Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus
Objective To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose....
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| Veröffentlicht in: | Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2012-05, Vol.64 (5), p.1579-1588 |
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| creator | Bengtsson, Anders A. Sturfelt, Gunnar Lood, Christian Rönnblom, Lars van Vollenhoven, Ronald F. Axelsson, Bengt Sparre, Birgitta Tuvesson, Helén Öhman, Marie Wallén Leanderson, Tomas |
| description | Objective
To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose.
Methods
The efficacy of paquinimod was studied in lupus‐prone MRL‐lpr/lpr mice and compared with that of established SLE treatments. Dose‐response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double‐blind, placebo controlled, dose‐ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks.
Results
Paquinimod treatment resulted in disease inhibition in MRL‐lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid‐sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once‐daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported.
Conclusion
Paquinimod effectively inhibited disease and had a steroid‐sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod. |
| doi_str_mv | 10.1002/art.33493 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_540404</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1010232612</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5783-fda382efd3983dff838902395fc069a213bfa196cc4d842a2dce88ca0853751d3</originalsourceid><addsrcrecordid>eNp1kmFP1TAUhqfRCKIf_AOmiTGB5A7a9W638xsQBeONGsDwsenaUyhs62g3Ltdf7xn3AokJWZqt3fOe9-zsTZIPjO4ySrM9Ffpdzqclf5lssjwrU8o4e5VsUkqnKc9LtpG8jfEKtxnP-ZtkI8sQYJRtvtj5falCo7S_di30TscJ6X0NQVWudv1yQlRrSBegdo1rVVgSsNZppZfEW9Kpm8G1rvGGbO8fnKQZy2f5bAdFpIUFGV_6GuumPNUqVP5ONc4AMRDcrerdLXwhp_1gHETiWlIP3RDTLvgWSOM03Fsr0gw19gVtD2FCAp75xv0FMyHGD1UNaYUOuOtqpaHyqfZtH3xdj0SADlSfGh9hxCOkqL9w7QWJaLscTTvsA2tHsnD9JYnL2AN6r3ohEJb9JTSq93GI75LXVtUR3q_vW8mfb1_PDo_T-a-j74f781TnM8FTaxQXGVjDS8GNtYKLEsde5lbTolQ4-MoqVhZaT42YZiozGoTQioqcz3Jm-FaSrurGBXRDJbvgGhy89MrJ9dE1PoHMpxQv5MtneRymeRI9CFk2zbNCYFdbyfxZLY4AV4Vr1FhaaMsFk7YohJwqWkmRVVYyTZlSVVbOsgLLba_Koe_NALGXjYsa6lq14IcoMXFomhVsdP70H3rlh9DiYCXL2YxRQcVI7awoHXyMAexjh4zKMfoSoy_vo4_sx3XFoWrAPJIPWUfg8xpQUavaYha0i09cLkqO34Hc3opbuBqWzzvK_ZOzB-v1L3MYn7tHhQrXspjhX5XnP4_kKTv4cXY8P5cn_B82TDAe</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1517108082</pqid></control><display><type>article</type><title>Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><creator>Bengtsson, Anders A. ; Sturfelt, Gunnar ; Lood, Christian ; Rönnblom, Lars ; van Vollenhoven, Ronald F. ; Axelsson, Bengt ; Sparre, Birgitta ; Tuvesson, Helén ; Öhman, Marie Wallén ; Leanderson, Tomas</creator><creatorcontrib>Bengtsson, Anders A. ; Sturfelt, Gunnar ; Lood, Christian ; Rönnblom, Lars ; van Vollenhoven, Ronald F. ; Axelsson, Bengt ; Sparre, Birgitta ; Tuvesson, Helén ; Öhman, Marie Wallén ; Leanderson, Tomas</creatorcontrib><description>Objective
To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose.
Methods
The efficacy of paquinimod was studied in lupus‐prone MRL‐lpr/lpr mice and compared with that of established SLE treatments. Dose‐response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double‐blind, placebo controlled, dose‐ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks.
Results
Paquinimod treatment resulted in disease inhibition in MRL‐lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid‐sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once‐daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported.
