Short Infusion Research Articles

Evaluation of the Clinical Outcomes of Cyclosporine Short Infusion Versus Continuous Infusion Postallogenic Stem Cell Transplantation.

Cyclosporin A (CsA) exhibits a narrow therapeutic index and large inter-individual variation in pharmacokinetics. Two intermittent and 24-h continuous infusions (CI) are both commonly used regimens in hematopoietic stem cell transplantation (HSCT), with no universal consensus. The objective of this study was to assess whether CsA as a 2-h, twice-daily intravenous infusion (2 h/12 h) is non-inferior to 22h CI every 24 h (22h-CI/24 h) in terms of acute graft-versus-host disease (aGVHD) incidence and adverse events in allogeneic HSCT adult patients. An open-label randomized trial recruited 31 allogeneic HSCT patients to receive the 2 h/12 h or 22 h-CI/24 h regimen. The primary outcomes were the incidence of aGVHD and CsA-related adverse events. The secondary outcomes included the correlation between the time concentration and area under the concentration-time curve (AUC) of 2 h/12 h versus 22 h-CI/24 h regimens. Six (19.4%) patients developed aGVHD. There was no statistically significant difference between the two groups concerning the incidence of aGVHD (13.3% in 2 h/12 h vs. 25% in 22 h-CI/24 h; p = 0.359). The distribution of different aGVHD types (p = 0.20) and mortality (p = 0.9) were not significantly different between the two groups. The two groups did not differ at any time with respect to AUCs, nephrotoxicity, hepatotoxicity, or electrolyte disturbance. The study suggested that the 2 h/12 h regimen is non-inferior to the conventional regimen (22 h CI/24 h) in terms of aGVHD incidence and adverse events. Further research is necessary to validate these findings and to guide practice, considering the small sample size of this study. ClinicalTrials.gov identifier NCT04575779 with initial release on 19 September 2020-Retrospectively registered, https://clinicaltrials.gov/study/NCT04575779 .

Cerebral net uptake of lactate contributes to neurological injury after experimental cardiac arrest in rabbits

During focal ischemia, neurons can use lactate as an alternative source of energy through its oxidation into pyruvate by the lactate dehydrogenase (LDH). After cardiac arrest, the neurological consequences of this phenomenon are unknown. Experimental study. Experimental laboratory. Male New-Zealand rabbits. Animals were surgically instrumented and randomly divided into five groups receiving short infusion duration of either lactate or pyruvate or a pre-cardiac arrest infusion of oxamate (an inhibitor of the lactate dehydrogenase) or injection of fluorocitrate (an inhibitor of astrocytic tricarboxylic acid), or Saline (lactate, pyruvate, Oxa, FC and Control groups, respectively). After randomization, animals were submitted to 10 min of ventricular fibrillation and subsequent resuscitation. All animals were then either followed during 4 h, for the evaluation of the cerebral net uptake and concentrations of metabolites by microdialysis (n = 6 in each experimental group, n = 12 in control group), or during 48 h for the evaluation of their neurological outcome (n = 7 in each groups and n = 14 in control group). Cardiac arrest was associated with a dramatic increase in cerebral net uptake of lactate during 120 min after resuscitation, which was increased by lactate or pyruvate administration. This was associated with an increase in the mean neurological dysfunction score (66.7 ± 4.7, 79.0 ± 4.5 vs 57.7 ± 1.5 in Lactate, Pyruvate and Control group respectively) at 48 h after cardiac arrest. Oxamate and FC administration were associated with a lower lactate cerebral uptake after cardiac arrest and with an improvement of the neurological recovery (28.85 ± 9.4, 23.86 ± 6.2 vs 57.7 ± 1.5 in Oxa, FC and Control group respectively). After cardiac arrest, immediate isotonic lactate or pyruvate administration is deleterious. Pre-cardiac arrest LDH inhibition was potently neuroprotective in this setting.

