Plazomicin is an aminoglycoside with activity against multidrug-resistant Enterobacteriaceae Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24 h, with dose adjustments being made for renal impairment and a body weight (BW) of ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1 to 3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration-time profiles. The base structural model included creatinine clearance (CLCR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The ranges of the α-, β-, and γ-phase half-lives for the analysis population were 0.328 to 1.58, 2.77 to 5.38, and 25.8 to 36.5 h, respectively. Total and renal clearances in a typical cUTI or HABP/VABP patient were 4.57 and 4.08 liters/h, respectively. Starting dose adjustments for CLCR are sufficient for minimizing the variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a milligram-per-kilogram basis with adjustments for CLCR and BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renally impaired.
Abstract Background ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses. The goal of our analysis was to develop a QSP model in which ADI concentrations in upper airway (UA) epithelial lining fluid (ELF) were linked to a viral dynamic model to describe the impact of ADI on SARS-CoV-2 viral load relative to placebo. Methods The QSP model was fit in NONMEM Version 7.4 using PK data from a Phase 1 study (N=24, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE; N=659, IM) and treatment (STAMP; N=189, IM) studies. Saliva and NP samples were collected from STAMP study participants (pts) infected with the delta or omicron variants. The viral dynamic model was based on a published model and was modified to include both active (V) and deactivated (DV) virus (Fig). The viral dynamic model was fit to the NP swab viral load data (2 samples/pt) standardized to time since infection based upon recorded symptom onset. Saliva data (7-8 samples/pt) was fit sequentially using a biophase compartment given the peak viral load was modestly lower and peaked later than Day 1. Viral dynamic model (A) and simulated median (90% PI) NP viral load reduction in ADI-treated or placebo participants for delta (B) and omicron (C) variants Results The QSP model provided an excellent fit to serum ADI concentration-time data after estimation of a transit rate to account for IM absorption, plasma volume, and the ADI-neonatal Fc receptor dissociation rate constant. The linked viral dynamic model captured the NP swab viral load data after estimating differences in within-host replication factor (R0) and viral production rate (p) by variant. Maximal ADI-induced effect (Smax) on stimulating viral clearance (c) was fixed to 0.43 based upon prior modeling. ADI concentration in UA ELF resulting in 50% of Smax (SC50) was estimated to be 0.086 for delta and 1.05 mg/L for omicron. Figure B and C show model-based simulated median (90% PI) viral load reduction in ADI-treated or placebo pts for delta and omicron variants. Conclusion This QSP model, in conjunction with information on new variants available early in outbreaks (IC50, infectivity (R0), viral production rate [each a model parameter]), allows for rapid dose identification in response to emerging variants. Disclosures Evan Tarbell, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Scott A. Van Wart, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Myra Popejoy, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Ellie Hershberger, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Andrew Santulli, BSE, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Paul Ambrose, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds|Institute for Clinical Pharmacodynamics: President.
Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, and new treatments that improve outcomes are required. We randomly assigned adults with TBM to treatment with standard antituberculosis treatment alone or in combination with ciprofloxacin (750 mg/12 h), levofloxacin (500 mg/12 h), or gatifloxacin (400 mg/24 h) for the first 60 days of therapy. Fluoroquinolone concentrations were measured with plasma and cerebrospinal fluid (CSF) specimens taken at predetermined, randomly assigned times throughout treatment. We aimed to describe the pharmacokinetics of each fluoroquinolone during TBM treatment and evaluate the relationship between drug exposure and clinical response over 270 days of therapy (Controlled Trials number ISRCTN07062956). Sixty-one patients with TBM were randomly assigned to treatment with no fluoroquinolone (n = 15), ciprofloxacin (n = 16), levofloxacin (n = 15), or gatifloxacin (n = 15). Cerebrospinal fluid penetration, measured by the ratio of the plasma area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the cerebrospinal fluid AUC(0-24), was greater for levofloxacin (median, 0.74; range, 0.58 to 1.03) than for gatifloxacin (median, 0.48; range, 0.47 to 0.50) or ciprofloxacin (median, 0.26; range, 0.11 to 0.77). Univariable and multivariable analyses of fluoroquinolone exposure against a range of different treatment responses revealed worse outcomes among patients with lower and higher plasma and CSF exposures than for patients with intermediate exposures (a U-shaped exposure-response). TBM patients most likely to benefit from fluoroquinolone therapy were identified, along with exposure-response relationships associated with improved outcomes. Fluoroquinolones add antituberculosis activity to the standard treatment regimen, but to improve outcomes of TBM, they must be started early, before the onset of coma.
Tigecycline, a novel glycylcycline, possesses broad‐spectrum antimicrobial activity. A structural population pharmacokinetic model for tigecycline was developed based on data pooled from 5 phase I studies. Intravenous tigecycline was administered as single (12.5–300 mg) or multiple (25–100 mg) doses every 12 hours for up to 10 days. Three‐compartment models with zero‐order input and first‐order elimination separately described the single‐ or multiple‐dose full‐profile data. Additional models were evaluated using a subset of the phase I data mimicking the phase II/III trial sparse‐sampling scheme and dosage. A 2‐compartment model best described the reduced phase I data following single or multiple doses and provided reliably accurate estimates of tigecycline AUC 0–12 . This modeling supported phase II/III population pharmacokinetic model development to further determine individual patient tigecycline exposures for safety and efficacy analyses.
