Dosing Interval Research Articles

Model-informed dose optimization for prophylactic piperacillin-tazobactam in perioperative pediatric critically ill patients.

Piperacillin/tazobactam (PTZ) is frequently prescribed during the perioperative period as prophylaxis in critically ill patients. Current international guidelines recommend that the pediatric intraoperative dosing regimen for PTZ be 90-112.5 mg/kg (80-100 mg/kg as piperacillin [PIP]) administered every 2 hours (Q2H). Concerns have been raised not only about the risk of nephrotoxicity due to elevated PIP exposure but also regarding the practicality of adhering to a 2-h dosing interval in clinical settings. To address these concerns, we employed population pharmacokinetic (PK) modeling and simulation approaches to optimize PTZ dosing regimens in pediatric intraoperative patients. PIP plasma concentration data were obtained from 34 patients using an opportunistic sampling strategy. A two-compartment model was found to adequately describe the PK data. Creatinine clearance was identified as a significant covariate on clearance. The inclusion of inter-occasion variability significantly improved model fit. Simulations across body weights of 10-70 kg and creatinine clearance of 20-130 mL/min/1.73 m2 demonstrated that 6-15 mg/kg Q2H, or a 10 mg/kg loading dose followed by 1.0-2.75 mg/kg/h continuous infusion would achieve free PIP concentrations being above the minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT >1× MIC). For achieving 100% fT >4× MIC, 25-55 mg/kg Q2H or a 20 mg/kg loading dose followed by 3.25-9.25 mg/kg/h continuous infusion was derived. The model-informed simulations indicated that both lower Q2H doses and continuous infusion methods are clinically viable options and potentially resolve current clinical challenges during intraoperative dosing.

Pulmonary disposition and pharmacokinetics of a single oral dose of chloramphenicol in healthy fasted adult horses.

To describe and compare the pulmonary and plasma pharmacokinetics of different oral formulations of chloramphenicol administered as a single dose to healthy adult horses. A single dose of chloramphenicol was administered to 6 healthy, university-owned fasted adult horses IV (25 mg/kg), orally as commercial tablets (50 mg/kg), or orally or intragastrically as compounded suspension (50 mg/kg), according to a randomized crossover protocol. Plasma was collected 5, 10, 15, 20, and 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after drug administration. Bronchoalveolar lavage (BAL) fluid was collected after 1, 4, and 8 hours and processed to obtain pulmonary epithelial lining fluid (PELF) and the BAL cell pellet (BALc). Chloramphenicol concentrations were determined by means of liquid chromatography-tandem mass spectrometry in plasma, PELF, and BALc. Data were used for plasma noncompartmental analysis and calculation of apparent PELF and BALc concentrations. Chloramphenicol concentrations were higher in the PELF than in plasma, irrespective of formulation and administration route (IV, orally, or intragastrically). Compounded suspension administered intragastrically yielded higher maximum concentration and drug exposure than administered orally, with a relative bioavailability of 79%. After oral administration, no significant differences were found between compounded suspension and commercial tablets. Oral administration of chloramphenicol achieved pulmonary concentrations ≥ 2 and 4 µg/mL for at least 4 hours (50% to 75% of a 6- to 8-hour dosing interval) in 4 out of 5 treated horses. Pulmonary pharmacokinetics can be used by practitioners to judiciously select an antimicrobial for the treatment of complex equine pneumonia cases.

Efficacy, safety, and pharmacokinetics of lenacapavir oral bridging when subcutaneous lenacapavir cannot be administered.

To assess efficacy, safety and pharmacokinetics (PK) of oral lenacapavir (LEN) when used as oral bridging (OB) between delayed subcutaneous (SC) LEN injections. Posthoc analysis of participants in two clinical trials of SC LEN for HIV-1 treatment who required OB when LEN SC dosing was interrupted. Oral LEN [300 mg once weekly (QW)] was initiated within 2 weeks of the next scheduled injection (dosing interval: 26 weeks). Efficacy, safety, and PK were assessed every 10-12 weeks. Overall, 139 participants received ≥1 dose of oral 300 mg QW LEN plus other antiretrovirals. Median duration of OB was 19 weeks in both clinical trials. By missing = excluded analysis, over 95% of participants maintained virologic suppression (HIV-1 RNA <50 copies/ml) at Weeks 10, 20, and 30. Treatment-emergent AEs (TEAEs) were similar to those with SC LEN (excluding injection site reactions). No Grade ≥3 or serious TEAEs were considered related to oral LEN. Throughout OB, mean LEN plasma concentrations and lower bound 90% confidence intervals (CIs) were consistently above inhibitory quotient 4 (4-fold in-vitro protein binding-adjusted 95% effective concentration). OB adherence (by pill count) was ≥95% in the majority of participants in both clinical trials. High rates of virological suppression were maintained during OB. Oral 300 mg QW LEN was well tolerated and provided adequate plasma concentrations to bridge SC LEN dosing. This analysis supports using 300 mg QW LEN for OB when SC LEN treatment is interrupted.

Long-Acting, Longer-Acting, and Ultralong-Acting Antiobesity Peptides.