Activity Assessment of Factor Replacement Therapies to Guide Infusion Rate Protocols in Patients with Bleeding Disorders

Abstract Introduction The development of institutional protocols guiding administration of clotting factor replacements in patients with bleeding disorders requires an understanding of product stability over infusion duration. Inclusion of new factor products on formulary at our institution raised consideration for optimal administration routes, including whether a bolus intravenous push versus infusion over 4-12h provided acceptable factor activities. Here we assessed the activity of two clotting factor replacement therapies over a 24h period to guide clinical care protocols. Method This study was performed in the Special Coagulation Lab as a collaboration between pharmacy, hematology, and laboratory medicine. Two vials each of Novoeight, a recombinant antihemophilic factor used in patients with factor VIII deficiency, and Vonvendi, a recombinant von Willebrand Factor (VWF) replacement approved for prophylaxis in adults with Type 3 von Willebrand Disease, were reconstituted to clinically relevant potencies (13 IU/ml, Novoeight; 27 IU/ml, Vonvendi). Products were spiked separately into factor VIII-deficient plasma (Novoeight) or assay diluent (Vonvendi), given inability to obtain VWF-deficient plasma, and tested for activity at various timepoints. Novoeight samples were assessed by traditional one-stage FVIII assays, while Vonvendi samples were assessed for VWF antigen, ristocetin cofactor activity (RCA), and glycoprotein Ib binding activity (GP1bM). Results Novoeight samples maintained similar FVIII activities at all timepoints tested, with differences falling within the coefficient of variation of the assay. Specifically, the two samples had FVIII levels of 108% and 95% at baseline and levels of 98% and 91%, respectively, at 12h, which was the timepoint of greatest interest given plans to allow 12h infusion rates. For Vonvendi samples, measurement of VWF antigen remained fairly stable throughout the 24h period. However, VWF activity decreased in both RCA and GP1bM assays over time, including by 4h. RCA values were 193% and 190% at baseline, 113% and 95% at 4h, and 63% and 63% at 12h. GP1bM was 140% and 133% at baseline, 92% and 91% at 4h, and 56% and 70% at 12h. Together, these results supported implementation of protocols allowing for extended (up to 12h) infusion of Novoeight and short (3-5min) bolus infusion of Vonvendi. Conclusion Our study demonstrated maintained Novoeight activity over the study period, confirming infusion rates of 12h should be efficacious. Conversely, Vonvendi yielded significantly decreased activity levels in as little as 4h, indicating the need for faster infusion rates. Based on our results, current practices at our institution were adapted to include extended infusion for Novoeight only. Drug activity studies may not directly reflect patient outcomes, and additional studies of factor activities following product infusion into patients and clinical hemostasis correlates are necessary. Nevertheless, the clinical lab should continue to play a primary role in testing, monitoring, and developing patient care protocols for therapeutic drugs through multidisciplinary collaboration.

Monte Carlo simulations of cefepime in children receiving continuous kidney replacement therapy support continuous infusions for target attainment

BackgroundSepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT.MethodsWe developed a CKRT “module” in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2–25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0–30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa.ResultsAssuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100–150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function.ConclusionsOur new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.

The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.

We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo. Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point. The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma. Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.

Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells.

Clinical studies showed that prolonged infusion of methotrexate (MTX) leads to more severe adverse reactions than short infusion of MTX at the same dose. We hypothesized that it is the saturation of folate polyglutamate synthetase (FPGS) at high MTX concentration that limits the intracellular synthesis rate of methotrexate polyglutamate (MTX-PG). Due to a similar accumulation rate, a longer infusion duration may increase the concentration of MTX-PG and, result in more serious adverse reactions. In this study, we validated this hypothesis. A549, BEL-7402 and MHCC97H cell lines were treated with MTX at gradient concentrations. Liquid chromatograph-mass spectrometer (UPLC-MS/MS) was used to quantify the intracellular concentration of MTX-PG and the abundance of FPGS and γ-glutamyl hydrolase (GGH). High quality data were used to fit the cell pharmacokinetic model. Both cell growth inhibition rate and intracellular MTX-PG concentration showed a nonlinear relationship with MTX concentration. The parameter Vmax in the model, which represents the synthesis rate of MTX-PG, showed a strong correlation with the abundance of intracellular FPGS. According to the model fitting results, it was confirmed that the abundance of FPGS is a decisive factor limiting the synthesis rate of MTX-PG. The proposed hypothesis was verified in this study. In addition, based on the intracellular metabolism, a reasonable explanation was provided for the correlation between the severity of adverse reactions of MTX and infusion time. This study provides a new strategy for the individualized treatment and prediction of efficacy/side effects of MTX.