Conclusion
Paquinimod effectively inhibited disease and had a steroid‐sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod.</description><identifier>ISSN: 0004-3591</identifier><identifier>ISSN: 2326-5191</identifier><identifier>ISSN: 1529-0131</identifier><identifier>EISSN: 1529-0131</identifier><identifier>EISSN: 2326-5205</identifier><identifier>DOI: 10.1002/art.33493</identifier><identifier>PMID: 22131101</identifier><identifier>CODEN: ARHEAW</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adult ; Aged ; Animals ; Biological and medical sciences ; Clinical Medicine ; Disease Models, Animal ; Diseases of the osteoarticular system ; Double-Blind Method ; Drug therapy ; Female ; Humans ; Immunosuppressive Agents - adverse effects ; Immunosuppressive Agents - pharmacokinetics ; Immunosuppressive Agents - therapeutic use ; Kidney - metabolism ; Kidney - pathology ; Klinisk medicin ; Lupus ; Lupus Erythematosus, Systemic - drug therapy ; Lupus Erythematosus, Systemic - metabolism ; Lupus Erythematosus, Systemic - pathology ; Male ; Medical and Health Sciences ; Medical sciences ; Medicin och hälsovetenskap ; Mice ; Mice, Inbred MRL lpr ; Middle Aged ; Mycophenolic Acid - analogs & derivatives ; Mycophenolic Acid - therapeutic use ; Prednisolone - therapeutic use ; Quinolines - adverse effects ; Quinolines - chemistry ; Quinolines - pharmacokinetics ; Quinolines - therapeutic use ; Reumatologi och inflammation ; Rheumatology and Autoimmunity ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; Severity of Illness Index ; Treatment Outcome ; Young Adult</subject><ispartof>Arthritis & rheumatology (Hoboken, N.J.), 2012-05, Vol.64 (5), p.1579-1588</ispartof><rights>Copyright © 2012 by the American College of Rheumatology</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 by the American College of Rheumatology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5783-fda382efd3983dff838902395fc069a213bfa196cc4d842a2dce88ca0853751d3</citedby><cites>FETCH-LOGICAL-c5783-fda382efd3983dff838902395fc069a213bfa196cc4d842a2dce88ca0853751d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fart.33493$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fart.33493$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,781,785,886,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25893297$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22131101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/2551630$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:124526802$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Bengtsson, Anders A.</creatorcontrib><creatorcontrib>Sturfelt, Gunnar</creatorcontrib><creatorcontrib>Lood, Christian</creatorcontrib><creatorcontrib>Rönnblom, Lars</creatorcontrib><creatorcontrib>van Vollenhoven, Ronald F.</creatorcontrib><creatorcontrib>Axelsson, Bengt</creatorcontrib><creatorcontrib>Sparre, Birgitta</creatorcontrib><creatorcontrib>Tuvesson, Helén</creatorcontrib><creatorcontrib>Öhman, Marie Wallén</creatorcontrib><creatorcontrib>Leanderson, Tomas</creatorcontrib><title>Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus</title><title>Arthritis & rheumatology (Hoboken, N.J.)</title><addtitle>Arthritis & Rheumatism</addtitle><description>Objective
To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose.
Methods
The efficacy of paquinimod was studied in lupus‐prone MRL‐lpr/lpr mice and compared with that of established SLE treatments. Dose‐response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double‐blind, placebo controlled, dose‐ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks.
Results
Paquinimod treatment resulted in disease inhibition in MRL‐lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid‐sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once‐daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported.
Conclusion
