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Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models
Background Combination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight. Objective Our obje...
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| Published in: | Clinical pharmacology and therapeutics 2002-10, Vol.72 (4), p.349-361 |
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| container_start_page | 349 |
| container_title | Clinical pharmacology and therapeutics |
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| creator | Jen, Juif Laughlin, Mark Chung, Carol Heft, Samuel Affrime, Melton B. Gupta, Samir K. Glue, Paul Hajian, Gerald |
| description | Background
Combination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.
Objective
Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles.
Methods
Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose‐concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800‐mg/d dose, empiric weight‐adjusted doses (ie, 1000 mg/d for patients who weighed ≤75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights ≤75/>75 kg] and 800 mg/d for patients who weighed 85 kg [800/1000/1200 mg/d on the basis of body weights 85 kg]), a dose of 13 mg/kg per day, and other per‐body weight doses between 9 and 16 mg/kg per day.
Results
Simulation results showed that both efficacy and toxicity increased as the milligrams‐per‐kilogram dose of ribavirin increased. The body weight‐based 800/1000/1200‐mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800‐mg/d dose. In particular, patients with genotype‐1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200‐mg/d and 13‐mg/kg per day dose groups.
Conclusions
This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa‐2b) for patients with chronic hepatitis C should be based on body weight.
Clinical Pharmacology & Therapeutics (2002) 72, 349–361; doi: 10.1067/mcp.2002.127112 |
| doi_str_mv | 10.1067/mcp.2002.127112 |
| format | article |
| fullrecord | <record><control><sourceid>wiley_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1067_mcp_2002_127112</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>CPTCLPT200296</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3996-bad173cf0bf9de8cf0d2ecd27355ea94a2a3ef16c99c14ac493310f9437ca72f3</originalsourceid><addsrcrecordid>eNqFkEtLAzEURoMoWqtrdzIbl1PzmFfcyeALCorU9XB7J7HReYRkqvTfmzLVLl3lfuF898Ih5ILRGaNZft2inXFK-YzxnDF-QCYsFTzOUpEekgmlVMaSi-yEnHr_EWIii-KYnDAuiiwT-YSYV7OEL-NMF9W9N917FCZcub4zGK2UhcEMxkflTXRrbWMw5L6Leh3Z3q6bMdkVuBaw_zSdGgzGv7nedNCGNW1fq8afkSMNjVfnu3dK3u7vFuVjPH9-eCpv5zEKKbN4CTXLBWq61LJWRRhqrrDmuUhTBTIBDkJplqGUyBLARArBqJaJyBFyrsWUXI970fXeO6Ur60wLblMxWm2lVUFatZVWjdJC43Js2PWyVfWe31kKwNUOAI_QaAcdGr_nkpQxJorA3Yzct2nU5r-7VfmyKOcvi-2XzEI5GssdDGun_trY2GGH_ACGYZSM</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models</title><source>Wiley-Blackwell Journals</source><creator>Jen, Juif ; Laughlin, Mark ; Chung, Carol ; Heft, Samuel ; Affrime, Melton B. ; Gupta, Samir K. ; Glue, Paul ; Hajian, Gerald</creator><creatorcontrib>Jen, Juif ; Laughlin, Mark ; Chung, Carol ; Heft, Samuel ; Affrime, Melton B. ; Gupta, Samir K. ; Glue, Paul ; Hajian, Gerald</creatorcontrib><description>Background
Combination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.
Objective
Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles.
Methods
Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose‐concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800‐mg/d dose, empiric weight‐adjusted doses (ie, 1000 mg/d for patients who weighed ≤75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights ≤75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65‐85/>85 kg]), a dose of 13 mg/kg per day, and other per‐body weight doses between 9 and 16 mg/kg per day.
Results
Simulation results showed that both efficacy and toxicity increased as the milligrams‐per‐kilogram dose of ribavirin increased. The body weight‐based 800/1000/1200‐mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800‐mg/d dose. In particular, patients with genotype‐1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200‐mg/d and 13‐mg/kg per day dose groups.