Low-dose short infusion ketamine as adjunct to morphine for acute long bone fracture in the emergency department: a randomized controlled trial

BackgroundKetamine is recognized as an alternative for pain management; however, concerns about emergent adverse reactions have limited its widespread adoption. This study aimed to assess the efficacy of a short infusion of low-dose ketamine (LDK) compared to intravenous morphine (MOR) as adjunctive analgesia for acute long bone fracture pain.MethodsThis single-blinded, randomized controlled trial was conducted in a single emergency department. Patients with acute long bone fractures and numerical rating scale (NRS) pain scores ≥ 6 following an initial dose of intravenous morphine were assigned to receive either a LDK (0.3 mg/kg) over 15 min or intravenous MOR at a dose of 0.1 mg/kg administered over 5 min. Throughout a 120-min observation period, patients were regularly evaluated for pain level (0–10), side effects, and the need for additional rescue analgesia.ResultsA total of 58 subjects participated, with 27 in the MOR group and 31 in the LDK group. Demographic variables and baseline NRS scores were comparable between the MOR (8.3 ± 1.3) and LDK (8.9 ± 1.2) groups. At 30 min, the LDK group showed a significantly greater mean reduction in NRS scores (3.1 ± 2.03) compared to the MOR group (1.8 ± 1.59) (p = 0.009). Similarly, at 60 min, there were significant differences in mean NRS score reductions (LDK 3.5 ± 2.17; MOR mean reduction = 2.4, ± 1.84) with a p-value of 0.04. No significant differences were observed at other time intervals. The incidence of dizziness was higher in the LDK group at 19.4% (p = 0.026).ConclusionShort infusion low-dose ketamine, as an adjunct to morphine, is effective in reducing pain during the initial 30 to 60 min and demonstrated comparability to intravenous morphine alone in reducing pain over the subsequent 60 min for acute long bone fractures. However, it was associated with a higher incidence of dizziness.Trial registrationNMRR17318438970 (2 May 2018;www.nmrr.gov.my).

How to use meropenem in pediatric patients undergoing CKRT? Integrated meropenem pharmacokinetic model for critically ill children.

Standard dosing could fail to achieve adequate systemic concentrations in ICU children or may lead to toxicity in children with acute kidney injury. The population pharmacokinetic analysis was used to simultaneously analyze all available data (plasma, prefilter, postfilter, effluent, and urine concentrations) and provide the pharmacokinetic characteristics of meropenem. The probability of target fT > MIC attainment, avoiding toxic levels, during the entire dosing interval was estimated by simulation of different intermittent and continuous infusions in the studied population. A total of 16 critically ill children treated with meropenem were included, with 7 of them undergoing continuous kidney replacement therapy (CKRT). Only 33% of children without CKRT achieved 90% of the time when the free drug concentration exceeded the minimum inhibitory concentration (%fT > MIC) for an MIC of 2 mg/L. In dose simulations, only continuous infusions (60-120 mg/kg in a 24-h infusion) reached the objective in patients <30 kg. In patients undergoing CKRT, the currently used schedule (40 mg/kg/12 h from day 2 in a short infusion of 30 min) was clearly insufficient in patients <30 kg. Keeping the dose to 40 mg/kg q8h without applying renal adjustment and extended infusions (40 mg/kg in 3- or 4-h infusion every 12 h) was sufficient to reach 90% fT > MIC (>2 mg/L) in patients >10 kg. In patients <10 kg, only continuous infusions reached the objective. In patients >30 kg, 60 mg/kg in a 24-h infusion is sufficient and avoids toxicity. This population model could help with an individualized dosing approach that needs to be adopted in critically ill pediatric patients. Critically ill patients subjected to or not to CKRT may benefit from the administration of meropenem in an extended or continuous infusion.

In-vivo inhibition of neutral endopeptidase 1 results in higher absorbed tumor doses of [177Lu]Lu-PP-F11N in humans: the lumed phase 0b study

