Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations]
Background. Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to deter...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wellcome
2022-11-01
|
| Series: | Wellcome Open Research |
| Subjects: | |
| Online Access: | https://wellcomeopenresearch.org/articles/7-72/v2 |
| _version_ | 1797858213971886080 |
|---|---|
| author | Helen McIlleron Lubbe Wiesner Charlotte Schutz Robert J. Wilkinson Graeme Meintjes Noha Abdelgawad David Barr Maxwell Chirehwa Saskia Janssen Amy Ward Muki Shey Rosie Burton Gary Maartens Paolo Denti |
| author_facet | Helen McIlleron Lubbe Wiesner Charlotte Schutz Robert J. Wilkinson Graeme Meintjes Noha Abdelgawad David Barr Maxwell Chirehwa Saskia Janssen Amy Ward Muki Shey Rosie Burton Gary Maartens Paolo Denti |
| author_sort | Helen McIlleron |
| collection | DOAJ |
| description | Background. Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Methods. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM® was used to analyze the data. Results. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin’s absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid’s clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide’s clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization. |
| first_indexed | 2024-04-09T21:09:41Z |
| format | Article |
| id | doaj.art-56113a50a2264986a7856b5529419cd9 |
| institution | Directory Open Access Journal |
| issn | 2398-502X |
| language | English |
| last_indexed | 2024-04-09T21:09:41Z |
| publishDate | 2022-11-01 |
| publisher | Wellcome |
| record_format | Article |
| series | Wellcome Open Research |
| spelling | doaj.art-56113a50a2264986a7856b5529419cd92023-03-29T01:00:01ZengWellcomeWellcome Open Research2398-502X2022-11-01720580Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations]Helen McIlleron0https://orcid.org/0000-0002-0982-6226Lubbe Wiesner1https://orcid.org/0000-0002-9070-8699Charlotte Schutz2Robert J. Wilkinson3https://orcid.org/0000-0002-2753-1800Graeme Meintjes4Noha Abdelgawad5https://orcid.org/0000-0002-4907-345XDavid Barr6Maxwell Chirehwa7Saskia Janssen8Amy Ward9Muki Shey10https://orcid.org/0000-0002-8776-4737Rosie Burton11Gary Maartens12https://orcid.org/0000-0003-3080-6606Paolo Denti13Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South AfricaDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South AfricaWellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South AfricaWellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South AfricaWellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South AfricaDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South AfricaWellcome Trust Liverpool Glasgow Centre for Global Health Research, University of Liverpool, Liverpool, L3 5QA, UKDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South AfricaAmsterdam University Medical Centre, University of Amsterdam, Amsterdam, 19268, The NetherlandsWellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South AfricaWellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South AfricaDepartment of Medicine, University of Cape Town, Observatory, 7925, South AfricaDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South AfricaDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South AfricaBackground. Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Methods. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM® was used to analyze the data. Results. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin’s absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid’s clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide’s clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.https://wellcomeopenresearch.org/articles/7-72/v2rifampicin isoniazid pyrazinamide hospitalization tuberculosiseng |
| spellingShingle | Helen McIlleron Lubbe Wiesner Charlotte Schutz Robert J. Wilkinson Graeme Meintjes Noha Abdelgawad David Barr Maxwell Chirehwa Saskia Janssen Amy Ward Muki Shey Rosie Burton Gary Maartens Paolo Denti Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations] Wellcome Open Research rifampicin isoniazid pyrazinamide hospitalization tuberculosis eng |
| title | Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations] |
| title_full | Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations] |
| title_fullStr | Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations] |
| title_full_unstemmed | Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations] |
| title_short | Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations] |
| title_sort | pharmacokinetics of antitubercular drugs in patients hospitalized with hiv associated tuberculosis a population modeling analysis version 2 peer review 1 approved 2 approved with reservations |
| topic | rifampicin isoniazid pyrazinamide hospitalization tuberculosis eng |
| url | https://wellcomeopenresearch.org/articles/7-72/v2 |
| work_keys_str_mv | AT helenmcilleron pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT lubbewiesner pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT charlotteschutz pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT robertjwilkinson pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT graememeintjes pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT nohaabdelgawad pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT davidbarr pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT maxwellchirehwa pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT saskiajanssen pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT amyward pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT mukishey pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT rosieburton pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT garymaartens pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations AT paolodenti pharmacokineticsofantituberculardrugsinpatientshospitalizedwithhivassociatedtuberculosisapopulationmodelinganalysisversion2peerreview1approved2approvedwithreservations |