Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis
Abstract Background Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use. Objectives To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistan...
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| Veröffentlicht in: | Journal of antimicrobial chemotherapy 2021-03, Vol.76 (4), p.1019-1024 |
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| container_title | Journal of antimicrobial chemotherapy |
| container_volume | 76 |
| creator | Alghamdi, Wael A Al-Shaer, Mohammad H Kipiani, Maia Barbakadze, Ketevan Mikiashvili, Lali Kempker, Russell R Peloquin, Charles A |
| description | Abstract
Background
Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
Objectives
To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
Methods
A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4–6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
Results
Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0–24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0–12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
Conclusions
We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents. |
| doi_str_mv | 10.1093/jac/dkaa550 |
| format | Article |
| fullrecord | <record><control><sourceid>oup_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7953320</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/jac/dkaa550</oup_id><sourcerecordid>10.1093/jac/dkaa550</sourcerecordid><originalsourceid>FETCH-LOGICAL-c412t-b89ec4bebf89d81c6957304a6b5d8f634039466edf49133b1150c45d0dd7f45d3</originalsourceid><addsrcrecordid>eNp9kEtLAzEUhYMotlZX7iUrNzo2mSTz2AhSfIGgC10Pd5JMm3ZeJhlFf72R1qIbVxfOOffcy4fQMSUXlORsugQ5VSsAIcgOGlOekCgmOd1FY8KIiFIu2AgdOLckhCQiyfbRiDGWZlzEY1Q_LcA2ILuVabU30uGuwqVW8DqYOkjnWOkaGmiNwtAqLOuugk_TBAubFvfgjW69w-_GL3Az1N4oO8wjq51xHlqP_VBqK4e6C8Ih2qugdvpoMyfo5eb6eXYXPTze3s-uHiLJaeyjMsu15KUuqyxXGZVJLlJGOCSlUFmVME5YzpNEq4rnlLGSUkEkF4oolVZhsgm6XPf2Q9loJcOHFuqit6YB-1F0YIq_TmsWxbx7K9JcMBaTUHC2LpC2c87qartLSfENvQjQiw30kD75fW6b_aEcAqfrQDf0_zZ9AXOLj6I</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis</title><source>MEDLINE</source><source>Oxford University Press Journals All Titles (1996-Current)</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Alghamdi, Wael A ; Al-Shaer, Mohammad H ; Kipiani, Maia ; Barbakadze, Ketevan ; Mikiashvili, Lali ; Kempker, Russell R ; Peloquin, Charles A</creator><creatorcontrib>Alghamdi, Wael A ; Al-Shaer, Mohammad H ; Kipiani, Maia ; Barbakadze, Ketevan ; Mikiashvili, Lali ; Kempker, Russell R ; Peloquin, Charles A</creatorcontrib><description>Abstract
Background
Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
Objectives
To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
Methods
A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4–6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
Results
Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0–24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0–12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
Conclusions
We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.</description><identifier>ISSN: 0305-7453</identifier><identifier>EISSN: 1460-2091</identifier><identifier>DOI: 10.1093/jac/dkaa550</identifier><identifier>PMID: 33378452</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Antitubercular Agents - therapeutic use ; Clofazimine ; Diarylquinolines ; Humans ; Nitroimidazoles ; Original Research ; Oxazoles ; Prospective Studies ; Tuberculosis, Multidrug-Resistant - drug therapy</subject><ispartof>Journal of antimicrobial chemotherapy, 2021-03, Vol.76 (4), p.1019-1024</ispartof><rights>The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-b89ec4bebf89d81c6957304a6b5d8f634039466edf49133b1150c45d0dd7f45d3</citedby><cites>FETCH-LOGICAL-c412t-b89ec4bebf89d81c6957304a6b5d8f634039466edf49133b1150c45d0dd7f45d3</cites><orcidid>0000-0003-1432-5175 ; 0000-0002-4484-6994</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33378452$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alghamdi, Wael A</creatorcontrib><creatorcontrib>Al-Shaer, Mohammad H</creatorcontrib><creatorcontrib>Kipiani, Maia</creatorcontrib><creatorcontrib>Barbakadze, Ketevan</creatorcontrib><creatorcontrib>Mikiashvili, Lali</creatorcontrib><creatorcontrib>Kempker, Russell R</creatorcontrib><creatorcontrib>Peloquin, Charles A</creatorcontrib><title>Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis</title><title>Journal of antimicrobial chemotherapy</title><addtitle>J Antimicrob Chemother</addtitle><description>Abstract
Background
Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
Objectives
To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
Methods
A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4–6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
Results
Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0–24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0–12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
Conclusions
We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.</description><subject>Antitubercular Agents - therapeutic use</subject><subject>Clofazimine</subject><subject>Diarylquinolines</subject><subject>Humans</subject><subject>Nitroimidazoles</subject><subject>Original Research</subject><subject>Oxazoles</subject><subject>Prospective Studies</subject><subject>Tuberculosis, Multidrug-Resistant - drug therapy</subject><issn>0305-7453</issn><issn>1460-2091</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLAzEUhYMotlZX7iUrNzo2mSTz2AhSfIGgC10Pd5JMm3ZeJhlFf72R1qIbVxfOOffcy4fQMSUXlORsugQ5VSsAIcgOGlOekCgmOd1FY8KIiFIu2AgdOLckhCQiyfbRiDGWZlzEY1Q_LcA2ILuVabU30uGuwqVW8DqYOkjnWOkaGmiNwtAqLOuugk_TBAubFvfgjW69w-_GL3Az1N4oO8wjq51xHlqP_VBqK4e6C8Ih2qugdvpoMyfo5eb6eXYXPTze3s-uHiLJaeyjMsu15KUuqyxXGZVJLlJGOCSlUFmVME5YzpNEq4rnlLGSUkEkF4oolVZhsgm6XPf2Q9loJcOHFuqit6YB-1F0YIq_TmsWxbx7K9JcMBaTUHC2LpC2c87qartLSfENvQjQiw30kD75fW6b_aEcAqfrQDf0_zZ9AXOLj6I</recordid><startdate>20210312</startdate><enddate>20210312</enddate><creator>Alghamdi, Wael A</creator><creator>Al-Shaer, Mohammad H</creator><creator>Kipiani, Maia</creator><creator>Barbakadze, Ketevan</creator><creator>Mikiashvili, Lali</creator><creator>Kempker, Russell R</creator><creator>Peloquin, Charles A</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1432-5175</orcidid><orcidid>https://orcid.org/0000-0002-4484-6994</orcidid></search><sort><creationdate>20210312</creationdate><title>Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis</title><author>Alghamdi, Wael A ; Al-Shaer, Mohammad H ; Kipiani, Maia ; Barbakadze, Ketevan ; Mikiashvili, Lali ; Kempker, Russell R ; Peloquin, Charles A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-b89ec4bebf89d81c6957304a6b5d8f634039466edf49133b1150c45d0dd7f45d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antitubercular Agents - therapeutic use</topic><topic>Clofazimine</topic><topic>Diarylquinolines</topic><topic>Humans</topic><topic>Nitroimidazoles</topic><topic>Original Research</topic><topic>Oxazoles</topic><topic>Prospective Studies</topic><topic>Tuberculosis, Multidrug-Resistant - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alghamdi, Wael A</creatorcontrib><creatorcontrib>Al-Shaer, Mohammad H</creatorcontrib><creatorcontrib>Kipiani, Maia</creatorcontrib><creatorcontrib>Barbakadze, Ketevan</creatorcontrib><creatorcontrib>Mikiashvili, Lali</creatorcontrib><creatorcontrib>Kempker, Russell R</creatorcontrib><creatorcontrib>Peloquin, Charles A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of antimicrobial chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alghamdi, Wael A</au><au>Al-Shaer, Mohammad H</au><au>Kipiani, Maia</au><au>Barbakadze, Ketevan</au><au>Mikiashvili, Lali</au><au>Kempker, Russell R</au><au>Peloquin, Charles A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis</atitle><jtitle>Journal of antimicrobial chemotherapy</jtitle><addtitle>J Antimicrob Chemother</addtitle><date>2021-03-12</date><risdate>2021</risdate><volume>76</volume><issue>4</issue><spage>1019</spage><epage>1024</epage><pages>1019-1024</pages><issn>0305-7453</issn><eissn>1460-2091</eissn><abstract>Abstract
Background
Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
Objectives
To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
Methods
A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4–6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
Results
Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0–24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0–12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
Conclusions
We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33378452</pmid><doi>10.1093/jac/dkaa550</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-1432-5175</orcidid><orcidid>https://orcid.org/0000-0002-4484-6994</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Antitubercular Agents - therapeutic use Clofazimine Diarylquinolines Humans Nitroimidazoles Original Research Oxazoles Prospective Studies Tuberculosis, Multidrug-Resistant - drug therapy |
| title | Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis |
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