BackgroundA new generation of radiolabeled minigastrin analogs delivers low radiation doses to kidneys and are considered relatively stable due to less enzymatic degradation. Nevertheless, relatively low tumor radiation doses in patients indicate limited stability in humans. We aimed at evaluating the effect of sacubitril, an inhibitor of the neutral endopeptidase 1, on the stability and absorbed doses to tumors and organs by the cholecystokinin-2 receptor agonist [177Lu]Lu-PP-F11N in patients. In this prospective phase 0 study eight consecutive patients with advanced medullary thyroid carcinoma and a current somatostatin receptor subtype 2 PET/CT scan were included. Patients received two short infusions of ~ 1 GBq [177Lu]Lu-PP-F11N in an interval of ~ 4 weeks with and without Entresto® pretreatment in an open-label, randomized cross-over order. Entresto® was given at a single oral dose, containing 48.6 mg sacubitril. Adverse events were graded and quantitative SPECT/CT and blood sampling were performed. Absorbed doses to tumors and relevant organs were calculated.ResultsPretreatment with Entresto® showed no additional toxicity and increased the stability of [177Lu]Lu-PP-FF11N in blood significantly (p < 0.001). Median tumor-absorbed doses were 2.6-fold higher after Entresto® pretreatment (0.74 vs. 0.28 Gy/GBq, P = 0.03). At the same time, an increase of absorbed doses to stomach, kidneys and bone marrow was observed, resulting in a tumor-to-organ absorbed dose ratio not significantly different with and without Entresto®.ConclusionsPremedication with Entresto® results in a relevant stabilization of [177Lu]Lu-PP-FF11N and consecutively increases radiation doses in tumors and organs.Trial registration clinicaltrails.gov, NCT03647657. Registered 20 August 2018.

Hypoxic environment of wounds and photosynthesis-based oxygen therapy.

The hypoxic environment is among the most important factors that complicates the healing of chronic wounds, such as venous leg ulcers, pressure injuries and diabetic foot ulcers, which seriously affects the quality of life of patients. Various oxygen supply treatments are used in clinical practice to improve the hypoxic environment at the wound site. However, problems still occur, such as insufficient oxygen supply, short oxygen infusion time and potential biosafety risks. In recent years, artificial photosynthetic systems have become a research hotspot in the fields of materials and energy. Photosynthesis is expected to improve the oxygen level at wound sites and promote wound healing because the method provides a continuous oxygen supply and has good biosafety. In this paper, oxygen treatment methods for wounds are reviewed, and the oxygen supply principle and construction of artificial photosynthesis systems are described. Finally, research progress on the photosynthetic oxygen production system to promote wound healing is summarized.

Phase 1/2 Trial to Jointly Optimize Dose and Administration Schedule of Evomela in Newly Diagnosed Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

Background: Eligible patients with multiple myeloma (MM) are offered autologous hematopoietic cell transplantation (auto-HCT) in their first remission. The usual conditioning regimen consists of melphalan (Alkeran) 200 mg/m 2 infused over ~ 30 minutes due to its limited stability. Evomela is a newer formulation of melphalan, which is stable at room temperature for ~ 24 hours. The current trial studied the dose escalation and compared the short versus extended infusion time of evomela used as a conditioning regimen before auto-HCT. Methods: Patients with newly diagnosed MM, age ≤ 70, were eligible. Two dose levels, 200 and 225 mg/m 2 were studied. Patients were randomized between two infusion schedules: 30-60 minutes (short) and an extended infusion of 8-9 hours. Disease response was measured using IMWG criteria. Minimal residual disease (MRD) was measured by flow cytometry at 10 -5. Results: Sixty patients were enrolled. The first 3 patients in each arm were treated at evomela 200 mg/m 2. Since no dose-limiting toxicity (DLT) was observed, all subsequent patients (n=54; 27 in each arm) were treated at evomela 225 mg/m 2. The results are presented for patients treated at evomela 225 mg/m 2. Patient characteristics were evenly distributed (Table 1). The median age was 58.6 years (range: 42.6 -70.3). Twelve (22%) patients had high-risk cytogenetics (4 [15%] in the short infusion; 8 [30%] in the extended infusion arm), p-value 0.19. There were no deaths, and no patient experienced grade &amp;gt; 3 adverse events (AE). Grade 2-3 AEs were seen in 53 (98%) patients (26 [96%] in the short infusion; 27 [100%] in the extended infusion). Twenty-four (44%) patients experience grade 2-3 diarrhea (16 [60%] in the short infusion; 8 [30%] in the extended infusion). Grade 2-3 esophagitis was seen in 3 (6%) patients overall (0 in the short infusion; 3 [11%] in the extended infusion). Atrial fibrillation was seen in one patient (grade 2, extended infusion). Before transplant, six (22%) patients were in stringent complete remission (sCR) or CR in the short infusion arm vs. 4 (15%) patients in the extended infusion arm. At day-90 post-transplant, 13 (48%) patients in each arm were in sCR/CR, and 17 (63%) patients in each arm achieved MRD-negative status. Overall, 23 (43%) patients achieved MRD-negative plus sCR/CR status at day-90 (11 [41%] in short and 12 [50%] in the extended infusion arm). The median follow-up was 14.5 (range: 6-40) months (13.8 months in the short infusion and 14.8 months in the extended infusion arm). The median progression-free survival (PFS) was not reached in the overall trial population (Figure). The median PFS in the short infusion arm was not reached vs. 28.2 months in the extended infusion arm. The 2-year progression-free survival (PFS) was 91% in the short infusion arm vs. 77% in the extended infusion arm (hazard ratio (HR)=9.5 with 95% CI: 1- 91.2), p-value=0.022. On multivariate analysis, controlling for age and cytogenetic risk category, the extended infusion arm was associated with a shorter PFS (HR 10.96; 95% CI 1.18 - 102.02), p-value 0.0355, although the range for HR was notably wide, which could be attributed to a small number of events in each arm. Conclusions: Dose escalation of evomela to 225 mg/m 2 is safe and associated with an acceptable toxicity profile and a high response rate. Short and extended infusions of evomela are well-tolerated and associated with high response rates. The PFS is longer with the short infusion schedule, however, to affirm these preliminary observations, additional follow-up is needed.