ABSTRACT Ceftaroline is a cephalosporin with broad-spectrum in vitro activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistant Staphylococcus aureus . Ceftaroline fosamil, the prodrug of ceftaroline, is approved for the treatment of patients with ABSSSI. Using data from the microbiologically evaluable population from two phase 2 and two phase 3 randomized, multicenter, double-blind studies of patients with ABSSSI, an analysis examining the relationship between drug exposure, as measured by the percentage of time during the dosing interval that free-drug steady-state concentrations remain above the MIC ( f % T >MIC), and clinical and microbiological responses was undertaken. The analysis population included 526 patients, of whom 423 had infections associated with S. aureus . Clinical and microbiological success percentages were 94.7 and 94.5%, respectively, among all of the patients and 95.3 and 95.7%, respectively, among those with S. aureus infections. Univariable analysis based on data from all of the patients and those with S. aureus infections demonstrated significant relationships between f % T >MIC and microbiological response ( P < 0.001 and P = 0.026, respectively). Multivariable logistic regression analyses demonstrated other patient factors in addition to f % T >MIC to be significant predictors of microbiological response, including age and infection type for all of the patients evaluated and age, infection type, and the presence of diabetes mellitus for patients with S. aureus infections. Results of these analyses confirm that a ceftaroline fosamil dosing regimen of 600 mg every 12 h provides exposures associated with the upper plateau of the pharmacokinetic-pharmacodynamic relationship for efficacy.
Abstract 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 (KD,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 KD,FcRn provided accurate predictions of NHP serum PK data (Figure C). NHP ADG20 KD,FcRn was optimized to be 35.7 nM and human ADG20 KD,FcRn (9.55 nM) was derived using a mean NHP:human KD,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. Disclosures Scott A. Van Wart, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Evan D. Tarbell, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Donald E. Mager, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee)
Tolvaptan is a selective V2 -receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM® based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240 mg). A two-compartment model with first-order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and apparent central volume of distribution (Vc /F). The CL/F was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. Vc /F was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child-Pugh score ≥ 10) relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115-130 mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK-PD relationships with respect to fluid and electrolyte balance.
Abstract 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 other SARS-like CoVs with pandemic potential and an extended half-life. ADG20 is administered intramuscularly (IM). A QSP/PBPK model was constructed to support dose selection for a Phase 2/3 trial of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671). Methods A QSP/PBPK model was used to simulate receptor occupancy (RO) and drug exposure in the upper airway (nasopharyngeal/oropharyngeal epithelial lining fluid [ELF] compartment). RO was linked to an existing viral dynamic model to enable the prediction of the natural time course of viral load and the effect of ADG20 on viral clearance and infectivity rate. RO was calculated using: 1) in vitro ADG20–SARS-CoV-2 binding kinetics (association rate constant (kon) of 1.52E+06 M-1•s1 and dissociation rate constant (koff) of 2.81E-04 s-1 from a Biacore assay; 2) time course of ADG20 concentrations in ELF; and 3) time course of viral load following ADG20 administration. Molar SARS-CoV-2 viral binding site capacity was calculated assuming 40 spike proteins per virion, 3 binding sites per spike, and an initial viral load of log 107 copies/mL for all patients. The QSP/PBPK model and a 2018 CDC reference body weight distribution (45–150 kg) were used to simulate 1000 concentration-time profiles for a range of candidate ADG20 regimens. ADG20 regimens were evaluated against 2 criteria: 1) ability to attain near complete ( >90%), and durable (28-day) SARS-CoV-2 RO in the ELF; and 2) ability to maintain ELF ADG20 concentrations relative to a concentration (0.5 mg/L) associated with 100% viral growth suppression in an in vitro post-infection assay. Results A single 300 mg IM ADG20 dose met the dose selection criteria in terms of RO (Figure A) and viral growth suppression (Figure B). Conclusion These data support the evaluation of an ADG20 300 mg IM dose for the treatment of mild to moderate COVID-19. ADG20 is forecasted to attain near complete ( >90%) SARS-CoV-2 RO in the ELF and maintain ELF ADG20 concentrations above that associated with 100% viral growth suppression in vitro. Figure. QSP/PBPK model forecast of ADG20 300 mg IM in adults (A) Predicted RO expressed as percent occupancy with the dotted line representing the threshold for 90% RO. (B) Predicted median concentration of ADG20 relative to a concentration (0.5 mg/L) associated with 100% viral growth suppression as indicated by the dotted line; the shaded area represents the 90% prediction interval. Disclosures Evan D. Tarbell, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Scott A. Van Wart, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Laura M. Walker, PhD, Adagio Therapeutics, Inc. (Other Financial or Material Support, Laura M. Walker is an inventor on a patent application submitted by Adagio Therapeutics, Inc., describing the engineered SARS-CoV-2 antibody.) Andrew Santulli, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Donald E Mager, PharmD, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee)
Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono- or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/MIC ratio was also borderline predictive of microbiological response (P = 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.
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