Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses for Delafloxacin to Provide Dose Selection Support for the Treatment of Patients With Community-Acquired Bacterial Pneumonia (CABP)

Abstract Background ME1100 (arbekacin inhalational solution) is an inhaled aminoglycoside being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). PK-PD target attainment analyses were undertaken to evaluate ME1100 regimens for patients with HABP/VABP arising from Klebsiella pneumoniae (KP), Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA), including those with renal impairment. Methods Data used included a population pharmacokinetic (PPK) model developed using Phase 1 and post-marketing PK data, nonclinical PK-PD targets from one compartment in vitro and/or in vivo infection models, and MIC data. Using parameter estimates from the PPK model (four-compartment model with first-order elimination), total-drug epithelial lining fluid concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr; mL/minute/1.73 m2) and by CLcr group. Twice daily (BID) ME1100 regimens ranging from 300 to 900 mg were assessed in simulated patients with CLcr >80 to ≤120 mL/minute/1.73 m2. Percent probabilities of PK-PD target attainment by MIC were determined based on total-drug ELF AUC:MIC ratio targets associated with 1- and 2-log10 CFU reductions from baseline for KP, PA and SA using Day 1 AUC. Regimens in simulated patients with renal impairment that best matched the BID regimen in the normal CLcr group with high percent probabilities of PK-PD target attainment and a low percent probability of Cmin > 2 mg/L were identified. Results ME1100 600 mg BID in simulated patients with CLcr >80 to ≤120 mL/minute/1.73 m2, with 600 mg once daily, 450 mg BID and 600 mg BID in simulated patients with CLcr of 0 to ≤30, >30 to ≤50 and >50 to ≤80 mL/minute/1.73 m2, respectively, achieved high percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at relevant MIC values for KP, PA and SA, and relatively lower Cmin values. In simulated patients with varying CLcr who received these regimens, high percent probabilities of PK-PD target attainment were achieved for KP, PA and SA at the upper margins of the MIC distributions (Figures 1–3). Conclusion The data provide support for ME1100 dose selection for patients with HABP/VAPB. Disclosures S. M. Bhavnani, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. J. P. Hammel, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. E. A. Lakota, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. B. D. VanScoy, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. Y. Nagira, Meiji Seika Pharma Co. Ltd.: Employee, Salary. C. M. Rubino, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. N. Sato, Meiji Seika Pharma Co. Ltd.: Employee, Salary. T. Koresawa, Meiji Seika Pharma Co. Ltd.: Employee, Salary. K. Kondo, Meiji Seika Pharma Co. Ltd.: Employee, Salary. P. G. Ambrose, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support.

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Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial

Critical Care ◽

10.1186/s13054-021-03773-5 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Andrew F. Shorr ◽

Christopher J. Bruno ◽

Zufei Zhang ◽

Erin Jensen ◽

Wei Gao ◽

...

Keyword(s):

Renal Function ◽

Normal Renal Function ◽

Clinical Cure ◽

Bacterial Pneumonia ◽

Target Attainment ◽

Augmented Renal Clearance ◽

Phase 3 ◽

Epithelial Lining Fluid ◽

All Cause Mortality ◽

Cure Rates

Abstract Background The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. Methods Baseline renal function was categorized as normal renal function (creatinine clearance 80–130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. Results A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [− 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; − 2.6 [− 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; − 2.1 [− 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [− 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [− 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [− 8.7 to 19.0]). Conclusions C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

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Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02019-20 ◽

2020 ◽

Vol 65 (3) ◽

Author(s):

Indy Sandaradura ◽

Jessica Wojciechowski ◽

Deborah J. E. Marriott ◽

Richard O. Day ◽

Sophie Stocker ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Drug Exposure ◽

Fungal Infections ◽

Therapeutic Drug ◽

Target Attainment ◽

Dose Selection ◽

Dose Individualization

ABSTRACT Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC24) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.

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Population Pharmacokinetic Analyses for Arbekacin after Administration of ME1100 Inhalation Solution

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00267-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 2

Author(s):

Elizabeth A. Lakota ◽

Nobuo Sato ◽

Tomokazu Koresawa ◽

Kenichiro Kondo ◽

Sujata M. Bhavnani ◽

...

Keyword(s):

Bacterial Pneumonia ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Phase 1 ◽

Time Profile ◽

Population Pharmacokinetic ◽

Dose Selection ◽

Mechanically Ventilated ◽

Model Following ◽

Hospital Acquired

ABSTRACT ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL = (weight/52.2)0.855·[(CLcrn–77)·0.0289 + 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data (r2 of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.

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