Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection
Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We...
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| creator | Flamm, Steven Reddy, K. Rajender Zadeikis, Neddie Hassanein, Tarek Bacon, Bruce R. Maieron, Andreas Zeuzem, Stefan Bourliere, Marc Calleja, Jose L. Kosloski, Matthew P. Oberoi, Rajneet K. Lin, Chih-Wei Yu, Yao Lovell, Sandra Semizarov, Dimitri Mensa, Federico J. |
| description | Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents.
We analyzed data from 2369 patients infected with HCV genotypes 1–6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8–16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents.
Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI.
In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection—even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I). |
| doi_str_mv | 10.1016/j.cgh.2018.07.003 |
| format | Article |
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We analyzed data from 2369 patients infected with HCV genotypes 1–6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8–16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents.
Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI.
In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection—even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).</description><identifier>ISSN: 1542-3565</identifier><identifier>EISSN: 1542-7714</identifier><identifier>DOI: 10.1016/j.cgh.2018.07.003</identifier><identifier>PMID: 30012435</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject><![CDATA[Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Animals ; Antiviral Agents - administration & dosage ; Antiviral Agents - pharmacokinetics ; ARA ; Benzimidazoles - administration & dosage ; Benzimidazoles - pharmacokinetics ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Combination ; DAA ; Drug Combinations ; Drug Interaction ; Drug Interactions ; Female ; Hepatitis C, Chronic - drug therapy ; Humans ; Male ; Middle Aged ; Proton Pump Inhibitors - administration & dosage ; Pyrrolidines - administration & dosage ; Pyrrolidines - pharmacokinetics ; Quinoxalines - administration & dosage ; Quinoxalines - pharmacokinetics ; Sulfonamides - administration & dosage ; Sulfonamides - pharmacokinetics ; Sustained Virologic Response ; Treatment Outcome ; Young Adult]]></subject><ispartof>Clinical gastroenterology and hepatology, 2019-02, Vol.17 (3), p.527-535.e6</ispartof><rights>2019 AGA Institute</rights><rights>Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-b248225fa5ebdec1c5f8040dca65deebc75d8f85b750806afebba90ec4e33bbb3</citedby><cites>FETCH-LOGICAL-c396t-b248225fa5ebdec1c5f8040dca65deebc75d8f85b750806afebba90ec4e33bbb3</cites><orcidid>0000-0003-4525-3549</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cgh.2018.07.003$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30012435$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Flamm, Steven</creatorcontrib><creatorcontrib>Reddy, K. Rajender</creatorcontrib><creatorcontrib>Zadeikis, Neddie</creatorcontrib><creatorcontrib>Hassanein, Tarek</creatorcontrib><creatorcontrib>Bacon, Bruce R.</creatorcontrib><creatorcontrib>Maieron, Andreas</creatorcontrib><creatorcontrib>Zeuzem, Stefan</creatorcontrib><creatorcontrib>Bourliere, Marc</creatorcontrib><creatorcontrib>Calleja, Jose L.</creatorcontrib><creatorcontrib>Kosloski, Matthew P.</creatorcontrib><creatorcontrib>Oberoi, Rajneet K.</creatorcontrib><creatorcontrib>Lin, Chih-Wei</creatorcontrib><creatorcontrib>Yu, Yao</creatorcontrib><creatorcontrib>Lovell, Sandra</creatorcontrib><creatorcontrib>Semizarov, Dimitri</creatorcontrib><creatorcontrib>Mensa, Federico J.</creatorcontrib><title>Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection</title><title>Clinical gastroenterology and hepatology</title><addtitle>Clin Gastroenterol Hepatol</addtitle><description>Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents.
We analyzed data from 2369 patients infected with HCV genotypes 1–6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8–16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents.
Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI.
