Prediction of Clinical Irrelevance of PK Differences in Atorvastatin Using PK/PD Models Derived From Literature-Based Meta-Analyses
To support the development of a fixed‐dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met tr...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2014-07, Vol.96 (1), p.101-109 |
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| creator | Vargo, R Adewale, A Behm, M O Mandema, J Kerbusch, T |
| description | To support the development of a fixed‐dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature‐based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non–clinically significant change of |
| doi_str_mv | 10.1038/clpt.2014.66 |
| format | Article |
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Clinical Pharmacology & Therapeutics (2014); 96 1, 101–109. doi:10.1038/clpt.2014.66</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1038/clpt.2014.66</identifier><identifier>PMID: 24682029</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>Basingstoke: Blackwell Publishing Ltd</publisher><subject>Atorvastatin Calcium ; Azetidines - pharmacokinetics ; Azetidines - pharmacology ; Biological and medical sciences ; Cholesterol, LDL - blood ; Drug Therapy, Combination ; Ezetimibe ; Heptanoic Acids - pharmacokinetics ; Heptanoic Acids - pharmacology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Medical sciences ; Meta-Analysis as Topic ; Models, Biological ; Pharmacology. Drug treatments ; Pyrroles - pharmacokinetics ; Pyrroles - pharmacology ; Therapeutic Equivalency</subject><ispartof>Clinical pharmacology and therapeutics, 2014-07, Vol.96 (1), p.101-109</ispartof><rights>2014 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2014 American Society for Clinical Pharmacology and Therapeutics 2014 American Society for Clinical Pharmacology and Therapeutics</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5006-c485da72efe798a1e5c7c59ed745b97e73b4694e1a9f6a75c2dc2d4c98cdf3f53</citedby><cites>FETCH-LOGICAL-c5006-c485da72efe798a1e5c7c59ed745b97e73b4694e1a9f6a75c2dc2d4c98cdf3f53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1038%2Fclpt.2014.66$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1038%2Fclpt.2014.66$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28594612$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24682029$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vargo, R</creatorcontrib><creatorcontrib>Adewale, A</creatorcontrib><creatorcontrib>Behm, M O</creatorcontrib><creatorcontrib>Mandema, J</creatorcontrib><creatorcontrib>Kerbusch, T</creatorcontrib><title>Prediction of Clinical Irrelevance of PK Differences in Atorvastatin Using PK/PD Models Derived From Literature-Based Meta-Analyses</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clinical Pharmacology & Therapeutics</addtitle><description>To support the development of a fixed‐dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature‐based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non–clinically significant change of <1.2% absolute difference in the percentage lowering of low‐density‐lipoprotein cholesterol . Both FDC doses were confirmed to be clinically equivalent to coadministration in the subsequent clinical equivalence trials. These data suggest that modeling of dose–response relationships may be useful in predicting clinical equivalence, lowering cost/timelines through effective powering of studies, and predicting the effectiveness of new dosage formulations without the need for additional clinical efficacy trials in regulatory settings.
Clinical Pharmacology & Therapeutics (2014); 96 1, 101–109. doi:10.1038/clpt.2014.66</description><subject>Atorvastatin Calcium</subject><subject>Azetidines - pharmacokinetics</subject><subject>Azetidines - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cholesterol, LDL - blood</subject><subject>Drug Therapy, Combination</subject><subject>Ezetimibe</subject><subject>Heptanoic Acids - pharmacokinetics</subject><subject>Heptanoic Acids - pharmacology</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</subject><subject>Medical sciences</subject><subject>Meta-Analysis as Topic</subject><subject>Models, Biological</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrroles - pharmacokinetics</subject><subject>Pyrroles - pharmacology</subject><subject>Therapeutic