Paquinimod effectively inhibited disease and had a steroid‐sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod.</description><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Clinical Medicine</subject><subject>Disease Models, Animal</subject><subject>Diseases of the osteoarticular system</subject><subject>Double-Blind Method</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Humans</subject><subject>Immunosuppressive Agents - adverse effects</subject><subject>Immunosuppressive Agents - pharmacokinetics</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Klinisk medicin</subject><subject>Lupus</subject><subject>Lupus Erythematosus, Systemic - drug therapy</subject><subject>Lupus Erythematosus, Systemic - metabolism</subject><subject>Lupus Erythematosus, Systemic - pathology</subject><subject>Male</subject><subject>Medical and Health Sciences</subject><subject>Medical sciences</subject><subject>Medicin och hälsovetenskap</subject><subject>Mice</subject><subject>Mice, Inbred MRL lpr</subject><subject>Middle Aged</subject><subject>Mycophenolic Acid - analogs & derivatives</subject><subject>Mycophenolic Acid - therapeutic use</subject><subject>Prednisolone - therapeutic use</subject><subject>Quinolines - adverse effects</subject><subject>Quinolines - chemistry</subject><subject>Quinolines - pharmacokinetics</subject><subject>Quinolines - therapeutic use</subject><subject>Reumatologi och inflammation</subject><subject>Rheumatology and Autoimmunity</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>Severity of Illness Index</subject><subject>Treatment Outcome</subject><subject>Young Adult</subject><issn>0004-3591</issn><issn>2326-5191</issn><issn>1529-0131</issn><issn>1529-0131</issn><issn>2326-5205</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kmFP1TAUhqfRCKIf_AOmiTGB5A7a9W638xsQBeONGsDwsenaUyhs62g3Ltdf7xn3AokJWZqt3fOe9-zsTZIPjO4ySrM9Ffpdzqclf5lssjwrU8o4e5VsUkqnKc9LtpG8jfEKtxnP-ZtkI8sQYJRtvtj5falCo7S_di30TscJ6X0NQVWudv1yQlRrSBegdo1rVVgSsNZppZfEW9Kpm8G1rvGGbO8fnKQZy2f5bAdFpIUFGV_6GuumPNUqVP5ONc4AMRDcrerdLXwhp_1gHETiWlIP3RDTLvgWSOM03Fsr0gw19gVtD2FCAp75xv0FMyHGD1UNaYUOuOtqpaHyqfZtH3xdj0SADlSfGh9hxCOkqL9w7QWJaLscTTvsA2tHsnD9JYnL2AN6r3ohEJb9JTSq93GI75LXVtUR3q_vW8mfb1_PDo_T-a-j74f781TnM8FTaxQXGVjDS8GNtYKLEsde5lbTolQ4-MoqVhZaT42YZiozGoTQioqcz3Jm-FaSrurGBXRDJbvgGhy89MrJ9dE1PoHMpxQv5MtneRymeRI9CFk2zbNCYFdbyfxZLY4AV4Vr1FhaaMsFk7YohJwqWkmRVVYyTZlSVVbOsgLLba_Koe_NALGXjYsa6lq14IcoMXFomhVsdP70H3rlh9DiYCXL2YxRQcVI7awoHXyMAexjh4zKMfoSoy_vo4_sx3XFoWrAPJIPWUfg8xpQUavaYha0i09cLkqO34Hc3opbuBqWzzvK_ZOzB-v1L3MYn7tHhQrXspjhX5XnP4_kKTv4cXY8P5cn_B82TDAe</recordid><startdate>201205</startdate><enddate>201205</enddate><creator>Bengtsson, Anders A.</creator><creator>Sturfelt, Gunnar</creator><creator>Lood, Christian</creator><creator>Rönnblom, Lars</creator><creator>van Vollenhoven, Ronald F.</creator><creator>Axelsson, Bengt</creator><creator>Sparre, Birgitta</creator><creator>Tuvesson, Helén</creator><creator>Öhman, Marie Wallén</creator><creator>Leanderson, Tomas</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D95</scope></search><sort><creationdate>201205</creationdate><title>Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus</title><author>Bengtsson, Anders A. ; Sturfelt, Gunnar ; Lood, Christian ; Rönnblom, Lars ; van Vollenhoven, Ronald F. ; Axelsson, Bengt ; Sparre, Birgitta ; Tuvesson, Helén ; Öhman, Marie Wallén ; Leanderson, Tomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5783-fda382efd3983dff838902395fc069a213bfa196cc4d842a2dce88ca0853751d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Clinical Medicine</topic><topic>Disease Models, Animal</topic><topic>Diseases of the osteoarticular system</topic><topic>Double-Blind Method</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Humans</topic><topic>Immunosuppressive Agents - adverse effects</topic><topic>Immunosuppressive Agents - pharmacokinetics</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Klinisk medicin</topic><topic>Lupus</topic><topic>Lupus Erythematosus, Systemic - drug therapy</topic><topic>Lupus Erythematosus, Systemic - metabolism</topic><topic>Lupus Erythematosus, Systemic - pathology</topic><topic>Male</topic><topic>Medical and Health Sciences</topic><topic>Medical sciences</topic><topic>Medicin och hälsovetenskap</topic><topic>Mice</topic><topic>Mice, Inbred MRL lpr</topic><topic>Middle Aged</topic><topic>Mycophenolic Acid - analogs & derivatives</topic><topic>Mycophenolic Acid - therapeutic use</topic><topic>Prednisolone - therapeutic use</topic><topic>Quinolines - adverse effects</topic><topic>Quinolines - chemistry</topic><topic>Quinolines - pharmacokinetics</topic><topic>Quinolines - therapeutic use</topic><topic>Reumatologi och inflammation</topic><topic>Rheumatology and Autoimmunity</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>Severity of Illness Index</topic><topic>Treatment Outcome</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bengtsson, Anders A.</creatorcontrib><creatorcontrib>Sturfelt, Gunnar</creatorcontrib><creatorcontrib>Lood, Christian</creatorcontrib><creatorcontrib>Rönnblom, Lars</creatorcontrib><creatorcontrib>van Vollenhoven, Ronald F.