1084. Comparative Outcomes Among Patients Receiving Varying Daptomycin Dosing Regimens in Hemodialysis

Abstract Background Daptomycin (DAP) has become an appealing treatment option for gram-positive infections, which are common in patients receiving hemodialysis (HD), due to frequent access and manipulation. The approved DAP dosing of 4 to 6 mg/kg every 48 hours (q48h) quickly becomes desynchronized from the patient’s HD schedule and requires the burden of additional IV access. Previous pharmacokinetic studies have suggested that DAP can be dosed three-times weekly following HD, but no studies have evaluated clinical outcomes of this regimen. Methods This was a multi-center, retrospective cohort study across 6 hospitals in the United States. Adult, nonpregnant patients who received HD and DAP between 2015 and 2020 were screened for inclusion. Electronic medical records were reviewed for relevant study data. The primary outcome was clinical and microbiological outcomes among patients who received DAP thrice weekly versus q48h dosing. Microbiological Failure was defined as positive cultures after 7 days and further study definitions are included under Table 3. Results Baseline characteristics are summarized in Table 1. Length of stay was similar between both groups at a median of 25 days and patients had a median QPitt score of 0 on admission. The average DAP dose used was 7 mg/kg and 7mg-7mg-9mg on HD days in the q48h dosing and thrice weekly dosing regimens, respectively. The majority of patients had bacteremia and the most commonly isolated bacteria was methicillin-resistant Staphylococcus aureus. No differences in clinical outcomes were observed (p=0.87). Microbiological failure was higher among patients who received DAP thrice weekly compared to q48h dosing (69.2% vs 34.8%, p=0.047). Conclusion DAP dosed thrice weekly on HD days offers similar clinical resolution compared to q48h dosing. While the thrice weekly dosing regimen did have a significantly higher rate of microbiological failure, the analysis was limited by a small sample size. As this is a retrospective analysis not accounting for confounding variables, additional prospective studies are warranted to confirm these findings. Disclosures Wesley D. Kufel, PharmD, Melinta (Research Grant or Support)Merck (Research Grant or Support)Theratechnologies, Inc. (Advisor or Review Panel member) P. Brandon Bookstaver, Pharm D, ALK Abello, Inc. (Grant/Research Support, Advisor or Review Panel member)Biomerieux (Speaker's Bureau)Kedrion Biopharma (Grant/Research Support, Advisor or Review Panel member)


Session: P-61. Novel Agents
Background. LBP-EC01 is the first CRISPR-engineered bacteriophage product to successfully complete Phase 1b testing in a clinical program designed to address infections caused by E. coli initially targeting urinary tract infections (UTIs). Thirtysix subjects were enrolled in this randomized, double blind study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of LBP-EC01 in patients with lower urinary tract colonization caused by E. coli.
Methods. N/A Results. No drug-related Treatment Emergent Adverse Events (TEAEs) were observed. All nondrug related TEAEs were Grade 2 or below and there were no tolerability signals associated with LBP-EC01.A modified ITT (mITT) population was defined to assess PK in subjects treated with LBP-EC01 (n=17). Subjects were removed from the PK analysis who had missing or insufficient colonization at baseline (n=3), were exposed to antibiotics during screening or study conduct (n=3) or exhibited a nondrug related SAE (n=1). Of these subjects, 12 were found to be sensitive to LBP-EC01 and of these, 10 (83%) showed phage amplification. A PD analysis compared the mITT populations of LBP-EC01 vs. placebo (n=6) and showed that the LBP-EC01 arm had a decrease in E. coli that was greatest within 24 hours of initial treatment and remained below baseline across the entire treatment period. The placebo arm showed increased levels of E. coli and higher variability over the treatment period. An average difference of 2-3 log (100x to 1,000x) existed in urine E. coli concentration (CFU/mL) between the LBP-EC01 and placebo arms across the duration of the treatment period.
Conclusion. LBP-EC01 has proved to be safe and well-tolerated in this Phase 1b study of subjects colonized by E. coli. In addition, phage amplification was observed in patients with E. coli isolates sensitive to LBP-EC01, demonstrating a clear proof of mechanism. Finally, the apparent difference in PD effect between LBP-EC01 and placebo which was irrespective of MDR status, provides promise that LBP-EC01 may someday be an excellent option for patients suffering from UTIs caused by E. coli, especially in strains that are resistant to conventional antibiotics.
Disclosures. Dave ousterout, PhD, InceptorBio (Advisor or Review Panel member, Shareholder)Locus Biosciences (Employee, Shareholder) Creighton University Schools of Medicine and Pharmacy, MDstewardship, Omaha, Nebraska; 5 Guthrie Robert Packer Hospital, Sayre, Pennsylvania; 6 CHI Health -Creighton University Medical Center -Bergan Mercy, Omaha, Nebraska; 7 University of South Carolina College of Pharmacy, Columbia, SC; 8 Rutgers, The State University of New Jersey, Asbury Park, New Jersey; 9 County of Santa Clara Health System, San Jose, California; 10 Touro College of Pharmacy, New York, NY Session: P-62. PK/PD Studies Background. Daptomycin (DAP) has become an appealing treatment option for gram-positive infections, which are common in patients receiving hemodialysis (HD), due to frequent access and manipulation. The approved DAP dosing of 4 to 6 mg/kg every 48 hours (q48h) quickly becomes desynchronized from the patient's HD schedule and requires the burden of additional IV access. Previous pharmacokinetic studies have suggested that DAP can be dosed three-times weekly following HD, but no studies have evaluated clinical outcomes of this regimen.