Conclusions
This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa‐2b) for patients with chronic hepatitis C should be based on body weight.
Clinical Pharmacology & Therapeutics (2002) 72, 349–361; doi: 10.1067/mcp.2002.127112</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1067/mcp.2002.127112</identifier><identifier>PMID: 12386637</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>New York, NY: Nature Publishing</publisher><subject>Adult ; Aged ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Biological and medical sciences ; Confidence Intervals ; Dose-Response Relationship, Drug ; Female ; Hepatitis C, Chronic - drug therapy ; Hepatitis C, Chronic - metabolism ; Humans ; Logistic Models ; Male ; Medical sciences ; Models, Biological ; Pharmacology. Drug treatments ; Ribavirin - administration & dosage ; Ribavirin - adverse effects ; Ribavirin - pharmacokinetics</subject><ispartof>Clinical pharmacology and therapeutics, 2002-10, Vol.72 (4), p.349-361</ispartof><rights>2002 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3996-bad173cf0bf9de8cf0d2ecd27355ea94a2a3ef16c99c14ac493310f9437ca72f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1067%2Fmcp.2002.127112$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1067%2Fmcp.2002.127112$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14511138$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12386637$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jen, Juif</creatorcontrib><creatorcontrib>Laughlin, Mark</creatorcontrib><creatorcontrib>Chung, Carol</creatorcontrib><creatorcontrib>Heft, Samuel</creatorcontrib><creatorcontrib>Affrime, Melton B.</creatorcontrib><creatorcontrib>Gupta, Samir K.</creatorcontrib><creatorcontrib>Glue, Paul</creatorcontrib><creatorcontrib>Hajian, Gerald</creatorcontrib><title>Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Background
Combination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.
Objective
Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles.
Methods
Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose‐concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800‐mg/d dose, empiric weight‐adjusted doses (ie, 1000 mg/d for patients who weighed ≤75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights ≤75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65‐85/>85 kg]), a dose of 13 mg/kg per day, and other per‐body weight doses between 9 and 16 mg/kg per day.
Results
Simulation results showed that both efficacy and toxicity increased as the milligrams‐per‐kilogram dose of ribavirin increased. The body weight‐based 800/1000/1200‐mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800‐mg/d dose. In particular, patients with genotype‐1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200‐mg/d and 13‐mg/kg per day dose groups.
Conclusions
This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa‐2b) for patients with chronic hepatitis C should be based on body weight.
Clinical Pharmacology & Therapeutics (2002) 72, 349–361; doi: 10.1067/mcp.2002.127112</description><subject>Adult</subject><subject>Aged</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Biological and medical sciences</subject><subject>Confidence Intervals</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Hepatitis C, Chronic - drug therapy</subject><subject>Hepatitis C, Chronic - metabolism</subject><subject>Humans</subject><subject>Logistic Models</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Models, Biological</subject><subject>Pharmacology. Drug treatments</subject><subject>Ribavirin - administration & dosage</subject><subject>Ribavirin - adverse effects</subject><subject>Ribavirin - pharmacokinetics</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNqFkEtLAzEURoMoWqtrdzIbl1PzmFfcyeALCorU9XB7J7HReYRkqvTfmzLVLl3lfuF898Ih5ILRGaNZft2inXFK-YzxnDF-QCYsFTzOUpEekgmlVMaSi-yEnHr_EWIii-KYnDAuiiwT-YSYV7OEL-NMF9W9N917FCZcub4zGK2UhcEMxkflTXRrbWMw5L6Leh3Z3q6bMdkVuBaw_zSdGgzGv7nedNCGNW1fq8afkSMNjVfnu3dK3u7vFuVjPH9-eCpv5zEKKbN4CTXLBWq61LJWRRhqrrDmuUhTBTIBDkJplqGUyBLARArBqJaJyBFyrsWUXI970fXeO6Ur60wLblMxWm2lVUFatZVWjdJC43Js2PWyVfWe31kKwNUOAI_QaAcdGr_nkpQxJorA3Yzct2nU5r-7VfmyKOcvi-2XzEI5GssdDGun_trY2GGH_ACGYZSM</recordid><startdate>200210</startdate><enddate>200210</enddate><creator>Jen, Juif</creator><creator>Laughlin, Mark</creator><creator>Chung, Carol</creator><creator>Heft, Samuel</creator><creator>Affrime, Melton B.