This perspective describes the current status and future prospects of developing long- to ultralong-acting anti-obesity peptides. First, we discuss the current status of lipidation, PEGylation, and Fc fusion technologies to obtain long-acting peptides administered once weekly, and we critique their proposed use for longer dosing intervals. Next, we describe the approach and current results of using macromolecular peptide prodrugs with preprogrammed releasable linkers to achieve longer-acting peptides that can be administered weekly or monthly. Finally, we posit novel modifications of the latter technology that could provide ultralong half-lives of over one month by advantageously exploiting the clearance rates of released peptides. As examples, we posit that prodrugs of low-clearance GLP-1 agonists derived from peptides already modified by lipidation, PEGylation, and Fc fusion could produce ultralong-acting agonists with dosing intervals reaching 3 to even 6 months.

Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for Screening Antifungal Exposure in Intensive Care Units-the SAFE-ICU study.

Appropriate antifungal therapy is a major determinant of survival in critically ill patients with invasive fungal disease. We sought to describe whether contemporary dosing of antifungals achieves therapeutic exposures in critically ill patients. In a prospective, open-label, multicenter pharmacokinetic study, intensive care unit (ICU) patients prescribed azoles, echinocandins, or polyene antifungals for treatment or prophylaxis of invasive fungal disease were enrolled. Blood samples were collected on two occasions, with three samples taken during a single dosing interval on each occasion. Total concentrations were centrally measured using validated chromatographic methods. Pharmacokinetic parameters were estimated using noncompartmental methods. Antifungal dosing adequacy was assessed using predefined PK/PD targets. We included 339 patients from 30 ICUs across 12 countries. Median age 62 (interquartile range [IQR], 51-70) years, median APACHE II score 22 (IQR, 17-28), and 61% males. Antifungal therapy was primarily prescribed for treatment (80.8%). Fluconazole was the most frequently prescribed antifungal (40.7%). The most common indication for treatment was intra-abdominal infection (30.7%). Fungi were identified in 45% of patients, of which only 26% had a minimum inhibitory concentration available. Target attainment was higher for patients receiving prophylaxis (> 80% for most drugs). For patients receiving treatment, low target attainment was noted for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%) and amphotericin B (41.7%). This study highlights the varying degrees of target attainment across antifungal agents in critically ill patients. While a significant proportion of patients achieved the predefined PK/PD targets, wide variability and subtherapeutic exposures persist. ClinicalTrials.gov Identifier: NCT03136926, 2017-04-21.

Pharmacokinetics of Tylvalosin Following Intravenous or Oral Administration at Different Doses in Broiler Chickens

Tylvalosin is a macrolide antimicrobial with antibacterial activity against Gram-positive bacteria, some Gram-negative organisms, and mycoplasma. It is used to treat respiratory and enteric bacterial infections in swine and poultry. In this study, we aimed to investigate the pharmacokinetic changes in tylvalosin following its intravenous or oral administration at doses of 5, 10, and 25 mg/kg in broiler chickens. Forty-eight broiler chickens were included in the study. The plasma concentrations of tylvalosin were measured by using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS), and its pharmacokinetic parameters were evaluated by using both non-compartmental and compartmental analyses. The linear mixed-effects model revealed no dose proportionality within the 5–25 mg/kg range for either administration route. Based on pharmacokinetic data from a single oral dose, this study simulated a multiple-dose regimen of tylvalosin (25 mg/kg), demonstrating that a 6-hour dosing interval reaches a steady state after the fourth dose. Furthermore, the results show that the absolute bioavailability of tylvalosin after oral administration in chickens was relatively low, with values of 5.92%, 3.56%, and 3.04% for the doses of 5, 10, and 25 mg/kg, respectively. Further studies are required to significantly improve the oral bioavailability of tylvalosin and similar compounds through formulation optimization.

Multi-objective control to schedule therapies for acute viral infections.

Antiviral therapies can yield different outcomes depending on their scheduling: a highly effective drug may produce treatment results ranging from successful to inconsequential, depending on therapeutic timing, dosing intervals, and dosage. The effectiveness of antiviral therapies can be assessed using mathematical models that describe viral spread within a host. In this work, we conduct a study based on the dynamic characterization of a target-cell model to address a multi-objective control problem aimed at designing highly effective and host-customizable antiviral therapies. These therapies involve finite-time antiviral treatments that minimize the viral load peak and the infection final size until infection clearance, while simultaneously reducing the total amount of drug intake as much as possible. Two optimization-based control strategies are proposed: a fixed-dose and a variable-dose approach. The variable-dose strategy achieves superior performance by explicitly considering the system dynamics in the design of the control. Simulation results, based on an identified model for COVID-19 patients treated with Paxlovid, illustrate the potential benefits of the proposed strategies.

Alternative dosing regimens of tislelizumab proposed using modeling and simulation.

