Dosing Recommendations Research Articles

On Inclusion of Covariates in Model Based Dose Finding Clinical Trial Designs.

There is a growing number of Phase I dose-finding studies that use a model-based approach, such as the CRM or the EWOC method to estimate the dose-toxicity relationship. It is common to assume that all patients will have similar toxicity risk given the dose regardless of patients' individual characteristics. In many trials, however, some patients' covariates (e.g., a concomitant drug assigned by a clinician) might have an impact on the dose-toxicity relationship. In this work, motivated by a real trial, we evaluate an impact of taking into account (or omitting) some patients' covariates on the individual target dose recommendations and patients' safety in Phase I model-based dose-finding study. We investigate several variable penalisation criteria and found that, for continuous and binary covariates, omitting a prognostic covariate leads to a drastically low proportion of correct selections and an increase of overdosing. At the same time, including a covariate can lead to good operating characteristics in all scenarios but can sometimes slightly decrease the proportion of good selections and increase the overdosing. To tackle this, we propose to use a Bayesian Lasso Bayesian Logistic Regression Model (BLRM) and Spike-and-Slab BLRM. We have found that the BLRM coupled to the Bayesian LASSO and the BLRM with Spike-and-Slab are on average better appropriate to consider variable inclusion.

Clinical Assessment of the Drug-Drug Interaction Potential of Omaveloxolone in Healthy Adult Participants.

Omaveloxolone is approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years. It is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro. Two drug-drug interaction studies (NCT04008186 and NCT05909644) were performed to evaluate (1) the effect of drug-metabolizing enzymes (DMEs) and drug transporter (DT) modulators on the pharmacokinetics of omaveloxolone and (2) the effect of omaveloxolone on the pharmacokinetics of DME and DT substrates. Additionally, the safety of coadministering these drugs with omaveloxolone was assessed. Coadministration of the strong CYP3A4 inhibitor itraconazole significantly increased omaveloxolone maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) by approximately 3- and 4-fold, respectively. Conversely, coadministration with the moderate CYP3A4 inducer efavirenz decreased Cmax and AUC0-∞ of omaveloxolone by 38.0% and 48.5%, respectively. Omaveloxolone exposure was also increased following coadministration with verapamil, a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor, but it was unaffected by the strong CYP2C8 inhibitor gemfibrozil. Coadministration of omaveloxolone reduced systemic exposure of the substrates of CYP3A4, CYP2C8, breast cancer resistance protein, and organic anion transporting polypeptide 1B1 but had no effect on those of P-gp and organic cation transporter 1. Omaveloxolone was well tolerated when administered alone and in combination with the DME and DT modulators or substrates. These findings support concomitant medication precautions and dosing recommendations for omaveloxolone when coadministered with a moderate or strong CYP3A4 inhibitor or inducer, as well as the substrates of certain CYP450 enzymesor transporters.

Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of Aficamten.

Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment. The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM. Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function. No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.

Dosage Recommendations for Off-label Use of Mycophenolate Mofetil in Pediatric Patients with Thalassemia Undergoing Hematopoietic Stem Cell Transplantation: An Approach Based on Population Pharmacokinetic Studies.

As an immunosuppressant, mycophenolate mofetil (MMF) is used to prevent graft versus host disease (GVHD) in patients after hematopoietic stem cell transplantation (HCT). This study aimed to establish a population pharmacokinetic model and simulate the dosage protocol in HCT patients with thalassemia (TM) to fill the gap of lacking MMF dosing regimen. The mycophenolic acid (MPA) plasma concentrations were obtained from HCT patients with TM after using MMF. The population pharmacokinetic (PPK) parameters were obtained by NONMEM (Version VII, Level 2.0; ICON Development Solutions, Ellicott City, MD, USA) program. Monte Carlo simulations were used to determine the optimal dosing. A total of 239 blood samples from 31 pediatric patients were available, the PPK of MPA was described as a two-compartment model. The typical values for MPA clearance (CL), central distribution volume (V2), peripheral distribution volume (V3), intercompartmental clearance (Q), and absorption rate constant (Ka) were 14.9 L/h, 83.5L, 141L, 3.13 L/h, and 1.37/h respectively. The inter-individual variability (IIV) of CL and V2 were 35% and 41%, respectively. Simulation results suggested that, as the patient's body surface area (BSA) value increased, MMF dosage initiated from 500 mg twice daily was effective. A 'tiered' dosage regimen including patient urea and with doses stratified across BSA quartiles, rather than a 'one dose fits all' regimen, would help individualize MMF therapy in this population.

