Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment : A physiologically based pharmacokinetic modeling and simulations study
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved..
OBJECTIVE AND METHODS: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.
RESULTS: The rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.
CONCLUSION: In this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:137 |
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| Enthalten in: |
Tuberculosis (Edinburgh, Scotland) - 137(2022) vom: 15. Dez., Seite 102271 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mehta, Krina [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.11.2022 Date Revised 23.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.tube.2022.102271 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Mehta, Krina |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment |b A physiologically based pharmacokinetic modeling and simulations study |
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| 500 | |a Date Revised 23.01.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a OBJECTIVE AND METHODS: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted | ||
| 520 | |a RESULTS: The rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing | ||
| 520 | |a CONCLUSION: In this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Isoniazid |2 NLM | |
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| 650 | 7 | |a Rifampin |2 NLM | |
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| 650 | 7 | |a Antitubercular Agents |2 NLM | |
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| 700 | 1 | |a Narayanan, Navaneeth |e verfasserin |4 aut | |
| 700 | 1 | |a Heysell, Scott K |e verfasserin |4 aut | |
| 700 | 1 | |a Bisson, Gregory P |e verfasserin |4 aut | |
| 700 | 1 | |a Subbian, Selvakumar |e verfasserin |4 aut | |
| 700 | 1 | |a Kurepina, Natalia |e verfasserin |4 aut | |
| 700 | 1 | |a Kreiswirth, Barry N |e verfasserin |4 aut | |
| 700 | 1 | |a Vinnard, Christopher |e verfasserin |4 aut | |
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