394 Background: Tislelizumab (TIS; BGB-A317) is approved for the treatment of multiple solid tumors, administered at 200 mg every 3 weeks (Q3W), and has demonstrated a flat exposure–response relationship across a wide range of doses. We evaluated alternative dosing regimens of TIS at 150 mg every 2 weeks (Q2W), 300 mg every 4 weeks (Q4W), and 400 mg every 6 weeks (Q6W) using a model-based approach with the aim of alleviating patient burden by providing longer dosing intervals and/or treatment flexibility compatible with background chemotherapy to meet the needs of patients and healthcare practitioners. Methods: A previously developed population pharmacokinetic (PK) model was used for simulating PK exposure of the alternative regimens, which were selected by exposure-matching to the reference dose of 200 mg Q3W. PK-based criteria (peak concentration [C max ] within 25% and trough concentration [C trough ] within 20% of the reference dose) were also used. Alternative dosing regimen exposures in the first least common time interval and at steady state were compared with the reference. Deviations from PK-based criteria were bridged using appropriate safety and efficacy references and exposure–response analyses using data from four phase 1, 2, and 3 clinical trials of TIS in patients with solid tumors, including gastric cancer and esophageal squamous cell carcinoma. Results: Simulations at steady state shown here demonstrate that the TIS alternative dosing regimens of 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W produce comparable exposures to the 200 mg Q3W reference regimen. Although the simulated C max at 300 mg Q4W and 400 mg Q6W were higher than with the 200 mg Q3W reference dose, these were below the C max of the 5 mg/kg Q3W safety reference (Table). And while the C trough for the 400 mg Q6W dosing regimen was lower than with the 200 mg Q3W reference dose, it was 10.7% higher compared with the 2 mg/kg efficacy reference dose; therefore, it was within the concentration range where a flat exposure–efficacy relationship of TIS has previously been established. Conclusions: TIS alternative dosing regimens of 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W are expected to result in similar safety and efficacy profiles as the 200 mg Q3W reference dosing regimen and may be used interchangeably for indications where 200 mg Q3W is approved. Clinical trial information: NCT04716634 , NCT05014828 , NCT04379635 , NCT02407990 , NCT04068519 , NCT03430843 and NCT03358875 . Steady-state PK exposure metrics for alternative TIS doses vs reference doses. Parameter 150 mg Q2W vs 200 mg Q3W 300 mg Q4Wvs 200 mg Q3W 300 mg Q4Wvs 5 mg/kg Q3W a 400 mg Q6Wvs 200 mg Q3W 400 mg Q6Wvs 5 mg/kg Q3W a 400 mg Q6Wvs 2 mg/kg Q3W b C max −5.8 (Yes) 31.4 (No) −18.7 (Yes) 52.2 (No) −5.8 (Yes) – C average 12.3 (Yes) 12.6 (Yes) – 0.4 (Yes) – – C trough 27.2 (Yes) 0.1 (Yes) – −28.4 (No) – 10.7 (Yes) Data are presented as difference (% = [GM test − GM reference /GM reference ] × 100) vs the 200 mg Q3W reference, a safety reference, or b efficacy reference (meets regulatory criteria, Yes/No). C average , average concentration; GM, geometric mean.

Population Pharmacokinetics and Transfer of Gabapentin When Used as a Pain Adjunct for Cesarean Deliveries.

Enhanced Recovery After Surgery (ERAS) protocols for cesarean deliveries (CDs) utilize multimodal pain management strategies that often include gabapentin. While gabapentin is excreted in breast milk, its pharmacokinetics in immediately postpartum lactating women are not known. This observational pharmacokinetic study (NCT05099484) enrolled 21 healthy singleton pregnant individuals, ≥ 18 years old, undergoing CD and planning to breastfeed. Participants received 300 mg oral gabapentin before CD and every 6 h for 48 h per hospital protocol. Serial maternal plasma and breast milk samples were collected over a single dosing interval. Gabapentin pharmacokinetics were assessed using two structurally distinct population pharmacokinetic (POPPK) models to describe transfer of drug into breast milk utilizing (A) milk-to-plasma ratio and (B) inter-compartmental rate constants. These models were then used to estimate exposure to breastfed infants. Postpartum gabapentin plasma concentrations fit a 1-compartment model that was adapted to include breast milk concentrations. The two POPPK models both estimated relative infant doses (RID0-48h) of gabapentin < 0.15% of maternal dose within the first 48 h postpartum. Infant daily dose (IDD) from 24 to 48 h was estimated to be 0.0137 (0.0058-0.0316) mg/kg/day and 0.0139 (0.00041-0.0469) mg/kg/day by models A and B, respectively. These findings indicate limited neonatal exposure to gabapentin administered as part of a postpartum enhanced recovery after surgery protocol.