Evaluation of the need for dosing adaptations in obese patients for surgical antibiotic prophylaxis: a model-based analysis of cefazolin pharmacokinetics.

Cefazolin is used as a prophylactic antibiotic to reduce surgical site infections (SSIs). Obesity has been identified as a risk factor for SSIs. Cefazolin dosing recommendations and guidelines are currently inconsistent for obese patients. As plasma and target-site exposure might differ, pharmacokinetic data from the sites of SSIs are essential to evaluate treatment efficacy: these data can be obtained via tissue microdialysis. This analysis was designed to evaluate the need for dosing adaptations in obese patients for surgical prophylaxis. Data from 15 obese (BMImedian= 52.6 kg m-2) and 15 age- and sex-matched nonobese patients (BMImedian= 26.0 kg m-2) who received 2 g cefazolin i.v. infusion for infection prophylaxis were included in the analysis. Pharmacokinetic data from plasma and interstitial space fluid (ISF) of adipose tissue were obtained and analysed simultaneously using nonlinear mixed-effects modelling. Dosing regimens were evaluated by calculating the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for plasma and ISF using unbound cefazolin concentration above minimum inhibitory concentration 100% of the time as target (fT>MIC= 100%). Dosing regimens were considered adequate when PTA and CFR were ≥90%. Evaluation of cefazolin doses of 1 and 2 g with redosing at either 3 or 4 h by PTA and CFR in plasma and ISF found 2 g cefazolin with redosing at 4 h to be the most suitable dosing regimen for both obese and nonobese patients (PTA >90% and CFR >90% for both). This model-based analysis, using fT>MIC= 100% as a target, showed that cefazolin dosing adaptations are not required for surgical prophylaxis in obese patients.

P-1217. Validation of Cefiderocol (FDC) Package Insert Dosing Recommendation for Patients receiving Continuous Renal Replacement Therapy (CRRT): A Prospective Multi-Center Pharmacokinetic Study

Abstract Background FDC is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving CRRT including modalities such as continuous venovenous hemodiafiltration (CVVHDF). The objective of this study was to investigate the population pharmacokinetics of FDC among patients receiving CRRT and validate these novel dosing recommendations. Methods A multicenter pharmacokinetic study among critically ill patients receiving CRRT was conducted. Subsequent blood sampling was performed at steady-state, and FDC concentrations were assayed by a validated Liquid Chromatography with tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R. The free time above the minimum inhibitory concentration (fT>MIC) was calculated with a target of ≥75% fT >MIC associated with clinical success. Total daily area under the concentration time curve (AUCdaily) was used as a surrogate for safety and tolerability. Results Fourteen patients on CVVHDF renal support were enrolled from August 2022 until December 2023; Hartford Hospital (n=7), Banner University Medical Center (n=5), and University of Kentucky Medical Center (n=2). Average age was 55 years and majority were male (n=9). Mean body weight was 113.5 kg, and effluent flow rates ranged from 2.1 to 5.1 L/h. FDC concentrations best fitted a two-compartment model. Mean ± SD parameter estimates for clearance, volume of the central compartment, and intercompartment transfer constants (K12 and K21) were 3.5 ± 1.5 L/h, 10.7 ± 8.4 L, 3.9 ± 1.8 h-1, and 2.2 ± 2.2 h-1, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% fT >MIC up to MIC 8 mg/L with an AUCdaily (mean ± SD) of 1444 ± 423 mg*h/ L (Table 1). FDC was well tolerated with no serious adverse events reported among these critically ill patients. Conclusion Based on these data, the current package insert dosing recommendations resulted in pharmacodynamically optimized FDC exposures. The simulated concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUCdaily were within the range observed in patients not receiving CRRT in the Phase 3 clinical trials, suggestive of a safe and therapeutic profile. Disclosures Emir Kobic, BCIDP, Shionogi: Grant/Research Support|Shionogi: Speaker Bureau Melissa L. Thompson Bastin, PharmD, PhD, Baxter Healthcare: Advisor/Consultant|Baxter Healthcare: Board Member|Fresenius: Advisor/Consultant Andrew J. Fratoni, PharmD, InsightRX: Grant/Research Support Xiaoyi Ye, MD, Sanofi: Advisor/Consultant Joseph L. Kuti, PharmD, Abbvie: Advisor/Consultant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria|Venatorx: Grant/Research Support David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support Tomefa E. Asempa, PharmD, FDA/CDER: Grant/Research Support|Paratek: Grant/Research Support|Shionogi: Grant/Research Support|Spero: Grant/Research Support|VenatoRx: Grant/Research Support