Reducing time toxicity: Impact of a fast-track infusion pathway on overall wait-times and patient satisfaction at a large safety-net health system.

386 Background: Time toxicity is an emerging concept focusing on the impact of cancer care beyond traditionally measured outcomes: the time spent towards receiving care. Although the inherent complexity of cancer care can pose a challenge to improve time toxicity, addressing system and workflow inefficiencies through process improvement is an effective mitigation strategy. Here we present the impact of a fast-track infusion pathway on the wait-times and patient satisfaction at a large safety-net system. Methods: Parkland Health (PH) is the safety-net system for Dallas County, TX. The PH oncology infusion center supports cancer disciplines and other subspecialties. Factors such as timely patient arrivals, preference for coupled visits and same-day lab draws, and heterogeneity of treatments (medicine specialties vs. oncology) significantly impact wait times. In July 2022, a multidisciplinary team was formed to reduce wait times at the infusion center, including members who had previously participated in the ASCO Quality Training Program (QTP). This report is focused on developing a fast-track pathway for patients with injections or &lt;30-minute infusions. Patients with coupled appointments and same-day lab draws were eligible for fast-track. Wait times were calculated from the time patients were checked in at the front desk to the first medication administered. A dedicated team (RN and MA) and separate waiting areas/infusion bays were designated for fast-track patients. Fast-track patients were surveyed for satisfaction. Results: Baseline infusion volume for the 3 months prior to fast-track implementation was 106 patients per day with average wait time of 167 minutes. In the seven-month period after fast-track implementation, average daily fast-track and main infusion center combined volume was 115. The first PDSA cycle was focused on improving workflows and communication with pharmacy. In the second PDSA cycle, the fast-track infusions were moved to another area to infusion chairs to better patient flow. In May 2023, average volumes and wait times for fast-track and main infusion were 28/80 minutes and 87/107 minutes, respectively. This represents a 40% decrease in wait time for fast-track and 36% for main infusion. In our survey, 89% of fast-track patients reported their wait time to be shorter and 92% rated their experience good or excellent. Conclusions: Implementing and optimizing a separate process for short treatments reduced the wait times for both the short infusions (fast-track) as well as long infusions (main infusion) without a need for additional staff, infusion chairs, or space. The observed decrease in main infusion wait-time is likely the result of decongestion of their process by moving some of the volume to fast-track. We hope to further decrease our wait-times through additional PDSA cycles and leveraging process improvement methodology.

Defining standard and high dosages for β-lactam agents administered by intermittent, prolonged or continuous infusion: a PK/PD simulation study.

The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable β-lactams, standard and high dosages have been proposed for short-infusion regimens only. To evaluate dosages for β-lactams administered by prolonged infusion (PI) and continuous infusion (CI). Monte Carlo simulations were performed for seven injectable β-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable. Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam. These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.

Disutilities Associated with Intravenous Iron Infusions: Results from a Time Trade-off Survey and Diminishing Marginal Utility Model for Treatment Attributes in China.

