patterns and retention of individuals initiating extended-release subcutaneous buprenorphine (BUP-ER), a monthly injectable OAT. MethodsWe conducted a population-based cohort study among adults aged 18+ initiated on BUP-ER between February 3, 2020 and March 31, 2022 in Ontario, Canada. Using administrative health data, we defined continuous BUP-ER use based on repeat injections within a 56-day period and used Kaplan-Meier curves to estimate time on treatment. Among new BUP-ER recipients, we described individual and prescriber characteristics, healthcare utilization and treatment patterns. Results2366 individuals initiated BUP-ER. The median time to BUP-ER discontinuation was 183 days (interquartile range: 66–428 days) and 52.0% of individuals were co-prescribed buprenorphine/naloxone at least once throughout the period of BUP-ER receipt. Among individuals who initiated on a dose of 300mg BUP-ER and had three or more injections, 18.8% continued to receive only 300mg doses (N=276 of 1470). Furthermore, 28.6% of those whose dose was reduced to 100mg (N=341 of 1194) had a subsequent dose increase to 300mg. ConclusionsOn average, people initiating BUP-ER discontinue within the first 6 months of treatment. While BUP-ER is likely providing an important OAT option, the high occurrence of discontinuation, supplementation with buprenorphine/naloxone, and frequent dose increases suggest inadequacy of current dosing recommendations among a proportion of individuals.

Review on the Biological and Bioactive components of Cocoa (Theobroma Cacao). Insight on Food, Health and Nutrition

Cocoa (&lt;i&gt;Theobroma cacao&lt;/i&gt;) is a well-known tropical plant extensively cultivated for its beans, which are the primary raw material for chocolate production. This article aims to comprehensively review and analyze the bioactive compounds present in cocoa and their corresponding biological activities, highlighting their potential implications for human health. A systematic literature review was conducted to gather relevant research articles and reviews related to the bioactive compounds of cocoa and their biological activities. The databases used for the search included PubMed, Scopus, and Google Scholar, with keywords such as "cocoa bioactive compounds," "flavonoids," "theobromine," "antioxidant activity," and "cardiovascular health" used for data retrieval. The analysis revealed that cocoa is rich in bioactive compounds, such as flavonoids (e.g., catechins, epicatechins), methylxanthines (e.g., theobromine, caffeine), and polyphenols. These bioactive compounds have been associated with various biological activities, including potent antioxidant effects, anti-inflammatory properties, and vasodilation, which may positively influence cardiovascular health. The consumption of cocoa and its bioactive compounds may offer several health benefits due to their antioxidant, anti-inflammatory, and cardiovascular-protective properties. However, further research is necessary to fully understand the mechanisms of action and to determine appropriate dosage recommendations for harnessing the potential health benefits of cocoa.