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Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits

SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug-resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109-resistant mutant has been directly isolated thus far in vitro, in mice, or in...

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Autores principales: Egbelowo, Oluwaseun, Sarathy, Jansy P., Gausi, Kamunkhwala, Zimmerman, Matthew D., Wang, Han, Wijnant, Gert-Jan, Kaya, Firat, Gengenbacher, Martin, Van, Nhi, Degefu, Yonatan, Nacy, Carol, Aldridge, Bree B., Carter, Claire L., Denti, Paolo, Dartois, Véronique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370215/
https://www.ncbi.nlm.nih.gov/pubmed/34228540
http://dx.doi.org/10.1128/AAC.00024-21
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author Egbelowo, Oluwaseun
Sarathy, Jansy P.
Gausi, Kamunkhwala
Zimmerman, Matthew D.
Wang, Han
Wijnant, Gert-Jan
Kaya, Firat
Gengenbacher, Martin
Van, Nhi
Degefu, Yonatan
Nacy, Carol
Aldridge, Bree B.
Carter, Claire L.
Denti, Paolo
Dartois, Véronique
author_facet Egbelowo, Oluwaseun
Sarathy, Jansy P.
Gausi, Kamunkhwala
Zimmerman, Matthew D.
Wang, Han
Wijnant, Gert-Jan
Kaya, Firat
Gengenbacher, Martin
Van, Nhi
Degefu, Yonatan
Nacy, Carol
Aldridge, Bree B.
Carter, Claire L.
Denti, Paolo
Dartois, Véronique
author_sort Egbelowo, Oluwaseun
collection PubMed
description SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug-resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109-resistant mutant has been directly isolated thus far in vitro, in mice, or in patients, which is tentatively attributed to its multiple targets. It is considered a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with the best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here, we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease—lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modeled using an “effect” compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000 and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high nonspecific caseum binding of SQ109, suggest that multiweek dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, nonreplicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval.
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spelling pubmed-83702152021-08-25 Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits Egbelowo, Oluwaseun Sarathy, Jansy P. Gausi, Kamunkhwala Zimmerman, Matthew D. Wang, Han Wijnant, Gert-Jan Kaya, Firat Gengenbacher, Martin Van, Nhi Degefu, Yonatan Nacy, Carol Aldridge, Bree B. Carter, Claire L. Denti, Paolo Dartois, Véronique Antimicrob Agents Chemother Pharmacology SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug-resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109-resistant mutant has been directly isolated thus far in vitro, in mice, or in patients, which is tentatively attributed to its multiple targets. It is considered a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with the best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here, we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease—lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modeled using an “effect” compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000 and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high nonspecific caseum binding of SQ109, suggest that multiweek dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, nonreplicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval. American Society for Microbiology 2021-08-17 /pmc/articles/PMC8370215/ /pubmed/34228540 http://dx.doi.org/10.1128/AAC.00024-21 Text en Copyright © 2021 Egbelowo et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pharmacology
Egbelowo, Oluwaseun
Sarathy, Jansy P.
Gausi, Kamunkhwala
Zimmerman, Matthew D.
Wang, Han
Wijnant, Gert-Jan
Kaya, Firat
Gengenbacher, Martin
Van, Nhi
Degefu, Yonatan
Nacy, Carol
Aldridge, Bree B.
Carter, Claire L.
Denti, Paolo
Dartois, Véronique
Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits
title Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits
title_full Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits
title_fullStr Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits
title_full_unstemmed Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits
title_short Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits
title_sort pharmacokinetics and target attainment of sq109 in plasma and human-like tuberculosis lesions in rabbits
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370215/
https://www.ncbi.nlm.nih.gov/pubmed/34228540
http://dx.doi.org/10.1128/AAC.00024-21
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