P-1238. Assessment of Body Weight upon PK of Olorofim in Patients with Invasive Mould Infections

Abstract Background Olorofim (OLO) is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans [LoPro]), and dimorphic moulds. Potential impact of bodyweight upon systemic exposure was explored using pharmacokinetic (PK) data from a Phase IIb study and PB (physiologically-based) PK modelling. Methods Adult patients in the Phase IIb study (N=203) received OLO (30 mg tablets) at a nominal dose of 90 mg BID and OLO PK profiles were determined over 1 or 2 dosing intervals after 7 to 14 days dosing, with an additional 8 to 9 scheduled pre-dose samples taken over the initial 84 days. A PBPK model was developed using both in vitro and in vivo data where oxidative cytochrome P450 (CYP)-mediated metabolism was determined to be the major pathway of olorofim clearance. The model was verified via demonstration of good independent recovery of observed systemic exposure in the presence and absence of CYP inhibitors and inducers and applied to the prediction of exposure in obese and morbidly obese subjects. Results Of the 168 patients with Invasive Fungal Infection (IFI), known body mass index (BMI) and full PK data over a dosing interval, 48% were normal body weight, 13 to 21% were classed as underweight, overweight or obese, with 1.8% classified as morbidly obese. Steady state systemic exposure (as determined by non-compartmental PK analysis) was similar across all BMI ranges (Table 1), apart from morbidly obese. The apparently higher mean exposure for morbidly obese is based on N=3 and values fall within the range seen for all other groups. These results agree with PBPK modelling which predicted negligible to mild increases in total plasma olorofim AUC and Cmax values in obese subjects (geometric mean ratios for normal to obese of up to 1.25-fold), whereas a negligible change was predicted in morbidly obese subjects (which further suggests that the observed elevation in exposure in morbidly obese is artefactual likely driven by limited number for this subject population). Conclusion As systemic exposure in adults with IFI was similar across a range of BMIs, dose adjustment based on body weight is not required when treating obese or morbidly obese patients. Disclosures Karen Cornelissen, PhD, F2G: Stocks/Bonds (Private Company) John H. Rex, MD, F2G: Employee Daniela Zinzi, MD. Infectious Diseases Specialist, VP Clinical R&amp;D at F2G: Stocks/Bonds (Private Company)

P-1682. Evaluation of Antibiotic Prescribing Practices for Pediatric Acute Otitis Media and Community-Acquired Pneumonia in an Emergency Department

Abstract Background Acute otitis media (AOM) and community-acquired pneumonia (CAP) are common reasons for antibiotic prescriptions in children. As a result, antimicrobial stewardship efforts ensuring evidence-informed antibiotic prescriptions may be impactful. The objective of this study was to assess whether antibiotic prescriptions for AOM and CAP in a pediatric emergency department (ED) are consistent with current guidelines, and to identify opportunities for improvement. Duration of antibiotics prescribed for acute otitis media Bar graph depicting prescribed durations of therapy for acute otitis media, Prescriptions consistent with current guideline recommendations are in blue, while those that aren’t are in orange. Guidelines advise 10 days, rather than 5 days, of antibiotic therapy for children &amp;lt;2, perforated otitis media, treatment failure and recurrent otitis media. Methods We conducted a retrospective review of outpatient antibiotic prescriptions for AOM and CAP in the ED of a pediatric hospital from September 2022 to September 2023. Patients ages 0 – 18 years discharged from the ED with a diagnosis of AOM or CAP were identified using the electronic medical record system. Exclusion criteria included absence of a new antibiotic prescription, concomitant infections requiring antibiotic treatment, hospital admission, and patients with immunocompromising conditions or medications. Prescriptions were considered consistent with guidelines if they followed the Canadian Paediatric Society recommendations. Descriptive statistics were used for analysis. Duration of antibiotics prescribed for community-acquired pneumonia Bar graph depicting prescribed durations of therapy for community-acquired pneumonia. Prescriptions consistent with current guideline recommendations are in blue, while those that aren’t are in orange. Results A total of 1143 and 765 cases of AOM and CAP were included, respectively. Of the prescriptions for AOM, 688 (60%) were consistent with current guidelines. The 454 prescriptions that were not guideline-consistent were due to duration (n=281, 62%, Figure 1), dosing interval (n=142, 31%), antibiotic selection (n=74, 16%), and dose (n=38, 8.4%). Deferred prescriptions were provided to 177 (16%) patients; an additional 139 (12%) were eligible, but prescribed treatment. For CAP, 146 (19%) prescriptions were consistent with current guidelines. Of the 618 prescriptions that were not consistent, the majority were due to duration (n=576, 92%, Figure 2), dosing interval (n=134, 22%), antibiotic selection (n=38, 6%) and dose (n=14, 2%). Conclusion A significant number of patients with AOM (40%) and CAP (79%) were given antibiotic prescriptions that were not consistent with current guideline recommendations, with the most common reason being prolonged duration. This identifies an important antimicrobial stewardship opportunity in the ED and likely other outpatient settings. Disclosures Kathryn E. Timberlake, PharmD, Avir Pharma: Advisor/Consultant|Sanofi: Honoraria|Wolters Kluwer: Advisor/Consultant

P-590. Impact of Pharmacoenhancers on the Pharmacokinetics and Safety of Lenacapavir in People with HIV

