Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far.

Autor:	Singh S; Department of Medicine, School of Medicine, University of Texas at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA., Boorgula GD; Department of Medicine, School of Medicine, University of Texas at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA., Aryal S; Department of Pharmaceutical Sciences and Health Outcomes, The Ben and Maytee Fisch College of Pharmacy, University of Texas at Tyler, Tyler, TX, USA., Philley JV; Section of Pulmonary and Critical Care, School of Medicine, University of Texas at Tyler, Tyler, TX, USA., Gumbo T; Quantitative Preclinical & Clinical Sciences Department, Praedicare Inc., Dallas, TX, USA.; Hollow Fiber System & Experimental Therapeutics Laboratories, Praedicare Inc, Dallas, TX, USA., Srivastava S; Department of Medicine, School of Medicine, University of Texas at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA.; Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX, USA.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2024 Jan 03; Vol. 79 (1), pp. 96-99.
DOI:	10.1093/jac/dkad352
Abstrakt:	Background: Poor sustained sputum culture conversion rates with the standard-of-care therapy highlight the need for better drugs to treat Mycobacterium avium complex pulmonary disease (MAC-PD). Objective: To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD. Methods: We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies. A dynamic hollow-fibre system model of intracellular MAC (HFS-MAC) study was performed mimicking six human-equivalent sarecycline dose concentration-time profiles to identify the PK/PD optimal exposure of sarecycline for MAC kill. The inhibitory sigmoid maximal effect (Emax) model was used for PK/PD analysis. Results: The sarecycline MIC of MAC ATCC 700898 was 1 mg/L, while the MIC for the 19 clinical strains ranged between 32 and >256 mg/L. The concentration mediating 50% of Emax (EC50) was similar between intracellular and extracellular MAC. In the HFS-MAC, all six sarecycline doses killed intracellular MAC, with an Emax of 1.0 log10 cfu/mL below Day 0 burden (stasis). The sarecycline EC80 (optimal) exposure was identified as AUC0-24/MIC = 139.46. Conclusions: Sarecycline demonstrated anti-MAC Emax in the HFS-MAC model better than ethambutol but worse than omadacycline (>5 log10 cfu/mL below stasis) in HFS-MAC. However, since currently approved highest oral sarecycline dose achieves an AUC0-24 of 48.2 mg·h/L and MAC MICs are >32 mg/L, the target AUC0-24/MIC of 139.46 is unlikely to be achieved in patients. (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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