P-1252. Individualizing Antibiotic Therapy: Pharmacokinetic Approach to Evaluate and Optimize dosing of Meropenem in Critically Ill Sepsis Patients

Abstract Background The optimization of antibiotic dosing poses a considerable challenge, particularly in cases of Sepsis with acute renal impairment requiring continuous renal replacement therapy (CRRT). This study centers on the widely prescribed broad-spectrum beta-lactams, specifically meropenem, recognizing its extensive use in severe and complex clinical scenarios. The primary objectives of this study is to formulate new guidelines facilitating dose individualization, thus enhancing therapeutic outcomes for this critical population. Meropenem dosing recommendations for sepsis shock patients with acute renal impairment Methods Three studies were conducted based on specific hypotheses. The initial study involved a comprehensive systematic literature review aimed at critically evaluating the existing evidence regarding the dosing regimens of meropenem. Subsequently, Studies 2 and 3 were undertaken as observational, prospective, open-labeled, multicenter pharmacokinetic investigations within the Intensive Care Unit of a prominent tertiary care hospital in Coimbatore, India. The study cohort comprised thirty patients administered with meropenem experiencing septic shock with acute renal impairment requiring continuous renal replacement therapy. Population Pharmacokinetic models were meticulously developed, validated, and subjected to Monte Carlo simulations for comprehensive analysis. Results A comprehensive literature review exposed the limitations of current dosing recommendations, pointing to varied sickness severities, renal function levels, admission diagnostics, CRRT settings, and disparate pharmacokinetic (PK) methodologies. For meropenem, a crucial relationship between 24-hour urine output and total clearance emerged. Oligoanuric patients (< 100mL/24h) displayed a 30% decrease in total clearance compared to those with preserved diuresis ( >500mL/24h). Monte Carlo simulations supported tailored dosing recommendations, addressing bacterial susceptibility and patient diuresis status. Conclusion For optimal antibiotic dosing, our findings highlight the importance of considering clinical and demographic factors, including 24-hour urine output and patient weight. These insights can be implemented at the bedside to help navigate the complexities of antibiotic optimization within the Intensive Care Unit. Disclosures All Authors: No reported disclosures

P-1789. Implementation of Pathogen Independent Model Informed Precision AUC-based Dosing of Vancomycin at University Hospital Wuerzburg (UKW)

Abstract Background The IDSA guideline concerning monitoring vancomycin in MRSA infections, published in March 2020, recommends model informed precision AUC based dosing for vancomycin. The application of pharmacometrics software with Bayesian calculating is recommended. The summary of product characteristics of vancomycin, issued by EMA (European Medicines Agency), includes also details regarding model informed precision dosing for vancomycin therapies, irrespective of targeted or identified pathogens. Due to the low prevalence of MRSA infections at UKW, model informed precision AUC-based dosing has been instituted for all parenteral vancomycin therapies. Methods The target for vancomycin AUC/MIC (minimum inhibitory concentration) is a range of 400 – 600 mg*h/L over 24 hours. Individual patient covariates, personal dosing information and vancomycin concentrations were converted into dosing recommendations with InsightRX. In order to record the effect of the intervention, the target attainment and the occurrence of AKI (acute kidney injury, defined as an increase in serum creatinine of ≥ 0.3 mg/dL within 48 h) is recorded 18 months before and 12 months after the implementation of the new dosing strategy. Results Since October 2022, a workflow for model informed AUC-based dosing has been launched across 12 wards - mainly intensive care units - encompassing 215 beds. In the conventional dosing strategy according to trough dosing, AKI occurred in 60 of 216 therapies, while AKI was detected in 8 out of 57 AUC-guided vancomycin therapies resulting in an odds ratio of 2.32 [CI 95 % 1.08 – 5.59]. Significantly more AUC guided therapies were in the therapeutic range of 400 – 600 mg*h/L after 120 hours than trough-based vancomycin therapies reached the target [55.1 % vs 70.2 %, OR 0.52, CI 95 % 0.27 – 0.97]. Additionally, more trough-based therapies were in a supratherapeutic range than AUC guided therapies [24.5 % vs 8.8 %, OR 3.23, CI 95 % 1.35 – 9.98] Conclusion The unique concept of pathogen independent model-informed AUC-based dosing of vancomycin was successfully integrated into the clinical routine work. Early dose individualization due to AUC-based dosing can contribute to increase drug therapy safety and improved patient safety for vancomycin therapies. Disclosures All Authors: No reported disclosures

Tranexamic dosing for major joint arthroplasty in adult patients with chronic kidney disease: A pharmacokinetic study and new dosing regimen.

