ArticleTuberculosis (Edinburgh, Scotland)2023
Isoniazid pharmacokinetics/pharmacodynamics as monotherapy and in combination regimen in the hollow fiber system model of Mycobacterium kansasii.
Article in Tuberculosis (Edinburgh, Scotland), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed, 3 citations in OpenAlex.
- Article
- Preclinical pharmacokinetics/pharmacodynamics studies defining the role of ethambutol inAntimicrobial agents and chemotherapy · 2026Article
- Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease.Nature reviews. Drug discovery · 2024Review
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6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundThere is limited high quality evidence to guide the optimal doses of drugs for the treatment of Mycobacterium kansasii pulmonary disease (Mkn-PD).
methodsWe performed (1) minimum inhibitory concentration experiment, (2) isoniazid dose-response study using the hollow fiber system model (HFS-Mkn) to determine PK/PD optimized exposure, and (3) another HFS-Mkn study to determine the efficacy of high dose isoniazid (15 mg/kg/day) with standard dose rifampin (10 mg/kg/day) and ethambutol (15 mg/kg/day). Inhibitory sigmoid maximal effect model and linear regression was used for data analysis.
resultsMIC of the 20 clinical isolates ranged between 0.5 mg/L to 32 mg/L. In the HFS-Mkn, isoniazid monotherapy failed to control the bacterial growth beyond day 7. On day 7, when the maximal Mkn kill was observed, the optimal isoniazid exposure for Mkn kill was calculated as 24hr area under the concentration-time curve to the MIC of 12.41. Target attainment probability of 300 mg/day dose fell below 90% above the MIC of 1 mg/L. High dose isoniazid combination sterilized the HFS-Mkn in 30-days with a kill rate of -0.15 ± 0.02 log
conclusionDespite initial kill, isoniazid monotherapy failed due to resistance emergence. Our pre-clinical model derived results suggest that higher than currently recommended 300 mg/day isoniazid dose may achieve better clinical efficacy against Mkn-PD.
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