Abstract Background Lenacapavir (LEN) is approved for treatment of multidrug-resistant HIV-1 in combination with other antiretrovirals in heavily treatment-experienced (HTE) people with HIV (PWH). In the pivotal Phase 2/3 CAPELLA study (NCT04150068), participants (N=72) received oral LEN loading doses (Days 1 and 2: 600 mg; Day 8: 300 mg), followed by a 927 mg subcutaneous (SC) maintenance dose given every 6 months (Q6M) starting from Day 15. LEN is a substrate of P-gp (P-glycoprotein), CYP (Cytochrome P450) 3A and UGT (UDP-glucuronosyltransferase) 1A1; pharmacoenhancers/boosters such as cobicistat and ritonavir inhibit P-gp and CYP3A and are likely to affect LEN PK. As boosted protease inhibitors are commonly used in HTE PWH, we evaluated the impact of pharmacoenhancers on LEN PK and safety in PWH from the CAPELLA study.Figure 1:LEN Ctrough following (A) oral loading period (Day 15), and (B) SC injection (Week 26), with and without pharmacoenhancers Horizontal lines of the box represent the median with its interquartile, and error bars represent the range. Median values are indicated in individual plots. Methods Sparse PK samples were collected during the oral loading and the maintenance periods in the CAPELLA study. LEN plasma concentrations were summarized in participants receiving background regimens with or without pharmacoenhancers, at the end of oral loading period on Day 15 (N=45 and N=27; respectively) and at the end of first dosing interval at Week 26 (N=42 and N=30; respectively). Treatment emergent adverse events (AE) were assessed among participants receiving background regimens with or without pharmacoenhancers. Results Following oral loading of LEN (Days 1, 2 and 8), Day 15 median Ctrough were 61.1 and 27.0 ng/mL with and without pharmacoenhancers, respectively. Following SC dose on Day 15, median Ctrough at the end of Week 26 were 36.2 ng/mL and 24.7 ng/mL with and without pharmacoenhancers, respectively. The safety profile of LEN with or without pharmacoenhancers was generally similar (respectively: LEN-related AEs, 61.9% vs. 63.3%). Conclusion Pharmacoenhancers led to a modest increase in LEN exposure, which was not considered clinically relevant. The safety profile of LEN with or without pharmacoenhancers was similar. LEN can be coadministered with background regimens containing pharmacoenhancers without dose adjustment. Disclosures Vamshi Jogiraju, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Naveed A. Shaik, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Furong Wang, n/a, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Hui Wang, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Hadas Dvory-Sobol, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Ramesh Palaparthy, PhD, Gilead Sciences, Inc.: 1475-US-PSP, 1475-WO-PCT, 1474-US-PSP, 1515-US-PSP, 1515-WO-PCT|Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Renu Singh, PhD, Gilead Sciences, Inc.: 1475-US-PSP, 1475-WO-PCT, 1474-US-PSP, 1515-US-PSP, 1515-WO-PCT|Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

P-2202. Immune response after hepatitis B vaccination among healthcare providers in Uzbekistan

Abstract Background About 2.5 million people in Uzbekistan have Hepatitis B virus (HBV). Mass HBV vaccination of healthcare providers was conducted in 2015 and 2022. Post-vaccination immunity testing was never performed. We aimed to estimate post-vaccination immune response and determine associated factors.Table 1.HBV tests and intepretation Methods We conducted a cross-sectional study in Tashkent in 2023. Participants were randomly-selected from a database of providers vaccinated in the 2015 and 2022 campaigns. Interviews and blood collection for hepatitis B surface antigen, anti-HBs, and core antigen testing was performed at the workplace (Table 1). We assessed differences in mean titers using the Kruskal-Wallis test and factors associated with protective immune response (anti-HBs ≥10mIU/mL) using multivariable Poisson regression expressed as adjusted prevalence ratios (aPR).Table 2.Characteristics of healthcare providers vaccinated against HBV, Uzbekistan Results Of 334 participants, 61% were vaccinated in 2015 and 39% in 2022 (Table 2). Average age was 40 years old (interquartile range:35–49 years), 87% were female, 52% were nurses, 53% worked in hospitals, and 9% had current or past HBV infection. Among those without prior infection (n=303), 71% had protective titers. Three-quarters (72%) had completed the entire 3-dose course, 21% had 2 doses, and 7% 1 dose; 41% followed recommended intervals between doses. Mean immune titers differed by age (68 mIU/mL among 19–32-year-olds vs 31 mIU/mL among &amp;gt;42-year-olds, p=0.021). The proportion with protective immunity did not differ by year vaccinated (70% in 2015 vs 71% in 2022), dose number (72% for those with 3 doses vs 67% with ≤2) or dose intervals (74% followed recommendation and 69% didn’t). Nurses and laboratorians were more likely than physicians to have protective immunity (aPR=1.11, 95% confidence intervals [CI]: 1.00–1.24, p=0.042 and aPR=1.13, CI:1.04–1.22, p=0.003, respectively), and primary care workers were less likely than hospital workers to be protected (aPR=0.91, CI:0.87-0.98, p=0.009) (Figure 1).Figure 1.Forest plot of factors associated with protective immunity following HBV vaccination among healthcare providers in Uzbekistan Conclusion A high proportion of healthcare providers remained unprotected after HBV vaccination in Uzbekistan, especially hospital workers and physicians. Strategies to increase compliance with vaccination schedules are needed. Adoption of post-vaccination immunity testing policy can identify providers that may require revaccination. Disclosures All Authors: No reported disclosures

Multiple-Dose Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Subcutaneous Rusfertide, a Hepcidin Mimetic, in Healthy Subjects.