Equivalency</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc9v0zAUxyMEYmVw44x84UY6xz_jC1JJ2ZjIIIeOHS3XeR6GNKnsrNAz_zgOHQUuSJas9_Xn-33We1n2vMDzAtPyzHbbcU5wweZCPMhmBackF5zyh9kMY6xyRag4yZ7E-CWVTJXl4-yEMFESTNQs-9EEaL0d_dCjwaGq8723pkOXIUAHO9NbmPTmPVp65yBAEiLyPVqMQ9iZOJoxFdfR97cJOmuW6GpooYtoCcHvoEXnYdig2o8QzHgXIH9jYlKvYDT5ojfdPkJ8mj1ypovw7P4-za7P366qd3n98eKyWtS55RiL3LKSt0YScCBVaQrgVlquoJWMr5UESddMKAaFUU4YyS1p02FWlbZ11HF6mr0-5G7v1htoLfRjMJ3eBr8xYa8H4_W_L73_rG-HnWZYkJKyFPDqEGDDEGMAd_QWWE_L0NMy9LQMLUTCX_zd7wj_nn4CXt4DJqahu5DG7eMfruSKiYIkTh64b76D_X-b6qpZVXWzmspfX8gPTh9H-H50mvBVC0kl1zcfLjQVN0v8qVaa0J9ZvLXV</recordid><startdate>201407</startdate><enddate>201407</enddate><creator>Vargo, R</creator><creator>Adewale, A</creator><creator>Behm, M O</creator><creator>Mandema, J</creator><creator>Kerbusch, T</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing Group</general><scope>BSCLL</scope><scope>24P</scope><scope>WIN</scope><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><scope>5PM</scope></search><sort><creationdate>201407</creationdate><title>Prediction of Clinical Irrelevance of PK Differences in Atorvastatin Using PK/PD Models Derived From Literature-Based Meta-Analyses</title><author>Vargo, R ; Adewale, A ; Behm, M O ; Mandema, J ; Kerbusch, T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5006-c485da72efe798a1e5c7c59ed745b97e73b4694e1a9f6a75c2dc2d4c98cdf3f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Atorvastatin Calcium</topic><topic>Azetidines - pharmacokinetics</topic><topic>Azetidines - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cholesterol, LDL - blood</topic><topic>Drug Therapy, Combination</topic><topic>Ezetimibe</topic><topic>Heptanoic Acids - pharmacokinetics</topic><topic>Heptanoic Acids - pharmacology</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</topic><topic>Medical sciences</topic><topic>Meta-Analysis as Topic</topic><topic>Models, Biological</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrroles - pharmacokinetics</topic><topic>Pyrroles - pharmacology</topic><topic>Therapeutic Equivalency</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vargo, R</creatorcontrib><creatorcontrib>Adewale, A</creatorcontrib><creatorcontrib>Behm, M O</creatorcontrib><creatorcontrib>Mandema, J</creatorcontrib><creatorcontrib>Kerbusch, T</creatorcontrib><collection>Istex</collection><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library (Open Access Collection)</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vargo, R</au><au>Adewale, A</au><au>Behm, M O</au><au>Mandema, J</au><au>Kerbusch, T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prediction of Clinical Irrelevance of PK Differences in Atorvastatin Using PK/PD Models Derived From Literature-Based Meta-Analyses</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clinical Pharmacology & Therapeutics</addtitle><date>2014-07</date><risdate>2014</risdate><volume>96</volume><issue>1</issue><spage>101</spage><epage>109</epage><pages>101-109</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>To support the development of a fixed‐dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature‐based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non–clinically significant change of <1.2% absolute difference in the percentage lowering of low‐density‐lipoprotein cholesterol . Both FDC doses were confirmed to be clinically equivalent to coadministration in the subsequent clinical equivalence trials. These data suggest that modeling of dose–response relationships may be useful in predicting clinical equivalence, lowering cost/timelines through effective powering of studies, and predicting the effectiveness of new dosage formulations without the need for additional clinical efficacy trials in regulatory settings.
Clinical Pharmacology & Therapeutics (2014); 96 1, 101–109. doi:10.1038/clpt.2014.66</abstract><cop>Basingstoke</cop><pub>Blackwell Publishing Ltd</pub><pmid>24682029</pmid><doi>10.1038/clpt.2014.66</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical pharmacology and therapeutics, 2014-07, Vol.96 (1), p.101-109 |
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| subjects | Atorvastatin Calcium Azetidines - pharmacokinetics Azetidines - pharmacology Biological and medical sciences Cholesterol, LDL - blood Drug Therapy, Combination Ezetimibe Heptanoic Acids - pharmacokinetics Heptanoic Acids - pharmacology Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Medical sciences Meta-Analysis as Topic Models, Biological Pharmacology. Drug treatments Pyrroles - pharmacokinetics Pyrroles - pharmacology Therapeutic Equivalency |
| title | Prediction of Clinical Irrelevance of PK Differences in Atorvastatin Using PK/PD Models Derived From Literature-Based Meta-Analyses |
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