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      Predictions of Bedaquiline Central Nervous System Exposure in Patients with Tuberculosis Meningitis Using Physiologically based Pharmacokinetic Modeling

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          Abstract

          Background and Objective

          The use of bedaquiline as a treatment option for drug-resistant tuberculosis meningitis (TBM) is of interest to address the increased prevalence of resistance to first-line antibiotics. To this end, we describe a whole-body physiologically based pharmacokinetic (PBPK) model for bedaquiline to predict central nervous system (CNS) exposure.

          Methods

          A whole-body PBPK model was developed for bedaquiline and its metabolite, M2. The model included compartments for brain and cerebrospinal fluid (CSF). Model predictions were evaluated by comparison to plasma PK time profiles following different dosing regimens and sparse CSF concentrations data from patients. Simulations were then conducted to compare CNS and lung exposures to plasma exposure at clinically relevant dosing schedules.

          Results

          The model appropriately described the observed plasma and CSF bedaquiline and M2 concentrations from patients with pulmonary tuberculosis (TB). The model predicted a high impact of tissue binding on target site drug concentrations in CNS. Predicted unbound exposures within brain interstitial exposures were comparable with unbound vascular plasma and unbound lung exposures. However, unbound brain intracellular exposures were predicted to be 7% of unbound vascular plasma and unbound lung intracellular exposures.

          Conclusions

          The whole-body PBPK model for bedaquiline and M2 predicted unbound concentrations in brain to be significantly lower than the unbound concentrations in the lung at clinically relevant doses. Our findings suggest that bedaquiline may result in relatively inferior efficacy against drug-resistant TBM when compared with efficacy against drug-resistant pulmonary TB.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s40262-024-01363-6.

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          Most cited references41

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          A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.

          The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.
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            Bedaquiline–Pretomanid–Linezolid Regimens for Drug-Resistant Tuberculosis

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              Applied Concepts in PBPK Modeling: How to Build a PBPK/PD Model

              The aim of this tutorial is to introduce the fundamental concepts of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on their practical implementation in a typical PBPK model building workflow. To illustrate basic steps in PBPK model building, a PBPK model for ciprofloxacin will be constructed and coupled to a pharmacodynamic model to simulate the antibacterial activity of ciprofloxacin treatment.
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                Author and article information

                Contributors
                krinaj@gmail.com
                Journal
                Clin Pharmacokinet
                Clin Pharmacokinet
                Clinical Pharmacokinetics
                Springer International Publishing (Cham )
                0312-5963
                1179-1926
                26 March 2024
                26 March 2024
                2024
                : 63
                : 5
                : 657-668
                Affiliations
                [1 ]Leiden Academic Centre for Drug Research, Leiden University, ( https://ror.org/027bh9e22) Leiden, The Netherlands
                [2 ]esqLabs GmbH, Saterland, Germany
                [3 ]GRID grid.518601.b, ISNI 0000 0004 6043 9883, Certara, ; Canterbury, UK
                Author information
                http://orcid.org/0000-0002-7621-6436
                Article
                1363
                10.1007/s40262-024-01363-6
                11106169
                38530588
                16fa4796-cb94-4ff9-95b6-1cad42f9fc34
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 15 February 2024
                Categories
                Original Research Article
                Custom metadata
                © Springer Nature Switzerland AG 2024

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