Comparative Outcomes Among Patients Receiving Varying Daptomycin Dosing Regimens in Hemodialysis
Methods. This was a multi-center, retrospective cohort study across 6 hospitals in the United States. Adult, nonpregnant patients who received HD and DAP between 2015 and 2020 were screened for inclusion. Electronic medical records were reviewed for relevant study data. The primary outcome was clinical and microbiological outcomes among patients who received DAP thrice weekly versus q48h dosing. Microbiological Failure was defined as positive cultures after 7 days and further study definitions are included under Table 3.
Results. Baseline characteristics are summarized in Table 1. Length of stay was similar between both groups at a median of 25 days and patients had a median QPitt score of 0 on admission. The average DAP dose used was 7 mg/kg and 7mg-7mg-9mg on HD days in the q48h dosing and thrice weekly dosing regimens, respectively. The majority of patients had bacteremia and the most commonly isolated bacteria was methicillin-resistant Staphylococcus aureus. No differences in clinical outcomes were observed (p=0.87). Microbiological failure was higher among patients who received DAP thrice weekly compared to q48h dosing (69.2% vs 34.8%, p=0.047).
Conclusion. DAP dosed thrice weekly on HD days offers similar clinical resolution compared to q48h dosing. While the thrice weekly dosing regimen did have a significantly higher rate of microbiological failure, the analysis was limited by a small sample size. As this is a retrospective analysis not accounting for confounding variables, additional prospective studies are warranted to confirm these findings. Background. Recent changes to vancomycin guidelines recommend dosing by targeting an AUC of 400-600 in most patients, due to similar effectiveness and reduced rates of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine of ≥ 0.5 mg/dl, a 50% increase in serum creatinine from baseline on two consecutive readings, or a decrease in creatinine clearance from 50% from baseline on two consecutive readings. The purpose of this study was to assess the incidence of AKI in patients receiving vancomycin dosed by AUC based trough goals and vancomycin dosed by traditional trough goals (15-20 mcg/mL) in the outpatient setting.

Disclosures
Methods. This study was performed by retrospective chart review using the electronic health record. Patients receiving vancomycin outpatient as continuation of therapy after discharge from December 1, 2018 through March 24, 2021 were reviewed. The primary objective was incidence of AKI in patients receiving vancomycin outpatient with trough goals derived from patient specific AUC calculations compared to patients receiving vancomycin by traditional goal troughs. Secondary objectives included rate of treatment failure, average AUC estimated trough range, and number of regimen changes required.
Results. There were a total of 65 patients in the traditional trough dosing group and 53 patients in the AUC trough dosing group. The incidence of AKI was higher in the traditional trough dosing group compared to the AUC trough group (23.1% vs 5.7%; p=0.01). There were no differences in incidence of treatment failure. The mean AUC estimated trough range was 11.4-16.9 mcg/mL. There were significantly less average regimen changes required in the AUC dosing group (1.64 vs 1.13; p=0.006). Patients receiving AUC trough dosing were 78% less likely to develop AKI as patients receiving traditional trough dosing (HR 0.221, 95%CI 0.051 -0.968).
Conclusion. There was a significantly lower incidence of AKI in patients receiving vancomycin dosed by AUC based troughs compared to traditional trough dosing. Continuing AUC trough based dosing for vancomycin in the outpatient setting is convenient and may lead to reduced rates of AKI.

A Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model that a priori Predicts Intramuscular (IM) Pharmacokinetics of ADG20: an Extended Half-life Monoclonal Antibody Being Developed for the Treatment and Prevention of Coronavirus Disease (COVID-19)
Scott A. Van Wart, PhD 1 ; Evan D. Tarbell, PhD 1 ; Donald E. Mager, PhD 2 ; Dhaval K. Shah, PhD 2 ; Lynn E. Connolly, MD, PhD 3 ; Paul G. Ambrose, PharmD 3 ; 1 Enhanced Pharmacodynamics LLC, Buffalo, New York; 2 University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York; 3 Adagio Therapeutics, Inc., Waltham, Massachusetts Session: P-62. PK/PD Studies Background. ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and additional SARS-like CoVs with pandemic potential and an extended half-life. A QSP/PBPK model was constructed using ADG20-specific physiochemical properties and published non-human primate (NHP) and human PK data for other antibodies; it was used to a priori predict and confirm NHP and human PK.
Methods. An existing QSP/PBPK model was modified to include 3 distinct lung sub-compartments: upper airway, lower airway, and alveolar tissue ( Figure A). Each sub-compartment ( Figure B) contained an epithelial lining fluid (ELF) space ( Figure  B). The model was fit separately to digitized NHP and human serum PK data for 7 extended half-life antibodies to estimate the apparent neonatal Fc receptor (FcRn) binding affinity (K D,FcRn ) and bioavailability by drug. Nasopharyngeal swab (upper airway) and lung (lower airway) ELF PK data from 4 additional antibodies were used to optimize a single rate constant for transcytosis in lung. Patches of positive charge was a covariate on the rate of pinocytosis of antibody entry and exit from the endosomal space ( Figure B). Observed NHP (ADG20 10 mg/kg IM) and human (ADG20 300 mg IM) PK data collected over the initial 21 days post dose were compared with model forecasts from a 1000-iteration simulation.
Results. The distribution of fitted NHP K D,FcRn provided accurate predictions of NHP serum PK data ( Figure C). NHP ADG20 K D,FcRn was optimized to be 35.7 nM and human ADG20 K D,FcRn (9.55 nM) was derived using a mean NHP:human K D,FcRn ratio of 3.74 across antibodies. Model-based simulated human serum PK data using inter-subject variability from NHP and actual weight distribution from an ongoing Phase 1 study aligned with initial 21-day data ( Figure D). Using an adult CDC weight distribution (45-150 kg), the simulated median exceeded 74 days.
Conclusion. The QSP/PBPK model a priori predicted NHP and human ADG20 PK. This innovative QSP-based modeling and simulation approach enabled the evaluation of candidate dose regimens prior to the availability of PK data, supporting the rapid advancement of the ADG20 clinical program during the COVID-19 pandemic. Figure. Overview of the QSP/PBPK model (A) Tissue-level diagram. (B) Cellular-level diagram specifically for the upper airway, lower airway, and alveolar spaces within the lung. (C) Predicted median ADG20 concentration in NHP serum following a single ADG20 10 mg/kg IM dose with observed NHP ADG20 concentration data overlaid (black dots). The shaded area represents the 90% prediction interval. (D) Predicted median human serum and ELF PK in humans following a single ADG20 300 mg IM dose with observed human serum (red line) ADG20 concentration data overlaid (black dots), ELF upper airway (blue line), and ELF lower airway (gold). The shaded area represents the 90% prediction interval. CLup, rate of pinocytosis of antibody entry and exit from the endosomal space; CLup_epi, rate of pinocytosis of antibody entry and exit from the epithelial space; FR, fraction of FcRn bound antibody that recycles to the vascular space; L, lymphatic flow rate; LG, large, kdeg, degradation constant; koff, first-order dissociation rate constant of antibody from FcRn; kon, second-order association rate constant for binding of antibody to FcRn; Q, blood or tissue flow rate; SM, small.