Systematic and quantitative analyses of hollow fiber model of Mycobacterium abscessus lung disease studies

Guideline-based combination therapy (GBT) achieves sputum culture conversion rates in 23-34% of patients with Mycobacterium abscessus complex (MAB) lung disease (LD). Thus, new therapies are needed. We performed a systematic review to validate and benchmark the hollow fiber system model of MAB-LD (HFS-MAB) for drug development. We performed a literature search to identify all published HFS-MAB pharmacokinetics (PK)-pharmacodynamics (PD) studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used for bias minimization. A total of 12 studies were identified. The average quality score was 13.7 out of 21. Eight were monotherapy (exposure-effect and dose-fractionation), one-double {beta}-lactam, and three GBT studies. For omadacycline and imipenem, HFS-MAB data was accompanied by clinical real-world evidence confirming HFS-MAB findings. Monotherapy or combination therapy microbial kill was always terminated by antimicrobial resistance. We used quantitative analyses to rank drugs efficacy. The three highest-ranked drugs based cfu/mL fold-kill compared to multi-drug GBT, were sulbactam-durlobactam (177-fold), epetraborole (15-fold), and omadacycline (7-fold). We used the PK/PD target exposures identified by studies in the systematic analysis in Monte Carlo experiments (MCE) to identify optimal doses for inhaled formulations. The optimal inhalational dose of imipenem/cilastatin was 250 mg/day, for tigecycline 4 mg/day, for cefoxitin 50 mg/day, and for amikacin liposome inhalation suspension 590mg once weekly. The HFS-MAB is tractable for exposure-effect, dose-fractionation, and factorial design combination studies. It can be used to rank drugs and inform on which drugs to test in novel combinations. The HFS-MAB fulfills the US Food and Drug Administration Roadmap definition of non-animal New Approach Methodologies.