Rusfertide, a peptide hepcidin mimetic, has shown efficacy in polycythemia vera. This trial investigated the multiple-dose pharmacokinetics, pharmacodynamics, and safety of once-weekly rusfertide 60mg for 5 weeks in healthy subjects. Subjects were randomized to subcutaneous injection in the abdomen, upper arm, or thigh. Eighteen subjects were enrolled, and 15 completed the study. Geometric mean peak rusfertide plasma concentrations (Cmax) following the first dose were 547, 387, and 560ng/mL following injection in the abdomen, thigh, and arm, respectively (P=.0054). There was no difference between injection sites in the rusfertide area under the plasma concentration-time curve (AUC) following the first dose (P ≥.179) or in the Cmax or AUC during the dosing interval following the last dose (P≥.238). Geometric mean accumulation (Dose 5/Dose 1) for AUC and Cmax was 1.5 and 1.2, respectively, and similar across injection sites. Mechanism-based decreases in serum iron, transferrin-iron saturation, hemoglobin, and hematocrit were noted following multiple doses. There were no differences between injection sites in the pharmacodynamic effect as measured by change from baseline in hematocrit values. There were no serious adverse events. Treatment-emergent adverse events in 2 or more subjects were injection-site reactions (erythema, induration, pruritus), fatigue, and headache. There were no clinically relevant findings in the safety laboratory parameters, vital signs, electrocardiograms, or physical examination. While a higher incidence of treatment-emergent adverse events was noted in these healthy participants following multiple doses of 60mg, rusfertide was generally well tolerated. There were no clinically meaningful differences in rusfertide pharmacokinetics or pharmacodynamics between injection sites.

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-1259. Transferring knowledge from gentamicin pharmacokinetics in neonates to other aminoglycosides

Abstract Background Gentamicin (GM) is frequently prescribed in the neonatal population, and its pharmacokinetics (PK) in this population are therefore well-studied. However, recent findings of diminished GM efficacy against Pseudomonas spp. have prompted increased use of other aminoglycosides with less well-defined PK, which poses a challenge for model-informed precision dosing (MIPD). Although ultimately the goal for dose individualization will be drug-specific models for neonatal patients, as an interim measure, this study investigates the performance of GM models in neonates receiving amikacin (AK) and tobramycin (TO). Patient Characteristics. Numbers are represented as counts or median (range) as appropriate. GA: gestational age; PMA: post-menstrual age; WT: weight; CR: creatinine. Methods Neonatal patient data entered into the InsightRX Nova model-informed precision dosing (MIPD) platform during routine clinical care were de-identified and analyzed retrospectively. Patients were included if their postnatal age was &amp;lt; 90 days or their postmenstrual age was &amp;lt; 44 weeks, received at least one dose of AK or TO and provided at least one therapeutic drug monitoring sample (TDM) within 48 hours of an administered dose. For each patient and for each model, samples were grouped by dosing interval and iteratively used to predict future levels using Bayesian forecasting, mimicking clinical implementation of MIPD. Prediction error was assessed using root mean square error (RMSE), mean percent error (MPE), and Accuracy, defined as percent of samples within 20% of predicted values or correctly identifying a trough under 1 mg/L. RMSE for aminoglycoside models developed on amikacin, gentamicin or tobramycin data sets and evaluated on clinical amikacin and tobramycin data sets. The best native performing model for each clinical data set serves as the reference model &amp; is listed first, with subsequent models ordered by best to worst performance. Asterisks denotes statistical significance relative to the reference model. Results Overall, 14 AK courses with 31 AK TDMs, and 48 TO courses with 63 TO TDMs were included in the analysis (Table 1). RMSE, MPE, and Accuracy are displayed in Figures 1-3. Data on TO peaks were excluded due to low sample size. Of the AK courses, most GM models outperformed available AK models for both peak and trough levels. Of the TO courses, GM models exhibited significantly improved RMSE and MPE values, as well as significantly higher rates of accuracy when predicting trough levels compared to those of the available TO model. Mean percent error for aminoglycoside models developed on amikacin, gentamicin or tobramycin data sets and evaluated on clinical amikacin and tobramycin data sets. The best native performing model for each clinical data set serves as the reference model &amp; is listed first, with subsequent models ordered by best to worst performance. Asterisks denotes statistical significance relative to the reference model. Conclusion PK models developed in neonates receiving GM match or outperform drug-specific models in predicting AK and TO exposures in neonates. Further research is needed to better understand model performance for TO peak levels in neonates and clinical implications of cross-module model use. Accuracy for aminoglycoside models developed on amikacin, gentamicin or tobramycin data sets and evaluated on clinical amikacin and tobramycin data sets. The best native performing model for each clinical data set serves as the reference model &amp; is listed first, with subsequent models ordered by best to worst performance. Asterisks denotes statistical significance relative to the reference model. Disclosures Tiffany Lee, PharmD, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company) Jasmine Hughes, PhD, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company) Jon Faldasz, PharmD, BCPS, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company)

P-1220. Humanizing Plasma and Pulmonary Epithelial Lining Fluid (ELF) Exposures of Cefiderocol in Standardized Murine Lung Infection Model

