Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study
Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU ve...
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| Published in: | Antibiotics (Basel) Vol. 10; no. 12; p. 1559 |
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| Abstract | Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures.
A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and C
/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state.
Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (
< 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (
< 0.0001). Clearance and volume of distribution were 93% (
< 0.0001) and 53% (
= 0.002) lower in ICU patients, respectively.
ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures. |
|---|---|
| AbstractList | Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures. Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and C /MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients ( < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients ( < 0.0001). Clearance and volume of distribution were 93% ( < 0.0001) and 53% ( = 0.002) lower in ICU patients, respectively. ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures. Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and C max /MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients ( p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients ( p < 0.0001). Clearance and volume of distribution were 93% ( p < 0.0001) and 53% ( p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures. BACKGROUNDTuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. METHODSA prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. RESULTSTen ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. CONCLUSIONSICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures. |
| Author | Sousa Garcia, Leandro Sanches, Cristina Lipman, Jeffrey Roberts, Jason A Pontarolo, Roberto Souza Carvalho, Brenda Karoline Parker, Suzanne L de Liz, Marcus Vinicius Fachi, Mariana Millan Beraldi-Magalhaes, Francisco Cordeiro-Santos, Marcelo |
| AuthorAffiliation | 3 Secretaria de Estado da Saúde do Paraná, Curitiba 80010-130, Brazil 9 Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia 1 Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus 69040-000, Brazil; leog14087@gmail.com (L.S.G.); biomedicinabrenda@gmail.com (B.K.S.C.); marcelocordeiro.br@gmail.com (M.C.-S.) 5 UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; suzanne.parker@uq.edu.au (S.L.P.); j.lipman@uq.edu.au (J.L.); j.roberts2@uq.edu.au (J.A.R.) 11 School of Medicine, Universidade Nilton Lins, Manaus 69058-040, Brazil 6 Department of Pharmacy, Universidade Federal de São João del-Rei, Divinopolis 35501-296, Brazil; csanches@ufsj.edu.br 2 Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus 69040-000, Brazil 12 Department of Pharmacy, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia 10 Division of Anaesthesiology Critical Care E |
| AuthorAffiliation_xml | – name: 9 Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia – name: 7 Department of Pharmacy, Universidade Federal do Paraná, Curitiba 80210-170, Brazil; marianamfachi@gmail.com (M.M.F.); pontarolo@ufpr.br (R.P.) – name: 8 Department of Chemistry and Biology, Universidade Federal Tecnológica do Paraná, Curitiba 81280-340, Brazil; marcusliz.utfpr@gmail.com – name: 4 School of Medicine, Faculdades Pequeno Príncipe, Curitiba 80230-020, Brazil – name: 1 Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus 69040-000, Brazil; leog14087@gmail.com (L.S.G.); biomedicinabrenda@gmail.com (B.K.S.C.); marcelocordeiro.br@gmail.com (M.C.-S.) – name: 11 School of Medicine, Universidade Nilton Lins, Manaus 69058-040, Brazil – name: 2 Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus 69040-000, Brazil – name: 3 Secretaria de Estado da Saúde do Paraná, Curitiba 80010-130, Brazil – name: 6 Department of Pharmacy, Universidade Federal de São João del-Rei, Divinopolis 35501-296, Brazil; csanches@ufsj.edu.br – name: 5 UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; suzanne.parker@uq.edu.au (S.L.P.); j.lipman@uq.edu.au (J.L.); j.roberts2@uq.edu.au (J.A.R.) – name: 10 Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, 30900 Nimes, France – name: 12 Department of Pharmacy, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia |
| Author_xml | – sequence: 1 givenname: Francisco orcidid: 0000-0002-0944-3321 surname: Beraldi-Magalhaes fullname: Beraldi-Magalhaes, Francisco organization: School of Medicine, Faculdades Pequeno Príncipe, Curitiba 80230-020, Brazil – sequence: 2 givenname: Suzanne L surname: Parker fullname: Parker, Suzanne L organization: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia – sequence: 3 givenname: Cristina orcidid: 0000-0002-8562-1337 surname: Sanches fullname: Sanches, Cristina organization: Department of Pharmacy, Universidade Federal de São João del-Rei, Divinopolis 35501-296, Brazil – sequence: 4 givenname: Leandro surname: Sousa Garcia fullname: Sousa Garcia, Leandro organization: Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus 69040-000, Brazil – sequence: 5 givenname: Brenda Karoline surname: Souza Carvalho fullname: Souza Carvalho, Brenda Karoline organization: Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus 69040-000, Brazil – sequence: 6 givenname: Mariana Millan surname: Fachi fullname: Fachi, Mariana Millan organization: Department of Pharmacy, Universidade Federal do Paraná, Curitiba 80210-170, Brazil – sequence: 7 givenname: Marcus Vinicius surname: de Liz fullname: de Liz, Marcus Vinicius organization: Department of Chemistry and Biology, Universidade Federal Tecnológica do Paraná, Curitiba 81280-340, Brazil – sequence: 8 givenname: Roberto orcidid: 0000-0002-7049-4363 surname: Pontarolo fullname: Pontarolo, Roberto organization: Department of Pharmacy, Universidade Federal do Paraná, Curitiba 80210-170, Brazil – sequence: 9 givenname: Jeffrey orcidid: 0000-0002-5965-9876 surname: Lipman fullname: Lipman, Jeffrey organization: Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, 30900 Nimes, France – sequence: 10 givenname: Marcelo surname: Cordeiro-Santos fullname: Cordeiro-Santos, Marcelo organization: School of Medicine, Universidade Nilton Lins, Manaus 69058-040, Brazil – sequence: 11 givenname: Jason A orcidid: 0000-0001-6218-435X surname: Roberts fullname: Roberts, Jason A organization: Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia |
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| CitedBy_id | crossref_primary_10_1016_j_ijantimicag_2023_106840 crossref_primary_10_3390_tropicalmed8060312 |
| Cites_doi | 10.1186/s12879-020-04954-3 10.1093/cid/ciw471 10.1128/AAC.02599-12 10.1016/B978-0-12-013320-8.50005-8 10.1128/AAC.01474-09 10.1128/AAC.01193-15 10.7196/SAMJ.6344 10.1086/431984 10.1007/s40262-015-0236-8 10.1007/s40265-014-0222-8 10.1128/AAC.01583-19 10.1128/AAC.03931-14 10.1007/s001340000849 10.1186/cc12760 10.1080/17512433.2017.1246179 10.1128/AAC.00274-11 10.1371/journal.pone.0141002 10.5588/ijtld.13.0044 10.1093/cid/civ427 10.1001/jama.2016.0287 10.1016/0742-8413(92)90003-P 10.1038/srep21610 10.1097/CCM.0b013e3181961bff 10.1001/jama.2011.436 10.1086/599040 10.1164/arrd.1965.91.1.51 10.1128/AAC.00008-18 10.1186/s12879-018-3230-6 10.5588/ijtld.18.0775 10.1289/ehp.96104400 10.1128/AAC.00641-18 10.1128/AAC.50.4.1170-1177.2006 10.7196/SAMJ.9148 10.1086/651377 10.1002/bmc.4812 10.2471/BLT.11.096644 10.1128/AAC.00924-17 10.1590/s1806-37562017000000316 10.1093/jac/dkz265 10.1002/cpt.180 10.1093/jac/dkw470 |
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| Keywords | critical care pharmacokinetics biological availability intensive care ethambutol tuberculosis |
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| Snippet | Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB... Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of... BACKGROUNDTuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of... |
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| SubjectTerms | Absorption Bioavailability biological availability Creatinine critical care Dosage Drug dosages Ethambutol Exposure HIV Hospitals Human immunodeficiency virus Intensive care Intensive care units Minimum inhibitory concentration Mortality Oral administration Patients Pharmacokinetics Pharmacology Population studies Tuberculosis Ventilation |
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| Title | Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study |
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