In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection—even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Animals</subject><subject>Antiviral Agents - administration & dosage</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>ARA</subject><subject>Benzimidazoles - administration & dosage</subject><subject>Benzimidazoles - pharmacokinetics</subject><subject>Clinical Trials, Phase II as Topic</subject><subject>Clinical Trials, Phase III as Topic</subject><subject>Combination</subject><subject>DAA</subject><subject>Drug Combinations</subject><subject>Drug Interaction</subject><subject>Drug Interactions</subject><subject>Female</subject><subject>Hepatitis C, Chronic - drug therapy</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Proton Pump Inhibitors - administration & dosage</subject><subject>Pyrrolidines - administration & dosage</subject><subject>Pyrrolidines - pharmacokinetics</subject><subject>Quinoxalines - administration & dosage</subject><subject>Quinoxalines - pharmacokinetics</subject><subject>Sulfonamides - administration & dosage</subject><subject>Sulfonamides - pharmacokinetics</subject><subject>Sustained Virologic Response</subject><subject>Treatment Outcome</subject><subject>Young Adult</subject><issn>1542-3565</issn><issn>1542-7714</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhS0EoqXwAGyQl2yS2kmcH7EajUpbqRIVorC07OvrGQ8z9mAnlfoWPDJOM7Bk5avr7xzpnkPIe85Kznh7uSthsy0rxvuSdSVj9QtyzkVTFV3Hm5enuRatOCNvUtoxVg3N0L0mZzVjvGpqcU5-X1nrQMETVd7Q-62KBwXhp_M4Okg0WHq9R1DHiI8uLozTEf2o0rz44cYtXQcPU5yX9CHhrFmBM8VXNBM4v6GrTf5K1Hl6r0b3PC-6bQzeAb1Zf6e33iKMLvi35JVV-4TvTu8Fefh89W19U9x9ub5dr-4KqId2LHTV9FUlrBKoDQIHYXvWMAOqFQZRQydMb3uhO8F61iqLWquBITRY11rr-oJ8XHyPMfyaMI3y4BLgfq88hinJinVctMPAu4zyBYUYUopo5TG6g4pPkjM5FyF3Mhch5yIk62QuIms-nOwnfUDzT_E3-Qx8WgDMRz46jDJBzgbQuJiTkCa4_9j_ARLFm58</recordid><startdate>201902</startdate><enddate>201902</enddate><creator>Flamm, Steven</creator><creator>Reddy, K. 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Rajender ; Zadeikis, Neddie ; Hassanein, Tarek ; Bacon, Bruce R. ; Maieron, Andreas ; Zeuzem, Stefan ; Bourliere, Marc ; Calleja, Jose L. ; Kosloski, Matthew P. ; Oberoi, Rajneet K. ; Lin, Chih-Wei ; Yu, Yao ; Lovell, Sandra ; Semizarov, Dimitri ; Mensa, Federico J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-b248225fa5ebdec1c5f8040dca65deebc75d8f85b750806afebba90ec4e33bbb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Animals</topic><topic>Antiviral Agents - administration & dosage</topic><topic>Antiviral Agents - pharmacokinetics</topic><topic>ARA</topic><topic>Benzimidazoles - administration & dosage</topic><topic>Benzimidazoles - pharmacokinetics</topic><topic>Clinical Trials, Phase II as Topic</topic><topic>Clinical Trials, Phase III as Topic</topic><topic>Combination</topic><topic>DAA</topic><topic>Drug Combinations</topic><topic>Drug Interaction</topic><topic>Drug Interactions</topic><topic>Female</topic><topic>Hepatitis C, Chronic - drug therapy</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Proton Pump Inhibitors - administration & dosage</topic><topic>Pyrrolidines - administration & dosage</topic><topic>Pyrrolidines - pharmacokinetics</topic><topic>Quinoxalines - administration & dosage</topic><topic>Quinoxalines - pharmacokinetics</topic><topic>Sulfonamides - administration & dosage</topic><topic>Sulfonamides - pharmacokinetics</topic><topic>Sustained Virologic Response</topic><topic>Treatment Outcome</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Flamm, Steven</creatorcontrib><creatorcontrib>Reddy, K. Rajender</creatorcontrib><creatorcontrib>Zadeikis, Neddie</creatorcontrib><creatorcontrib>Hassanein, Tarek</creatorcontrib><creatorcontrib>Bacon, Bruce R.