Treatment process attributes can affect health state utilities associated with therapy. For intravenous iron, used to treat iron deficiency and iron deficiency anemia, research into process attributes is still lacking. This study estimated utilities associated with process attributes for intravenous iron infusions. An online survey including seven health state vignettes and time trade-off tasks was administered to participants, who were not patients living with iron deficiency or iron deficiency anemia, from a Chinese online panel. Vignettes used an identical description of iron deficiency and iron deficiency anemia but differed in the annual number of infusions, infusion duration, and infusion-associated risk of hypophosphatemic osteomalacia. Disutilities and their rate of change as the number of infusions increased were examined using a power model. The survey was completed by 1091 participants. The highest utilities were observed for one annual infusion of 15-30 minutes or 30-60 minutes, without risk of hypophosphatemic osteomalacia (0.754 and 0.746, respectively). In comparison, more infusions and infusions with a risk of hypophosphatemic osteomalacia were associated with lower utilities. Utility continued to decrease, but at a diminishing rate, as the annual number of infusions increased, with utility decrements of 0.006 and 0.002, respectively, when going from zero to one and from four to five infusions per year. All marginal disutilities were small (values <0.01). This study suggested that treatment attributes of intravenous iron infusions affect health state utilities. Using intravenous iron formulations that allow for fewer and shorter infusions without the risk of hypophosphatemic osteomalacia can reduce the number of visits required and increase patients' quality of life.

Propofol for Anesthesia in Pediatric Patients With Epilepsy on the Ketogenic Diet: A Single-Center Experience

BackgroundPropofol use is contraindicated in patients on ketogenic diet (KD) due to higher risk of propofol infusion syndrome (PIS). This study is intended to provide a descriptive analysis of our experience with propofol bolus and short infusions for anesthetic care in patients on the KD and to evaluate if any signs of PIS were observed. MethodsAll patients on the KD who underwent anesthesia with propofol between 2012 and 2022 were reviewed. Anesthetic encounters and charts were studied for type of surgical procedure; signs of PIS, including new cardiac arrhythmias, acidosis, or rhabdomyolysis in the periprocedural period; hypoglycemia; unplanned admissions within 24 hours of the procedure; if procedure was unexpectedly aborted; and increased seizure frequency within one week. ResultsWe identified 65 patients, aged from one to 20 years who underwent 165 anesthetic encounters with propofol, of which 123 were boluses and 42 were infusions.In bolus dosing, the average dose was 2.8 mg/kg (0.7 to 12.8 ± 1.8 mg/kg). Of these, four encounters developed acidosis, one developed rhabdomyolysis, and one developed increased seizures. With infusions, the average infusion rate was 9 mg/kg/hour, with mean infusion duration of 83 minutes (10 to 352 ± 75 minutes). Of these, one developed acidosis and one increased seizures. No cases of PIS were identified. None of the adverse effects were attributed to propofol. ConclusionsBoluses and brief infusions of propofol for anesthetic use in patients on the KD did not cause PIS in our cohort.

Metal-Organic Framework-Derived ZnO, N Dually Doped Nanocages as an Efficient Host for Stable Li Metal Anodes.

The drastic volume expansion and dendrite growth of lithium metal anodes give rise to poor electrochemical reversibility. Herein, ZnO, N dually doped nanocages (c-ZNCC) were synthesized as the host for lithium metal anodes using the zeolitic imidazolate framework-8 (ZIF-8). The synthesis is based on a two-step core@shell evolution mechanism, which could guide lithium deposition rapidly and offer a fast lithium-ion diffusion during the cycling process. Benefiting from the unique design, the as-obtained c-ZNCC can render a record short lithium infusion as low as 1.5 s, a stable lithium stripping/plating capability as long as 3000 h, and a voltage hysteresis of 95 mV when cycling at 10 mA cm-2 to 10 mA h cm-2. A low Tafel slope of 3.45 mA cm-2 demonstrates the efficient charge transfer of c-ZNCC-Li, and the galvanostatic intermittent titration technique measurement shows high diffusion coefficient of c-ZNCC-Li during the charging process. In addition, the LNMO||c-ZNCC-Li cell exhibits a capacity retention as high as 93.7% at 1 C after 200 cycles. This work creates a new design for deriving nanocages with dual lithiophilic spots using a metal-organic framework and carbon cloth for favorable Li metal anodes.

Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org.