Tranexamic acid is an anti-fibrinolytic agent routinely used during hip and knee joint replacement surgery to minimize bleeding. Chronic kidney disease is a common chronic health problem seen among adults requiring major arthroplasty surgery. Tranexamic acid is renally cleared and may accumulate in chronic kidney disease. Optimal tranexamic acid dosing and dose adjustment for chronic kidney disease patients needing major arthroplasty is unknown. The objective of this study was to serially measure plasma tranexamic acid concentrations in patients with varied kidney function undergoing hip or knee replacement surgery for population pharmacokinetic modelling and to guide new dosing recommendations. Prospective cohort study enrolled 21 adults undergoing hip or knee replacement surgery between June 2020 - September 2022. Based on estimated glomerular filtration rate (eGFR), patients were stratified into good (≥ 60 mL/min/1.73 m2) and poor (< 60 mL/min/1.73 m2) renal function. Serial blood samples were taken to measure plasma tranexamic acid concentration levels (primary outcome) after an intravenous tranexamic acid 20 mg/kg bolus dose post anesthesia induction. Secondary clinical outcomes included adverse events (thromboembolic events, seizures), red cell transfusion, mortality, length of hospital stay. Analyses used curve stripping and population pharmacokinetic modelling and simulation. Plasma tranexamic acid concentration levels were higher in patients with poor renal function and clearance compared to good renal function. Population pharmacokinetic modelling tested various tranexamic acid bolus and maintenance infusion regimens. Simulations revealed single bolus tranexamic acid administration leads to rapid rise and decline in plasma concentrations. We identified that plasma tranexamic acid levels of 50-75 mg/L were maintained for approximately 4 hours using a tranexamic acid bolus infusion of 15 mg/kg over 15 min together with a maintenance infusion of 7.5 mg/kg/h or 5 mg/kg/h for 2 hours for the good and poor renal function groups, respectively. There was no difference in secondary outcomes. Using population pharmacokinetic modelling and simulation, we recommend a new dosing regimen to optimize the anti-fibrinolytic effect of tranexamic acid and avoid excessive dosing.

P-1264. Explore The Pharmacokinetic/pharmacodynamics Target Attainment (PTA) of cefoperazone/sulbactam

Abstract Background Cefoperazone/sulbactam (CPZ/SUL) are broad-spectrum antibiotics. Current dosage guidelines consider the renal elimination characteristics of SUL. However, with the risk of antimicrobial resistance, whether current dosage recommendation of CPZ/SUL achieves the desired probability of target attainment (PTA) is unclear. The purpose of this study is to compare the PTA between adjusted-dose (AD) CPZ/SUL and standard-dose (SD) CPZ/SUL therapy. Methods This observational study was conducted in a tertiary hospital in Taiwan during November 2023 to March 2024. Patients using CPZ/SUL (1:1 ratio) were prospectively enrolled. Two blood samples were collected during the dosing interval to measure CPZ and SUL concentrations by using ultra-high performance liquid-chromatography. Concentrations at the middle of the dosing interval (Cm) and before dosing (Ct) were calculated based on measured concentration. PTA was represented by the fraction of time the free concentration was above the minimum inhibitory concentration (fT &amp;gt;MIC). 50% fT &amp;gt;MIC was defined as Cm &amp;gt;MIC, and 100% fT &amp;gt;MIC was defined as Ct &amp;gt;MIC. AD group was defined as reduced CPZ/SUL doses according to the labeling, while SD group had no dose adjustment despite renal impairments. Results A total of 37 patients were enrolled (59.5% male, mean age, 75.4±16.0 years). The most common indication of CPZ/SUL was pneumonia (83.8%). There were 26 patients (70.3%) in the AD group and 11 patients (29.7%) in the SD group. The proportion of patients with 100% fT &amp;gt;MIC was lower in the AD group, as compared to the SD group (CPZ: 15.4% versus 54.5%, P&amp;lt; 0.01; SUL: 11.5% versus 72.7%, P&amp;lt; 0.01). Additionally, 7.7% of patients in the AD group compared to 45.5% of patients in the SD group achieved 100% fT &amp;gt;MIC for both CPZ and SUL (P&amp;lt; 0.01). Thirty patients (81.1%) received weekly vitamin K to prevent CPZ-related coagulopathy, and none had an international normalized ratio above 2. Conclusion PTA was inadequate in patients receiving CPZ/SUL based on current dosage adjustment recommendations. Future investigation is needed to determine if inadequate PTA is linked to worse clinical outcomes, especially in resistant pathogens. Disclosures All Authors: No reported disclosures

