Informing and Validating Translational Mechanism‐Based Models for Antibiotics by Experimental and Computational Approaches

Bulitta, Jürgen B.

doi:10.1002/cpt.2367

Cited by 3 publications

(2 citation statements)

References 6 publications

(33 reference statements)

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“…More sophisticated methods for dose prediction have been extensively discussed in recent literature 10–20 . These approaches rely on mathematical description of experimental data conducted in vitro or in animals to project the drug effect on pathogen dynamics in patients.…”

Section: Introductionmentioning

confidence: 99%

“…More sophisticated methods for dose prediction have been extensively discussed in recent literature. [10][11][12][13][14][15][16][17][18][19][20] These approaches rely on mathematical description of experimental data conducted in vitro or in animals to project the drug effect on pathogen dynamics in patients. They have the appeal of mechanistical reflection of the drug-disease interaction and the ability of situational predictions, at the cost of more extensive laboratory experimentation and the need for sometimes unverifiable assumptions.…”

Section: Introductionmentioning

confidence: 99%

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The area under the effect curve as an efficacy determinant for anti‐infectives

Chen

Lavezzi²,

Iavarone

2022

CPT Pharmacom & Syst Pharma

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Pharmacokinetic/pharmacodynamic (PK/PD) indices making use of area under the curve, maximum concentration, and the duration that in vivo drug concentration is maintained above a critical level are commonly applied to clinical dose prediction from animal efficacy experiments in the infectious disease arena. These indices make suboptimal use of the nonclinical data, and the prediction depends on the shape of the PK profiles in the animals, determined by the species-specific absorption, distribution, metabolism, and elimination properties, and the dosing regimen used in the efficacy experiments. Motivated by the principle that efficacy is driven by pharmacology, we conducted simulations using a generalized pathogen dynamic model, to assess the properties of an alternative efficacy predictor: the area under the effect curve (AUEC), computed using in vitro PD and in vivo PK. Across a wide range of hypothetical scenarios, the AUEC consistently showed regimen-independent strong correlation (R 2 0.76-0.98) with in vivo efficacy, superior to all other indices. These findings serve as proof of concept that AUEC should be considered in practice as a translation tool for cross-species dose prediction. Using AUEC for clinical dose prediction could also potentially cut down animal use by reducing or avoiding dose fractionation experiments. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Several pharmacokinetic/pharmacodynamic (PK/PD) indices are commonly used in predicting efficacy for anti-infectives. WHAT QUESTION DID THIS STUDY ADDRESS?The area under the effect curve (AUEC) was assessed as a novel index potentially overcoming some of the limitations of the conventional PK/PD indices. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Simulations using a generalized disease-drug model under a range of experimental conditions suggest that the AUEC could be a more reliable predictor than the conventional indices, while being a simpler approach compared with more mechanistic ones.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The area under the effect curve as an efficacy determinant for anti‐infectives

Chen

Lavezzi²,

Iavarone

2022

CPT Pharmacom & Syst Pharma

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Distinguishing Inducible and Non-Inducible Resistance to Colistin in Pseudomonas aeruginosa by Quantitative and Systems Pharmacology Modeling at Low and Standard Inocula

Bulitta,

Shin,

Bergen

et al. 2024

Journal of Pharmaceutical Sciences

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Comprehensive stability analysis of 13 β-lactams and β-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation

Zhou,

Qian,

Lang

et al. 2024

Antimicrob Agents Chemother

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Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain β-lactams (e.g., imipenem) and β-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 β-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at −20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on β-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of β-lactamase-related degradation.

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Informing and Validating Translational Mechanism‐Based Models for Antibiotics by Experimental and Computational Approaches

Cited by 3 publications

References 6 publications

The area under the effect curve as an efficacy determinant for anti‐infectives

The area under the effect curve as an efficacy determinant for anti‐infectives

Distinguishing Inducible and Non-Inducible Resistance to Colistin in Pseudomonas aeruginosa by Quantitative and Systems Pharmacology Modeling at Low and Standard Inocula

Comprehensive stability analysis of 13 β-lactams and β-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation

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