</creatorcontrib><creatorcontrib>Axelsson, Bengt</creatorcontrib><creatorcontrib>Sparre, Birgitta</creatorcontrib><creatorcontrib>Tuvesson, Helén</creatorcontrib><creatorcontrib>Öhman, Marie Wallén</creatorcontrib><creatorcontrib>Leanderson, Tomas</creatorcontrib><collection>Istex</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>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Lunds universitet</collection><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bengtsson, Anders A.</au><au>Sturfelt, Gunnar</au><au>Lood, Christian</au><au>Rönnblom, Lars</au><au>van Vollenhoven, Ronald F.</au><au>Axelsson, Bengt</au><au>Sparre, Birgitta</au><au>Tuvesson, Helén</au><au>Öhman, Marie Wallén</au><au>Leanderson, Tomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus</atitle><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle><addtitle>Arthritis & Rheumatism</addtitle><date>2012-05</date><risdate>2012</risdate><volume>64</volume><issue>5</issue><spage>1579</spage><epage>1588</epage><pages>1579-1588</pages><issn>0004-3591</issn><issn>2326-5191</issn><issn>1529-0131</issn><eissn>1529-0131</eissn><eissn>2326-5205</eissn><coden>ARHEAW</coden><abstract>Objective
To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose.
Methods
The efficacy of paquinimod was studied in lupus‐prone MRL‐lpr/lpr mice and compared with that of established SLE treatments. Dose‐response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double‐blind, placebo controlled, dose‐ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks.
Results
Paquinimod treatment resulted in disease inhibition in MRL‐lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid‐sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod were linear and well suitable for once‐daily oral treatment. The majority of the adverse events (AEs) were mild or moderate, and transient. The most frequent AEs were arthralgia and myalgia, reported with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported.
Conclusion
Paquinimod effectively inhibited disease and had a steroid‐sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>22131101</pmid><doi>10.1002/art.33493</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0004-3591 |
| ispartof | Arthritis & rheumatology (Hoboken, N.J.), 2012-05, Vol.64 (5), p.1579-1588 |
| issn | 0004-3591 2326-5191 1529-0131 1529-0131 2326-5205 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_540404 |
| source | MEDLINE; Access via Wiley Online Library |
| subjects | Adult Aged Animals Biological and medical sciences Clinical Medicine Disease Models, Animal Diseases of the osteoarticular system Double-Blind Method Drug therapy Female Humans Immunosuppressive Agents - adverse effects Immunosuppressive Agents - pharmacokinetics Immunosuppressive Agents - therapeutic use Kidney - metabolism Kidney - pathology Klinisk medicin Lupus Lupus Erythematosus, Systemic - drug therapy Lupus Erythematosus, Systemic - metabolism Lupus Erythematosus, Systemic - pathology Male Medical and Health Sciences Medical sciences Medicin och hälsovetenskap Mice Mice, Inbred MRL lpr Middle Aged Mycophenolic Acid - analogs & derivatives Mycophenolic Acid - therapeutic use Prednisolone - therapeutic use Quinolines - adverse effects Quinolines - chemistry Quinolines - pharmacokinetics Quinolines - therapeutic use Reumatologi och inflammation Rheumatology and Autoimmunity Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis Severity of Illness Index Treatment Outcome Young Adult |
| title | Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-14T19%3A33%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pharmacokinetics,%20tolerability,%20and%20preliminary%20efficacy%20of%20paquinimod%20(ABR-215757),%20a%20new%20quinoline-3-carboxamide%20derivative:%20Studies%20in%20lupus-prone%20mice%20and%20a%20multicenter,%20randomized,%20double-blind,%20placebo-controlled,%20repeat-dose,%20dose-ranging%20study%20in%20patients%20with%20systemic%20lupus%20erythematosus&rft.jtitle=Arthritis%20&%20rheumatology%20(Hoboken,%20N.J.)&rft.au=Bengtsson,%20Anders%20A.&rft.date=2012-05&rft.volume=64&rft.issue=5&rft.spage=1579&rft.epage=1588&rft.pages=1579-1588&rft.issn=0004-3591&rft.eissn=1529-0131&rft.coden=ARHEAW&rft_id=info:doi/10.1002/art.33493&rft_dat=%3Cproquest_swepu%3E1010232612%3C/proquest_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1517108082&rft_id=info:pmid/22131101&rfr_iscdi=true |