P-1218. Assessment of Cefepime-Taniborbactam (FEP-TAN) Transmembrane Clearance (CLTM) in an Ex vivo Continuous Renal Replacement Therapy (CRRT) Model

Abstract Background Optimal antibiotic dosing in patients undergoing CRRT is influenced by many factors that affect drug adsorption and clearance. These factors include filter type, CRRT mode, effluent rate (ER), and drug characteristics. FEP-TAN is an investigational β-lactam/β-lactamase inhibitor combination having broad-spectrum activity against carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. Both FEP and TAN are primarily eliminated through glomerular filtration. Hence, we conducted an ex vivo CRRT model to characterize the adsorption and CLTM when co-administered. Methods CLTM was characterized in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex ST150 and HF1400 hemofilter sets. One liter of heparinized bovine blood was allowed to circulate in the CRRT system for 10 minutes. FEP and TAN were then added simultaneously to attain plasma concentrations of 70 and 20 mg/L, respectively, the average Cmax achieved in humans following FEP-TAN 2g/0.5g q8h as a 4h infusion. Pre-filter blood, post-filter blood, and effluent samples were collected over 60 minutes to determine FEP and TAN concentrations. Combinations of filters, modes, and points of fluid replacement were tested at ERs of 2, 3, and 4 L/h. The sieving coefficient (SC) for CVVH and the saturation coefficient (SA) for CVVHD were calculated to determine CLTM. Protein binding (PB) was assessed by ultrafiltration. Adsorption was determined using a closed circuit bypassing effluent elimination. Results Adsorption and degradation in the ex vivo CRRT model were negligible for both drugs. Mean ± SD initial FEP and TAN concentrations were 66.9 ± 5.3 and 18.7 ± 1.7 mg/L, respectively. PB was 0% for FEP and 5.4 ± 3.7% for TAN in bovine plasma. The overall mean ± SD SC/SA across different modes, filters, and ERs were 1.1 ± 0.06 for FEP and 1.0 ± 0.05 for TAN. The CLTM at ERs of 2, 3, and 4 L/h were 2.1 ± 0.2, 2.9 ± 0.3, and 3.8 ± 0.5 for FEP and 1.9 ± 0.2, 2.7 ± 0.2, and 3.4 ± 0.3 L/h for TAN, respectively. Conclusion FEP and TAN were efficiently cleared by both CVVH and CVVHD CRRT modes through ST150 and HF1400 filters. When incorporated into an established population pharmacokinetic models, these data can be used to develop dosing recommendations for FEP-TAN in patients undergoing CRRT. Disclosures Joseph L. Kuti, PharmD, Abbvie: Advisor/Consultant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria|Venatorx: Grant/Research Support

P-1659. Clinical and Safety Outcomes of Uniform Thrice-Weekly Daptomycin Dosing Based on Adjusted Body Weight in Patients Receiving Intermittent Hemodialysis

Abstract Background Limited evidence exists on optimal dosing of daptomycin (DAP) in patients receiving intermittent dialysis (HD). Current labeling recommends every 48 hour (q48h) dosing which often causes additional DAP doses to be given throughout the week when the schedules become unaligned. Alternatively, current recommendations for thrice weekly dosing suggest a larger dose for the 72-hour interdialytic interval, which makes operationalization difficult within current inpatient electronic systems. Methods A retrospective observational cohort study comparing clinical and safety outcomes of adult patients receiving DAP with HD was performed between 01/2021 and 04/2024. Updated dosing recommendations for DAP with HD was modified on 1/2023 to indication based uniform adjusted body weight (AdjBW) dosing with each HD session compared to the previous recommendation of q48h based on total body weight. Clinical outcomes included microbiologic recurrence and escalation of dose or antibiotic therapy. Safety outcomes included CK elevation and development of rhabdomyolysis. Patients were excluded if they were on DAP prior to admission or received &amp;lt; 2 DAP doses. Results In total, 79 patients met inclusion. BMI, acuity of infection, length of stay, and duration of therapy were similar between the q48h (n=42) and the with each HD groups (n=37). There was a significant reduction in total weekly AdjBW DAP received in the with each HD group (23.8mg/kg vs 28.8 mg/kg, p &amp;lt; .0001) despite a higher utilization of the 8 mg/kg strategy (64.9% vs 26.2%). There was no significant difference in the clinical failure (5.4% vs 4.8%, p = 0.90) or safety outcomes (0% vs 6.5%, p = 0.12) between the post- and pre-groups, including after propensity matching based on BMI, AdjBW dose received, and receipt of source control. Conclusion Utilizing uniform DAP doses with each HD compared to standard q48h frequency in patients receiving HD did not result in worse clinical or safety outcomes while reducing the overall weekly exposure to DAP. This strategy further supports the use of AdjBW as the preferred dosing weight for DAP, including in HD patients, who have been underrepresented in previous studies. This method could also be useful in the outpatient setting to help optimize DAP exposure. Disclosures All Authors: No reported disclosures

