Systematic and quantitative analyses of pre-clinical Mycobacterium avium Lung Disease Tools for Drug Development and Transition from Animal Models to New Approach Methodologies

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, ranking antibiotics effect, and for translation to clinical doses. The analyses inform us of HFS-MAC recommendations for regulatory authorities and drug developers, including quality scores for optimal PK/PD design for target identification, resistance suppression, and choice of the best novel regimen.