Omadacycline pharmacokinetics/pharmacodynamics and efficacy against multidrug-resistant Mycobacterium tuberculosis in the hollow fiber system model.

Autor: Singh S; Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA., Gumbo T; Quantitative Preclinical and Clinical Sciences Department, Praedicare Inc., Dallas, Texas, USA.; Hollow Fiber System and Experimental Therapeutics Laboratories, Praedicare Inc., Dallas, Texas, USA., Boorgula GD; Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA., Thomas TA; Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA., Philley JV; Section of Pulmonary and Critical Care, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA., Srivastava S; Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA.; Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Feb 07; Vol. 68 (2), pp. e0108023. Date of Electronic Publication: 2023 Dec 22.
DOI: 10.1128/aac.01080-23
Abstrakt: Seventy-five years ago, first-generation tetracyclines demonstrated limited efficacy in the treatment of tuberculosis but were more toxic than efficacious. We performed a series of pharmacokinetic/pharmacodynamic (PK/PD) experiments with a potentially safer third-generation tetracycline, omadacycline, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Mycobacterium tuberculosis ( Mtb ) H37Rv and an MDR-TB clinical strain (16D) were used in the minimum inhibitory concentration (MIC) and static concentration-response studies in test tubes, followed by a PK/PD study using the hollow fiber system model of TB (HFS-TB) that examined six human-like omadacycline doses. The inhibitory sigmoid maximal effect ( E max ) model and Monte Carlo experiments (MCEs) were used for data analysis and clinical dose-finding, respectively. The omadacycline MIC for both Mtb H37Rv and MDR-TB clinical strain was 16 mg/L but dropped to 4 mg/L with daily drug supplementation to account for omadacycline degradation. The Mycobacteria Growth Indicator Tube MIC was 2 mg/L. In the test tubes, omadacycline killed 4.39 log 10 CFU/mL in 7 days. On Day 28 of the HFS-TB study, the E max was 4.64 log 10 CFU/mL, while exposure mediating 50% of E max (EC 50 ) was an area under the concentration-time curve to MIC (AUC 0-24 /MIC) ratio of 22.86. This translates to PK/PD optimal exposure or EC 80 as AUC 0-24 /MIC of 26.93. The target attainment probability of the 300-mg daily oral dose was 90% but fell at MIC ≧4 mg/L. Omadacycline demonstrated efficacy and potency against both drug-susceptible and MDR-TB. Further studies are needed to identify the omadacycline effect in combination therapy for the treatment of both drug-susceptible and MDR-TB.
Competing Interests: T.G. founded and is the president and CEO of Praedicare Inc., a system of systems drug development company, and founded Praedicare Africa, a clinical contract research organization. J.V.P. is an advisor for Insmed, Paratek, and AN2 and a research investigator for Insmed, Paratek, AN2, and Zambon. All other authors have nothing to declare.
Databáze: MEDLINE
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