Cannabidiol in Foods and Food Supplements: Evaluation of Health Risks and Health Claims

Background: Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5–40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. Methods: The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. Results: Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3–4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. Conclusions: The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers.

P-1233. Application of Pharmacometrics in the Personalized Colistin Dosing Recommendation

Abstract Background Colistin is frequently used as a treatment for infections caused by carbapenem-resistant Gram-negative bacteria. Colistin dosing should be adjusted according to the patient's renal function because the prodrug, colistin methanesulfonate (CMS), is partially removed by the kidney. Intensive care unit (ICU) patients may require individualized dosing to prevent nephrotoxicity or treatment failure due to the highly variable pharmacokinetics (PK) of colistin.Figure 1.Example of colistin dosing recommendation program – Patient information input Methods Colistin plasma concentration data from ICU patients who received colistin from June 2019 to August 2022 in Korea University Hospital were included in the dataset for this population PK analysis. We developed a population PK model for colistin using ICU patients, and established therapeutic drug monitoring software. A population PK analysis was performed using the first-order conditional estimation method with interaction in non-linear mixed effects modeling. We used the open-source R Shiny program to establish Colistin TDM software. The structural PK model and the final estimates of both fixed-effect and random-effect parameters were translated into an R code.Figure 2.Example of colistin dosing recommendation program – Simulation outputRecommendations provide the loading and maintenance doses based on patient information. Maintenance dose depends on the predicted colistin trough and peak levels, and the interval and infusion time of colistin administration. Results We enrolled 176 colistin observations from 22 patients in the dataset. A two-compartment, first-order elimination model best described the PK of Colistin A, one-compartment, first-order elimination model for PK of Colistin B, and one-compartment, first-order elimination model for PK of CMS. In the results from the covariate analysis, GFR estimated by Cockcroft–Gault equation and albumin level was included as a statistically significant covariate of total clearance of CMS, and body weight was selected as a covariate of CMS volume of distribution. The two-compartment structure model for Colistin and CMS, the final estimates of both fixed effects and random effects from the PK model and the log-likelihood Equation (5) for estimating ηi were implemented in R script. A draft version of the software is now available at http://mychloe00.shinyapps.io/colistin_new. Conclusion We developed colistin TDM software using PK parameters in ICU patients for individualized colistin administration. Further research is needed to determine whether colistin is actually administered within the therapeutic range through the application of this software. Disclosures All Authors: No reported disclosures

Effect of Target-Mediated Disposition on Iptacopan Clinical Pharmacokinetics in Participants with Normal or Impaired HepaticFunction.

Iptacopan, a first-in-class complement factor B inhibitor acting proximally in the alternative complement pathway, has been shown to be safe and effective for patients with complement-mediated diseases. Iptacopan selectively binds with high affinity to factor B, a soluble, plasma-based, hepatically produced protein. Factor B is abundant in the circulation but can be saturated at the iptacopan clinical dose of 200 mg twice daily. Iptacopan pharmacokinetics (PK) are influenced by target binding. This target-mediated drug disposition (TMDD) behavior makes PK data useful for understanding target occupancy and motivates modeling of drug-target binding to connect exposure with pharmacological effect. A phase I hepatic impairment (HI) PK study measuring both total and unbound iptacopan PK profiles provided an opportunity to characterize the effect of variation in target concentration (due to varying hepatic function) on iptacopan PK. HI caused no change in total iptacopan exposure but increased unbound iptacopan exposure 1.38- to 3.72-fold in participants with mild, moderate, or severe HI relative to demographically matched participants with normal hepatic function, with the largest increases in severe HI. A two-site competitive binding model was developed to elucidate the relationship between iptacopan PK and factor B occupancy to characterize exposure thresholds for maximal target engagement. The model was used to assess alternative dose regimens to provide insight into how to approach dose recommendations for patients with severe HI. This study provides an example of small-molecule TMDD, a behavior typically associated with targeted biologics; its importance is too often underappreciated in small-molecule drug development.