Abstract Background The clinical translation of preclinical in vivo murine infection models can be enhanced by humanizing exposures. However, humanizing plasma exposures does not ensure equivalent exposures at other target sites, such as the ELF, due to interspecies differences in penetration. We developed both plasma and ELF human simulated regimens (HSRs) of cefiderocol in a standardized murine lung infection model.Table 1.Cefiderocol %free time&amp;gt;MIC plasma profiles of mouse and man Methods In accordance with the collaboration for prevention and treatment of MDR bacterial infections (COMBINE) murine lung infection model, specific pathogen-free, 6-8 week old female CD-1 mice were rendered neutropenic and received a single 5 mg/kg IP injection of uranyl nitrate 3 days prior to inoculation. Under isoflurane anesthesia, mice were inoculated with 0.05 mL of a ∼108 CFU/mL bacterial suspension of Klebsiella pneumoniae via intranasal route. A historic cefiderocol plasma HSR from a murine thigh model was used as a baseline regimen. Two hours after inoculation, cefiderocol HSRs were administered. Groups of 6 mice were euthanized at predefined timepoints throughout the dosing interval for plasma and bronchoalveolar fluid collection. Samples were assayed by LC-MS/MS and urea correction was used to determine ELF concentrations. Murine plasma protein binding (32%) was determined previously and used to calculate free drug. Pharmacokinetic models for both plasma and ELF were fitted to the data in Phoenix WinNonlin and HSRs were mathematically altered and subsequently confirmed in the model.Figure 1.Free cefiderocol plasma concentration-time profiles in humans receiving 2g q8h as 3h infusion and mice receiving a human-simulated regimen. Results Cefiderocol 2g q8h 3h infusion plasma exposures were recapitulated in the murine model with 5, 7.5, 10, 3.5, and 1 mg/kg at 0, 1, 2, 4, and 6h, administered every 8h, as presented in Table/Figure 1. ELF penetration for cefiderocol was greater in infected mice relative to man, necessitating a dosage reduction to 3.75, 5, 6.25, 1.75, and 1 mg/kg at 0, 1, 2, 4, and 6h, administered every 8h, to humanize ELF exposures (Figure 2).Figure 2.Cefiderocol pulmonary epithelial lining fluid concentration-time profiles in humans receiving 2g q8h as 3h infusion and mice receiving a human-simulated regimen. Conclusion Plasma and ELF HSRs for cefiderocol were developed and validated in the COMBINE murine neutropenic lung infection model. Cefiderocol ELF penetration was greater in mice than man, underscoring the importance of understanding interspecies differences in target site penetration for bench-to-bedside translation. Disclosures Andrew J. Fratoni, PharmD, InsightRX: Grant/Research Support Erin Duffy, PhD, CARB-X: Employee 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

P-1243. Evaluation of Single and Multiple Dose Safety and Pharmacokinetics of Ledaborbactam Etzadroxil and Ceftibuten-Ledaborbactam Etzadroxil in Healthy Volunteers

Abstract Background Ledaborbactam etzadroxil (LED-E), a novel oral prodrug that converts to the active β-lactamase inhibitor ledaborbactam (LED), is being developed in combination with ceftibuten (CTB) to address the urgent need for new oral (PO) treatments against drug-resistant gram-negative infections. Methods In part 1, healthy participants (PT) received single (100mg to 1000mg) or multiple (75mg to 500mg q8h for 10 days) PO doses of LED-E or matching placebo (PBO); PTs in Part 2 received single doses of LED-E 500mg, CBT 400mg, and LED-E+CTB 500mg+400mg; Part 3 PT received LED-E+CTB 300mg+400mg, LED-E+CTB 500mg+400mg or PBO q8h for 10 days. Serial blood and urine samples were obtained to determine single dose and steady-state plasma PK of CTB, LED-E, and LED. Safety was assessed by recording adverse events (AE), and changes in laboratory, vital signs, and ECGs. Results AUC of LED-E was ≤ 2% of exposures of LED across the dose range tested, suggesting extensive conversion of the prodrug to the active drug. LED exposures increased in a generally dose proportional manner across single LED-E doses from 100mg to 1000mg and multiple doses from 75mg to 500mg q8h. The terminal half-life of LED in plasma is approximately 11-12 h, with 30-35% accumulation of LED following q8h dosing of LED-E. Excretion in urine of LED-E derived material was 84.4% over the 8-hour dosing interval at steady state. No clinically relevant changes in the pharmacokinetics of CTB, LED, or LED-E occurred when CTB and LED-E were co-administered compared to each administered alone (Table 1). The number of participants with treatment-emergent AEs (TEAE) was similar in the LED-E (+/- CTB) (81.7%) and PBO (77.8%) groups. Headache and nausea were the most frequently reported TEAEs in LED-E dosed PTs (Table 2). Most events were mild and only 1 TEAE led to drug discontinuation. No serious adverse events or deaths occurred. No clinical relevant changes were noted in clinical labs, ECGs, or vital signs Conclusion LED exposure increased in a dose proportional manner. No clinically relevant drug-drug interaction was observed between LED and CTB When LED-E and CTB are co-administered. LED-E was safe and well tolerated when given with CTB at multiple doses up to 1500mg daily for 10 days. Disclosures Carlos Fernando de Oliveira, MD, PhD, MS, Venatorx Pharmaceuticals: Stocks/Bonds (Private Company) Mary Beth Dorr, PhD, Merck: Stocks/Bonds (Public Company)|Pfizer: Stocks/Bonds (Public Company)|Venatorx: Stocks/Bonds (Private Company) Kathryn Lowe, MS, Venatorx Pharmaceuticals: Stocks/Bonds (Private Company) Gregory A. Winchell, PhD, Certara: Advisor/Consultant|Merck: Advisor/Consultant|Venatorx: Advisor/Consultant Paul McGovern, MD, Venatorx Pharmaceuticals, Inc.: employee|Venatorx Pharmaceuticals, Inc.: Stocks/Bonds (Private Company)