</creatorcontrib><creatorcontrib>Maieron, Andreas</creatorcontrib><creatorcontrib>Zeuzem, Stefan</creatorcontrib><creatorcontrib>Bourliere, Marc</creatorcontrib><creatorcontrib>Calleja, Jose L.</creatorcontrib><creatorcontrib>Kosloski, Matthew P.</creatorcontrib><creatorcontrib>Oberoi, Rajneet K.</creatorcontrib><creatorcontrib>Lin, Chih-Wei</creatorcontrib><creatorcontrib>Yu, Yao</creatorcontrib><creatorcontrib>Lovell, Sandra</creatorcontrib><creatorcontrib>Semizarov, Dimitri</creatorcontrib><creatorcontrib>Mensa, Federico J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical gastroenterology and hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flamm, Steven</au><au>Reddy, K. Rajender</au><au>Zadeikis, Neddie</au><au>Hassanein, Tarek</au><au>Bacon, Bruce R.</au><au>Maieron, Andreas</au><au>Zeuzem, Stefan</au><au>Bourliere, Marc</au><au>Calleja, Jose L.</au><au>Kosloski, Matthew P.</au><au>Oberoi, Rajneet K.</au><au>Lin, Chih-Wei</au><au>Yu, Yao</au><au>Lovell, Sandra</au><au>Semizarov, Dimitri</au><au>Mensa, Federico J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection</atitle><jtitle>Clinical gastroenterology and hepatology</jtitle><addtitle>Clin Gastroenterol Hepatol</addtitle><date>2019-02</date><risdate>2019</risdate><volume>17</volume><issue>3</issue><spage>527</spage><epage>535.e6</epage><pages>527-535.e6</pages><issn>1542-3565</issn><eissn>1542-7714</eissn><abstract>Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents.
We analyzed data from 2369 patients infected with HCV genotypes 1–6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8–16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents.
Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI.
In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection—even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30012435</pmid><doi>10.1016/j.cgh.2018.07.003</doi><orcidid>https://orcid.org/0000-0003-4525-3549</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1542-3565 |
| ispartof | Clinical gastroenterology and hepatology, 2019-02, Vol.17 (3), p.527-535.e6 |
| issn | 1542-3565 1542-7714 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2071569917 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral Adult Aged Aged, 80 and over Animals Antiviral Agents - administration & dosage Antiviral Agents - pharmacokinetics ARA Benzimidazoles - administration & dosage Benzimidazoles - pharmacokinetics Clinical Trials, Phase II as Topic Clinical Trials, Phase III as Topic Combination DAA Drug Combinations Drug Interaction Drug Interactions Female Hepatitis C, Chronic - drug therapy Humans Male Middle Aged Proton Pump Inhibitors - administration & dosage Pyrrolidines - administration & dosage Pyrrolidines - pharmacokinetics Quinoxalines - administration & dosage Quinoxalines - pharmacokinetics Sulfonamides - administration & dosage Sulfonamides - pharmacokinetics Sustained Virologic Response Treatment Outcome Young Adult |
| title | Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T05%3A52%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Efficacy%20and%20Pharmacokinetics%20of%20Glecaprevir%20and%20Pibrentasvir%20With%20Concurrent%20Use%20of%20Acid-Reducing%20Agents%20in%20Patients%20With%20Chronic%20HCV%20Infection&rft.jtitle=Clinical%20gastroenterology%20and%20hepatology&rft.au=Flamm,%20Steven&rft.date=2019-02&rft.volume=17&rft.issue=3&rft.spage=527&rft.epage=535.e6&rft.pages=527-535.e6&rft.issn=1542-3565&rft.eissn=1542-7714&rft_id=info:doi/10.1016/j.cgh.2018.07.003&rft_dat=%3Cproquest_cross%3E2071569917%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2071569917&rft_id=info:pmid/30012435&rft_els_id=S154235651830702X&rfr_iscdi=true |