Variable temocillin protein binding and pharmacokinetics in different clinical conditions: Implications for target attainment.

The beta-lactam antibiotic temocillin is increasingly used to treat extended-spectrum beta-lactamase (ESBL-producing) strains; however, its protein binding is complex. This study aims to predict unbound temocillin concentrations in various participant groups to determine its impact on the probability of target attainment (PTA) and to improve dosing recommendations. The plasma pharmacokinetics were analysed using non-linear mixed-effects modelling. Data from individuals in four groups: healthy volunteers (HV), urinary tract infection patients (UTI), ventriculitis patients and sepsis-ICU patients were included. Simulations were performed to compare the PTA for different dosing regimens and participant-groups. A two-compartment protein-binding model best fitted the 1085 concentrations (543 unbound, 542 total). Temocillin clearance was influenced by creatinine clearance, serum albumin (ALB) and C-reactive protein (CRP). For 2g q8h intermittent infusion, the PTAs at an MIC of 16 mg/L were 2.3%, 39.5%, 10.0% and 72.5%, for HV, UTI, ventriculitis and sepsis-ICU patients, respectively. The effects of the covariates on the PTA were simulated for two example patients with intermittent infusion: the PTAs at an MIC of 8mg/L for a sepsis-ICU patient (CRP 300 mg/L, albumin 15 g/L) and a mild-UTI patient (CRP 30 mg/L, albumin 35 g/L) were 94.3% and 62.4%, respectively. Continuous infusion consistently outperformed intermittent infusion in achieving the desired pharmacodynamic target (time above MIC). Our study underscores the significant variation in temocillin clearance and unbound fractions among different participant groups, challenging the efficacy of traditional 2g q12h dosing. For patients with enhanced renal function and lower inflammation, continuous infusion emerges as a more effective strategy to achieve optimal target attainment.

Injectable Estradiol Use in Transgender and Gender-Diverse Individuals in the U.S.: A Multicenter Retrospective Study.

Guidelines for use of injectable estradiol esters (valerate [EV] and cypionate [EC]) among transgender and gender diverse (TGD) individuals designated male at birth vary considerably, with many providers noting supraphysiologic serum estradiol concentrations based on current dosing recommendations. 1. Determine dose of injectable estradiol (subcutaneous [SC] and intramuscular [IM]) needed to reach guideline-recommended estradiol concentrations for TGD adults using EC/EV. 2. Describe relationship between estradiol concentration relative to timing/dose of last estradiol injection and other covariates. 3. Determine dosing differences between IM/SC EV/EC. Cross-sectional retrospective study across six United States medical centers including TGD adults on same-dose injectable estradiol for >75 days, with confirmed timing of estradiol concentration relative to last injection, from 1/1/2019---12/31/2023. Descriptive statistics were used to describe patient characteristics and weighted linear mixed models to evaluate relationship between various covariates and estradiol concentration. Data from 562 patients were included. Among those injecting every seven days who reached the guideline-recommended estradiol concentration (n=131, 27.5%), the median estradiol dose was 4.0 mg (interquartile range 3.0---5.0 mg). Among all patients, the majority reached supraphysiologic estradiol concentrations (>200 pg/mL [>734 pmol/L]) while dose and timing in the injection cycle were significant covariates for the estradiol concentration. There were no significant dosing differences between IM/SC EV/EC. Injectable estradiol esters effectively reach guideline-recommended estradiol concentrations but at lower doses than previously recommended. Estradiol concentrations are best interpreted relative to timing of last injection. Route of administration and type of ester do not significantly impact estradiol concentrations.

A Quantitative Examination and Comparison of the Ability of Australian Gentamicin Dosing Guidelines to Achieve Target Therapeutic Concentrations in Neonates.

