Systematic and quantitative analyses of pre-clinical Mycobacterium avium Lung Disease Tools for Drug Development and Transition from Animal Models to New Approach Methodologies
Abstract
ABSTRACT Animal and new approach methodologies such as the hollow fiber system model [HFS] are used for Mycobacterium avium-complex [MAC] lung disease [LD] preclinical drug development. Our objective was to perform a systematic review to benchmark these pre-clinical tools. We performed a literature search to identify preclinical pharmacokinetics/pharmacodynamics [PK/PD] studies for MAC-LD. Preferred Reporting Items for Systematic Reviews and Meta-analyses was used for bias minimization. Twenty HFS-MAC and 3 mouse studies met PK/PD inclusion criteria. We created a novel quality score tool based on predictors of clinical response, design optimization, and information theory. The quality score was judged high in 10%, good in 50%, adequate in 30%, and poor in 10% of studies. Monte Carlo experiments for PK/PD target attainment were reported in 61% of studies. On repetitive sampling, the PK/PD target exposure estimate varied significantly between sampling days in 76% of studies. The solution was ordinary differential equations with parameter outputs such as γ [nonlinear kill-slope] and time-to-extinction applied to both HFS-MAC and patients’ sputa CFU/mL output. Next, we ranked the antibiotics by extent of microbial kill as fold-improvement over guideline-based therapy. The three top ranked drugs for microbial kill were omadacycline [69-fold], tedizolid [19-fold], and ceftriaxone [8-fold]. We recommend the HFS-MAC as tractable for exposure-effect and dose-fractionation studies,…
How strong is the evidence?
Evidence Hub reads this as a preprint, done in animal, not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
Read the paper
Related studies
- Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching
- Ferulic acid regulates the AKT/GSK-3β/CRMP-2 signaling pathway in a middle cerebral artery occlusion animal model
- Association between cord blood 25-hydroxyvitamin D concentrations and respiratory tract infections in the first 6 months of age in a Korean population: a birth cohort study (COCOA)
- Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli
- Neuroprotective Effects of Epicatechin against Oxidative Stress-Induced Cognitive Impairment: A Systematic Review and Meta-Analysis
- Photochemical behavior of levofloxacin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.