Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania

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dc.contributor.authorDenti, Paoloen_ZA
dc.contributor.authorJeremiah, Kidolaen_ZA
dc.contributor.authorChigutsa, Emmanuelen_ZA
dc.contributor.authorFaurholt-Jepsen, Danielen_ZA
dc.contributor.authorPrayGod, Georgeen_ZA
dc.contributor.authorRange, Nyagosyaen_ZA
dc.contributor.authorCastel, Sandraen_ZA
dc.contributor.authorWiesner, Lubbeen_ZA
dc.contributor.authorHagen, Christian Munchen_ZA
dc.contributor.authorChristiansen, Michaelen_ZA
dc.date.accessioned2015-11-23T12:36:24Z
dc.date.available2015-11-23T12:36:24Z
dc.date.issued2015en_ZA
dc.description.abstractExposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients.en_ZA
dc.identifier.apacitationDenti, P., Jeremiah, K., Chigutsa, E., Faurholt-Jepsen, D., PrayGod, G., Range, N., ... Christiansen, M. (2015). Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania. <i>PLoS One</i>, http://hdl.handle.net/11427/15336en_ZA
dc.identifier.chicagocitationDenti, Paolo, Kidola Jeremiah, Emmanuel Chigutsa, Daniel Faurholt-Jepsen, George PrayGod, Nyagosya Range, Sandra Castel, Lubbe Wiesner, Christian Munch Hagen, and Michael Christiansen "Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania." <i>PLoS One</i> (2015) http://hdl.handle.net/11427/15336en_ZA
dc.identifier.citationDenti, P., Jeremiah, K., Chigutsa, E., Faurholt-Jepsen, D., PrayGod, G., Range, N., ... & Andersen, A. B. (2015). Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania. PloS one, 10(10), e0141002. doi:10.1371/journal.pone.0141002en_ZA
dc.identifier.ris TY - Journal Article AU - Denti, Paolo AU - Jeremiah, Kidola AU - Chigutsa, Emmanuel AU - Faurholt-Jepsen, Daniel AU - PrayGod, George AU - Range, Nyagosya AU - Castel, Sandra AU - Wiesner, Lubbe AU - Hagen, Christian Munch AU - Christiansen, Michael AB - Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients. DA - 2015 DB - OpenUCT DO - 10.1371/journal.pone.0141002 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania TI - Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania UR - http://hdl.handle.net/11427/15336 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15336
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0141002
dc.identifier.vancouvercitationDenti P, Jeremiah K, Chigutsa E, Faurholt-Jepsen D, PrayGod G, Range N, et al. Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania. PLoS One. 2015; http://hdl.handle.net/11427/15336.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2015 Denti et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherIsoniaziden_ZA
dc.subject.otherHIVen_ZA
dc.subject.otherTuberculosisen_ZA
dc.subject.otherPharmacokineticsen_ZA
dc.subject.otherDrug absorptionen_ZA
dc.subject.otherSputumen_ZA
dc.subject.otherTuberculosis diagnosis and managementen_ZA
dc.subject.otherDrug therapyen_ZA
dc.titlePharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzaniaen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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