P-1152. Cefepime, Meropenem, and Piperacillin Therapeutic Drug Monitoring in Neonatal and Pediatric Patients

Abstract Background Pharmacokinetics of beta-lactams vary widely in neonatal and pediatric patients due to developmental biology and critical illness. Cefepime (FEP), meropenem (MEM), and piperacillin/tazobactam (TZP) are highly susceptible to pharmacokinetic changes as hydrophilic, small molecules with renal clearance. Subtherapeutic levels are associated with clinical and microbiologic failure, and supratherapeutic levels associated with toxicity. Beta-lactam therapeutic drug monitoring (TDM) may optimize the effectiveness and safety of these agents. The purpose of this investigation is to describe the % of pediatric and neonatal patients with beta-lactam serum levels within target range. Methods In August 2023, TDM launched at the Mayo Clinic Children’s Center for select patients treated with FEP, MEM, or TZP with expected durations ≥ 48 hours, or who were on kidney replacement therapy (KRT), extracorporeal membrane oxygenation (ECMO), weighed &amp;gt; 120 kg, had a BMI &amp;gt; 95th percentile, or at the discretion of pediatric ID team. Validated drug assays were performed daily, Monday through Friday. A two-level sampling strategy was preferred with a peak 1 hour after the end of the infusion and a trough 30 minutes before the next dose. Empiric trough target ranges were set at FEP 8-50 mg/L, MEM 2-30 mg/L, and piperacillin 16-150 mg/L. These target ranges were adjusted with confirmed microbiology to a time above the minimum inhibitory concentration of the organism for 100% of the dosing interval (100%T &amp;gt; MIC). Results From August 2023 to April 2024, 74 episodes of TDM were performed on 45 patients. Thirty-seven (82%) patients were in an intensive care unit (ICU) at the time of TDM, 8/45 (22%) of whom were in the neonatal ICU. Target range was achieved in 67% of patients on FEP, 50% on MEM, and 52% on TZP. Median (IQR) trough values were 22.1 (8.6, 44.2) mg/L for FEP, 0.6 (0, 4.1) mg/L for MEM, and 15.5 (3.8, 27.1) mg/L for TZP. Seven levels were above target for FEP and 0 for MEM and TZP. Seven levels were below target for FEP, 4 for MEM, and 11 for TZP. Conclusion Implementation of a TDM program for FEP, MEM and TZP in pediatric and neonatal patients revealed drug levels frequently outside target range. TDM may facilitate dose individualization to optimize medication efficacy and minimize toxicity. Disclosures Raymond Stetson, MD, MS, Moderna: Grant/Research Support Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member Erin F. Barreto, PharmD, MSc, Baxter Health: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant

Carboplatin and vinblastine monthly in optic pathway and hypothalamic gliomas: a retrospective analysis in a single institute

Abstract Objective Chemotherapy plays an important role in the treatment of optic pathway hypothalamic gliomas (OPHGs). Commonly used regimens include carboplatin and vincristine and monotherapy with vinblastine weekly. In this retrospective study, we used a monthly regimen of carboplatin and vinblastine to treat progressive/recurrent OPHGs and evaluated its effectiveness, visual preservation, and toxicity. Methods The study involved patients with OPGH who were treated with carboplatin and vinblastine once per month. The response, disease progression, overall survival, vision changes, and toxicity were recorded according to their medical charts at our institute, and survival was analyzed. Results A total of 25 patients were included, including 15 males (60%) and 10 females (40%). The response rate was 11/25 (44%), and the stabilization rate (complete response rate + partial response rate + minor response rate + and stable disease rate) was 21/25 (84%). The 3-year progression-free survival rate was 54.6%, and the 5-year progression-free survival rate was 46.8%. The 5-year overall survival rate was 100%. There were 6 patients who showed improved visual acuity (28.6%). Stable vision was found in 52.4% of patients. Only 2 patients experienced severe allergic reactions to carboplatin. Conclusions The results showed that extending the dosing interval of carboplatin and vinblastine to every month can be seen as a similar response compared with previous regimens. The toxicity of this regimen is milder, and patients benefit from a lower frequency of hospital visits. The regimen can be considered as a choice of the first line of chemotherapy for OPHG patients.