Background: Effective gentamicin dosing is crucial to the survival of neonates with suspected sepsis but requires a careful balance between attaining both effective peak and safe trough concentrations. We aimed to systematically compare existing gentamicin dosing guidelines for neonates in Australia to determine the extent to which they reach therapeutic targets. Methods: Simulations of a single gentamicin dose to a virtual representative neonatal population according to each Australian guideline were performed using population pharmacokinetic modelling. We determined the proportion of neonates who would achieve peak gentamicin concentrations of ≥5 or ≥10 mg/L and trough concentrations of ≤1 or ≤2 mg/L. We calculated the probability of target attainment (PTA) according to gestation at birth (22 to 40 weeks) and postnatal age (1-7, 8-14, 15-21, 22-28 days). Results: Five unique dosing guidelines were identified. Guidelines varied considerably with respect to dose (4.5 to 7 mg/kg), dosing interval (24 to 48 h), and characteristics used to individualise dosing regimens (e.g., gestation at birth and postnatal age). Guidelines were satisfactory in routinely achieving effective peak concentrations ≥ 5 mg/L, but PTAs for effective peak concentrations ≥ 10 mg/L varied considerably from 5% to 100% based on dose, gestation, and postnatal age. PTAs for trough concentrations ≤ 1 mg/L ranged from 0% to 100%, being lowest among extremely preterm infants. Conclusions: Current Australian gentamicin guidelines demonstrate significant variability in their ability to achieve defined therapeutic targets, necessitating efforts to improve standardisation of dosing recommendations. Further research to define optimal pharmacodynamic targets in neonates with respect to clinical outcomes are also urgently warranted.

Effect of Compost Fertilizer Dosage and Compost Tea on the Growth of Red Calliandra (Calliandra calothyrsus Meisn.) Seedlings

Kaliandra (Calliandra calothyrsus Meisn) is a plant capable of producing large amounts of biomass, potentially as a renewable energy source that supports the reduction of dependence on fossil fuels. The transition from fossil fuels to renewable energy is an urgent and long-term solution, as the use of fossil fuels as an energy source contributes to global warming and climate change.This study aims to evaluate the effect of compost fertilizer dosage and compost tea on the growth of height and diameter of kaliandra seedlings. Using a one-factor complete randomized design (CRD) method with treatment of compost fertilizer doses K0 (0 grams), K1 (60 grams), K2 (75 grams) and K3 (90 grams) and compost tea doses TK1 (0 ml), TK1 (50 ml), TK2 (75 ml) and TK3 (100 ml). Research results: 1. The treatment of compost doses and compost tea showed significant differences in the height growth of calliandra seedlings. 2. Compost fertilizer with a dose of 90 grams (K3) showed a better height growth rate than compost tea fertilizer with a dose of 100 ml (TK3), 75 ml (TK2), and 50 ml (TK1). 3. Compost tea fertilizer with doses of 50 ml (TK1) and 75 ml (TK2) showed a better height growth rate than compost fertilizer with doses of 60 grams (K1) and 75 grams (K2). 4. The compost fertilizer dose treatment showed a significant difference in the growth rate of Calandra seedling diameter, while the compost tea dose treatment did not show a significant difference. 5. Compost fertilizer with doses of 75 grams (K2) and 90 grams (K3) showed better diameter growth than compost tea fertilizer with doses of 75 ml (TK2) and 100 ml (TK3). 6. The optimal dosage recommendation in this study is 90 grams of compost fertilizer and 75 ml of compost tea.

A Pooled Pharmacokinetic Analysis for Piperacillin/Tazobactam Across Different Patient Populations: From Premature Infants to the Elderly.

The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (fUNB_PIP). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life. Population PK models were separately built for PIP and TAZ based on data from 13 studies in various patient populations. In the development of those single-drug models, postnatal age (PNA), postmenstrual age (PMA), total body weight (TBW), height, and serum creatinine (SCR) were tested as covariates. Subsequently, a combined population PK model was established and the correlations between the PK of PIP and TAZ were tested. Monte Carlo simulations were performed based on the final combined model to evaluate the current dosing recommendations. The final combined model for PIP/TAZ consisted of four compartments (two for each drug), with covariates including TBW, PMA, and SCR. For a 70-kg, 35-year-old patient with SCR of 0.83mgL-1, the PIP values for V1, CL, V2 and Q2 were 10.4L, 10.6Lh-1, 11.6 L and 15.2Lh-1, respectively, and the TAZ values were 10.5 L, 9.58Lh-1, 13.7 L and 16.8Lh-1, respectively. The CL for both drugs show maturation in early life, reaching 50% at 54.2weeks PMA. With advancing age, CL of TAZ declines to 50% at 61.6years PMA, whereas CL of PIP declines more slowly, reaching 50% at 89.1 years PMA. The fUNB_PIP was estimated as 64.5% and non-linear elimination was not supported by our data. The simulation results indicated considerable differences in PK/PD target attainment for different patient populations under current recommended dosing regimens. We developed a combined population PK model for PIP/TAZ across a broad range of patients covering the extremes of patient characteristics. This model can be used as a robust a priori model for Bayesian forecasting to achieve individualised dosing. The simulations indicate that adjustments based on the allometric theory as well as maturation and decline of CL of PIP may help the current dosing recommendations to provide consistent target attainment across patient populations.