</creator><creator>Gupta, Samir K.</creator><creator>Glue, Paul</creator><creator>Hajian, Gerald</creator><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>200210</creationdate><title>Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models</title><author>Jen, Juif ; Laughlin, Mark ; Chung, Carol ; Heft, Samuel ; Affrime, Melton B. ; Gupta, Samir K. ; Glue, Paul ; Hajian, Gerald</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3996-bad173cf0bf9de8cf0d2ecd27355ea94a2a3ef16c99c14ac493310f9437ca72f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Biological and medical sciences</topic><topic>Confidence Intervals</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Hepatitis C, Chronic - drug therapy</topic><topic>Hepatitis C, Chronic - metabolism</topic><topic>Humans</topic><topic>Logistic Models</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Models, Biological</topic><topic>Pharmacology. Drug treatments</topic><topic>Ribavirin - administration & dosage</topic><topic>Ribavirin - adverse effects</topic><topic>Ribavirin - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jen, Juif</creatorcontrib><creatorcontrib>Laughlin, Mark</creatorcontrib><creatorcontrib>Chung, Carol</creatorcontrib><creatorcontrib>Heft, Samuel</creatorcontrib><creatorcontrib>Affrime, Melton B.</creatorcontrib><creatorcontrib>Gupta, Samir K.</creatorcontrib><creatorcontrib>Glue, Paul</creatorcontrib><creatorcontrib>Hajian, Gerald</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jen, Juif</au><au>Laughlin, Mark</au><au>Chung, Carol</au><au>Heft, Samuel</au><au>Affrime, Melton B.</au><au>Gupta, Samir K.</au><au>Glue, Paul</au><au>Hajian, Gerald</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2002-10</date><risdate>2002</risdate><volume>72</volume><issue>4</issue><spage>349</spage><epage>361</epage><pages>349-361</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Background
Combination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.
Objective
Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles.
Methods
Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose‐concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800‐mg/d dose, empiric weight‐adjusted doses (ie, 1000 mg/d for patients who weighed ≤75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights ≤75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65‐85/>85 kg]), a dose of 13 mg/kg per day, and other per‐body weight doses between 9 and 16 mg/kg per day.
Results
Simulation results showed that both efficacy and toxicity increased as the milligrams‐per‐kilogram dose of ribavirin increased. The body weight‐based 800/1000/1200‐mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800‐mg/d dose. In particular, patients with genotype‐1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200‐mg/d and 13‐mg/kg per day dose groups.
Conclusions
This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa‐2b) for patients with chronic hepatitis C should be based on body weight.
Clinical Pharmacology & Therapeutics (2002) 72, 349–361; doi: 10.1067/mcp.2002.127112</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>12386637</pmid><doi>10.1067/mcp.2002.127112</doi><tpages>13</tpages></addata></record> |
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| ispartof | Clinical pharmacology and therapeutics, 2002-10, Vol.72 (4), p.349-361 |
| issn | 0009-9236 1532-6535 |
| language | eng |
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| source | Wiley-Blackwell Journals |
| subjects | Adult Aged Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Confidence Intervals Dose-Response Relationship, Drug Female Hepatitis C, Chronic - drug therapy Hepatitis C, Chronic - metabolism Humans Logistic Models Male Medical sciences Models, Biological Pharmacology. Drug treatments Ribavirin - administration & dosage Ribavirin - adverse effects Ribavirin - pharmacokinetics |
| title | Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models |
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