The MTXPK.org webtool was launched in December 2019 and was developed to facilitate model-informed supportive care and optimal use of glucarpidase following the administration of high-dose methotrexate (HDMTX). One limitation identified during the original development of the MTXPK.org tool was the perceived generalizability because the modeled population comprised solely of Nordic pediatric patients receiving 24-h infusions for the treatment of acute lymphoblastic leukemia. The goal of our study is to describe the pharmacokinetics of HDMTX from a diverse patient population (e.g., races, ethnicity, indications for methotrexate, and variable infusion durations) and identify meaningful factors that account for methotrexate variability and improve the model's performance. To do this, retrospectively analyzed pharmacokinetic and toxicity data from pediatric and adolescent young adult patients who were receiving HDMTX (>0.5 g/m2 ) for the treatment of a cancer diagnosis from three pediatric medical centers. We performed population pharmacokinetic modeling referencing the original MTXPK.org NONMEM model (includes body surface area and serum creatinine as covariates) on 1668 patients, 7506 administrations of HDMTX, and 30,250 concentrations. Our results support the parameterizations of short infusion duration (<8 h) and the presence of Down syndrome on methotrexate clearance, the parameterization of severe hypoalbuminemia (<2.5 g/dL) on the intercompartmental clearance (Q2 and Q3), and the parameterization of pleural effusion on the volume of distribution (V1 and V2). These novel parameterizations will increase the generalizability of the MTXPK.org model once they are added to the webtool.

Camrelizumab combined with lenvatinib and RALOX-HAIC for hepatocellular carcinoma (HCC) in BCLC stage B and C: A prospective, single-arm, phase II trial (Cal Era study).

e16128 Background: The combination of systemic therapies and hepatic arterial infusion chemotherapy (HAIC) showed promising outcomes for advanced hepatocellular carcinoma (HCC). Raltitrexed, an antimetabolic drug with long plasma concentrations half-life, could be used in short infusions. HAIC with raltitrexed plus oxaliplatin (RALOX) was reported to be effective and safe in HCC. This study aimed to investigate the efficacy and safety of combined camrelizumab and lenvatinib plus RALOX-HAIC as a first-line treatment in advanced HCC patients. Methods: This single-arm, phase II study included treatment-naive adult (≥18 years) patients with HCC in BCLC stage B and C and Child-Pugh score small or equal to 7 points (NCT05003700). Patients were administrated with RALOX-HAIC (oxaliplatin 100mg/m2, raltitrexed 3 mg/m2, every 3 weeks), combined with camrelizumab (200mg by IV infusion, every 3 weeks) and lenvatinib (8mg orally once daily) for 6 cycles, followed by maintenance therapy with camrelizumab and lenvatinib until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Results: Between March 2021 and October 2022, 36 patients (33 men and 3 women; median age, 54.5 years) were enrolled. The median tumor size was 11.4 cm, 86.1% of patients had portal vein invasion, and 38.9% had extrahepatic metastasis. As of February 1, 2023, the median follow-up was 14.2 months, and all patients had at least one post-baseline tumor assessment. The confirmed ORR per RECIST v1.1 and per mRECIST was respectively 61.1% (95% CI, 44.4−77.8), and 83.3% (95% CI, 70.5−96.1) including 4(11.1%) patients who achieved a complete radiological response. The median progression-free survival (PFS) time was 13.8 months (95%CI, 8.8-20.5) per RECIST v1.1. The 6-month and 12-month overall survival rate were 94.3% and 64.9%, respectively. Grade 3-4 treatment-related adverse events (AEs) occurred in 75% of patients, and the most common were neutropenia (44.4%) thrombocytopenia (36.1%), elevated aspartate aminotransferase (25.0%), and leucopenia (19.4%). All AEs were expected and manageable, and no treatment-related deaths were reported. Conclusions: Combination treatment with camrelizumab and lenvatinib plus RALOX-HAIC showed promising antitumor activity and acceptable toxicity in patients with advanced HCC. Clinical trial information: NCT05003700 .

P-361 Safety and efficacy of short cetuximab infusion for patients with metastatic colorectal cancer

P-361 Safety and efficacy of short cetuximab infusion for patients with metastatic colorectal cancer

Infusion-Related Reactions With Ocrelizumab: Risk Factors, Symptom Management and Patient Choices in the ENSEMBLE PLUS Study (P7-3.003)

Infusion-Related Reactions With Ocrelizumab: Risk Factors, Symptom Management and Patient Choices in the ENSEMBLE PLUS Study (P7-3.003)