The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis

Aims Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). Methods We...

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Published in:British journal of clinical pharmacology 2023-01, Vol.89 (1), p.290-298
Main Authors: Aydin, Volkan, Bahar, Ayfer, Vizdiklar, Caner, Akici, Ahmet
Format: Article
Language:English
Subjects:
drug regulation
Drug-Related Side Effects and Adverse Reactions
Humans
pharmacoepidemiology
pharmacovigilance
pure enantiomer
Stereoisomerism
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creator Aydin, Volkan
Bahar, Ayfer
Vizdiklar, Caner
Akici, Ahmet
description Aims Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). Methods We searched the literature regarding withdrawn drugs due to safety‐related issues (n = 391) to compare them with all available small‐molecule drugs (n = 1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC‐1 (Anatomical Therapeutic Chemical) level and ADR. Results We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6–2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9–3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4 ± 0.8 years), followed by achiral drugs (55.4 ± 0.9 years, P 
doi_str_mv 10.1111/bcp.15486
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We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). Methods We searched the literature regarding withdrawn drugs due to safety‐related issues (n = 391) to compare them with all available small‐molecule drugs (n = 1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC‐1 (Anatomical Therapeutic Chemical) level and ADR. Results We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6–2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9–3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4 ± 0.8 years), followed by achiral drugs (55.4 ± 0.9 years, P < .01) and chiral mixtures (52.4 ± 1.4 years, P < .01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P = .02), in 1961–1980 (P < .001) or 1981–2000 (P < .001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P = .02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P < .01) and cardiovascular ADRs (P < .01). Conclusion Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity.]]></description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.15486</identifier><identifier>PMID: 35942905</identifier><language>eng</language><publisher>England</publisher><subject>drug regulation ; Drug-Related Side Effects and Adverse Reactions ; Humans ; pharmacoepidemiology ; pharmacovigilance ; pure enantiomer ; Stereoisomerism</subject><ispartof>British journal of clinical pharmacology, 2023-01, Vol.89 (1), p.290-298</ispartof><rights>2022 British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3606-e4c4858cda36d01a8f0f4872b7029ddb1b2df9308b7a49880196c14f4d54f1473</citedby><cites>FETCH-LOGICAL-c3606-e4c4858cda36d01a8f0f4872b7029ddb1b2df9308b7a49880196c14f4d54f1473</cites><orcidid>0000-0002-8593-0818</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35942905$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aydin, Volkan</creatorcontrib><creatorcontrib>Bahar, Ayfer</creatorcontrib><creatorcontrib>Vizdiklar, Caner</creatorcontrib><creatorcontrib>Akici, Ahmet</creatorcontrib><title>The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description><![CDATA[Aims Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). Methods We searched the literature regarding withdrawn drugs due to safety‐related issues (n = 391) to compare them with all available small‐molecule drugs (n = 1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC‐1 (Anatomical Therapeutic Chemical) level and ADR. Results We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6–2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9–3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4 ± 0.8 years), followed by achiral drugs (55.4 ± 0.9 years, P < .01) and chiral mixtures (52.4 ± 1.4 years, P < .01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P = .02), in 1961–1980 (P < .001) or 1981–2000 (P < .001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P = .02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P < .01) and cardiovascular ADRs (P < .01). Conclusion Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity.]]></description><subject>drug regulation</subject><subject>Drug-Related Side Effects and Adverse Reactions</subject><subject>Humans</subject><subject>pharmacoepidemiology</subject><subject>pharmacovigilance</subject><subject>pure enantiomer</subject><subject>Stereoisomerism</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp1kLtOwzAUhi0EoqUw8ALIK0NaO77EYSsVN6kSDGWOHF-oUdpEtkuVt69pgI2z_Gf4zq-jD4BrjKY4zaxW3RQzKvgJGGPCWZbjnJ2CMSKIZyxneAQuQvhECBPM2TkYEVbSvERsDNRqbaAMoVVORtduYWuhWjsvmxTSSxWNdyE6BfcurqH2u4_jpr3cJ0bvDIwtDNKa2N_BOVTtpktn0X2l2q1s-uDCJTizsgnm6icn4P3xYbV4zpavTy-L-TJThKdHDVVUMKG0JFwjLIVFlooirwuUl1rXuM61LQkSdSFpKQTCJVeYWqoZtZgWZAJuh17l2xC8sVXn3Ub6vsKo-hZVJVHVUVRibwa229Ubo__IXzMJmA3A3jWm_7-pul-8DZUHZ3Fy_Q</recordid><startdate>202301</startdate><enddate>202301</enddate><creator>Aydin, Volkan</creator><creator>Bahar, Ayfer</creator><creator>Vizdiklar, Caner</creator><creator>Akici, Ahmet</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-8593-0818</orcidid></search><sort><creationdate>202301</creationdate><title>The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis</title><author>Aydin, Volkan ; Bahar, Ayfer ; Vizdiklar, Caner ; Akici, Ahmet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3606-e4c4858cda36d01a8f0f4872b7029ddb1b2df9308b7a49880196c14f4d54f1473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>drug regulation</topic><topic>Drug-Related Side Effects and Adverse Reactions</topic><topic>Humans</topic><topic>pharmacoepidemiology</topic><topic>pharmacovigilance</topic><topic>pure enantiomer</topic><topic>Stereoisomerism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aydin, Volkan</creatorcontrib><creatorcontrib>Bahar, Ayfer</creatorcontrib><creatorcontrib>Vizdiklar, Caner</creatorcontrib><creatorcontrib>Akici, Ahmet</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aydin, Volkan</au><au>Bahar, Ayfer</au><au>Vizdiklar, Caner</au><au>Akici, Ahmet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2023-01</date><risdate>2023</risdate><volume>89</volume><issue>1</issue><spage>290</spage><epage>298</epage><pages>290-298</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><abstract><![CDATA[Aims Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). Methods We searched the literature regarding withdrawn drugs due to safety‐related issues (n = 391) to compare them with all available small‐molecule drugs (n = 1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC‐1 (Anatomical Therapeutic Chemical) level and ADR. Results We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6–2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9–3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4 ± 0.8 years), followed by achiral drugs (55.4 ± 0.9 years, P < .01) and chiral mixtures (52.4 ± 1.4 years, P < .01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P = .02), in 1961–1980 (P < .001) or 1981–2000 (P < .001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P = .02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P < .01) and cardiovascular ADRs (P < .01). Conclusion Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity.]]></abstract><cop>England</cop><pmid>35942905</pmid><doi>10.1111/bcp.15486</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-8593-0818</orcidid><oa>free_for_read</oa></addata></record>
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subjects drug regulation
Drug-Related Side Effects and Adverse Reactions
Humans
pharmacoepidemiology
pharmacovigilance
pure enantiomer
Stereoisomerism
title The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis
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