Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers
Aims Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at ≥0.5 but
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| Veröffentlicht in: | British journal of clinical pharmacology 2007-04, Vol.63 (4), p.459-468 |
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| container_title | British journal of clinical pharmacology |
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| creator | Stypinski, Daria Obaidi, Mohammad Combs, Michelle Weber, Meg Stewart, Adrian J. Ishikawa, Hiroaki |
| description | Aims
Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at ≥0.5 but |
| doi_str_mv | 10.1111/j.1365-2125.2006.02779.x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2203250</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>70306727</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5689-9e84f1ce292f0409e33fb50da51d52598330e8792da5df6f50d8fc2918f8da4a3</originalsourceid><addsrcrecordid>eNqNkc1u1DAUhS0EokPhFZA3sCLBP3HiLECCEX9SJZCAtfE4140HJ57amdKw4hF4Rp4Ehxm1sMMbWz7fPffaByFMSUnzerotKa9FwSgTJSOkLglrmra8uoVW18JttCKc1IVggp6geyltCaGc1uIuOqENaetaViv05aO2MM1P8BQ8RL1x3k0z1mOHd72OgzbhqxthcibhYHHvznuIv3787EICPLjvIbpN1rEbcQ_aT_2MB-0BXwa_HyeAmO6jO1b7BA-O-yn6_PrVp_Xb4uz9m3frF2eFEbVsixZkZakB1jJLKtIC53YjSKcF7fILWsk5Adm0LN90trZZktawlkorO11pfoqeH3x3-80AnYFxitqrXXSDjrMK2ql_ldH16jxcKsYIZ4Jkg8dHgxgu9pAmNbhkwHs9Qtgn1Sy_2bAmg_IAmhhSimCvm1CilnjUVi0pqCUFtcSj_sSjrnLpw7-HvCk85pGBR0dAJ6O9jXo0Lt1wUkhZ1TRzzw7cN-dh_u8B1Mv1h-XEfwPY5K8G</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>70306727</pqid></control><display><type>article</type><title>Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers</title><source>MEDLINE</source><source>Wiley Online Library</source><source>Wiley Online Library Journals Frontfile Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Stypinski, Daria ; Obaidi, Mohammad ; Combs, Michelle ; Weber, Meg ; Stewart, Adrian J. ; Ishikawa, Hiroaki</creator><creatorcontrib>Stypinski, Daria ; Obaidi, Mohammad ; Combs, Michelle ; Weber, Meg ; Stewart, Adrian J. ; Ishikawa, Hiroaki</creatorcontrib><description>Aims
Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at ≥0.5 but <3 µg ml−1. It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2–5 mg kg−1 day−1. The safety, tolerability and pharmacokinetics from two clinical trials of higher‐dose mizoribine treatments in healthy male volunteers are presented.
Methods
Forty‐eight healthy White male nonsmokers participated in two randomized, double‐blind, placebo‐controlled trials: 32 in a single‐dose study (3, 6, 9 and 12 mg kg−1) and 16 in a multiple‐dose study [6 mg kg−1 day−1 once daily for 5 days or twice daily (12 mg kg−1 day−1) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed.
Results
The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg−1 day−1) in the multiple‐dose study. Orally administered mizoribine reached peak concentrations within 2–3 h and was eliminated mostly via the kidney (65–100% of dose) with a 3‐h half‐life. Only the 12 mg kg−1 day−1 group achieved trough concentrations that were within the therapeutic window.
Conclusions
Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6–12 mg kg−1 day−1 range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/j.1365-2125.2006.02779.x</identifier><identifier>PMID: 17096684</identifier><identifier>CODEN: BCPHBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Administration, Oral ; Adolescent ; Adult ; Biological and medical sciences ; Dose-Response Relationship, Drug ; Double-Blind Method ; Humans ; Immunoglobulins - drug effects ; immunosuppression ; Immunosuppressive Agents - administration & dosage ; Immunosuppressive Agents - adverse effects ; Immunosuppressive Agents - pharmacokinetics ; Kidney Transplantation ; Lymphocytes - drug effects ; Male ; Medical sciences ; Middle Aged ; mizoribine ; Pharmacokinetics ; Pharmacology. Drug treatments ; renal transplant ; Ribonucleosides - administration & dosage ; Ribonucleosides - adverse effects ; Ribonucleosides - pharmacokinetics ; safety ; Treatment Outcome</subject><ispartof>British journal of clinical pharmacology, 2007-04, Vol.63 (4), p.459-468</ispartof><rights>2007 INIST-CNRS</rights><rights>2006 The Authors; Journal compilation © 2006 Blackwell Publishing Ltd 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5689-9e84f1ce292f0409e33fb50da51d52598330e8792da5df6f50d8fc2918f8da4a3</citedby><cites>FETCH-LOGICAL-c5689-9e84f1ce292f0409e33fb50da51d52598330e8792da5df6f50d8fc2918f8da4a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2125.2006.02779.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2125.2006.02779.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18588461$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17096684$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stypinski, Daria</creatorcontrib><creatorcontrib>Obaidi, Mohammad</creatorcontrib><creatorcontrib>Combs, Michelle</creatorcontrib><creatorcontrib>Weber, Meg</creatorcontrib><creatorcontrib>Stewart, Adrian J.</creatorcontrib><creatorcontrib>Ishikawa, Hiroaki</creatorcontrib><title>Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aims
Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at ≥0.5 but <3 µg ml−1. It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2–5 mg kg−1 day−1. The safety, tolerability and pharmacokinetics from two clinical trials of higher‐dose mizoribine treatments in healthy male volunteers are presented.
Methods
Forty‐eight healthy White male nonsmokers participated in two randomized, double‐blind, placebo‐controlled trials: 32 in a single‐dose study (3, 6, 9 and 12 mg kg−1) and 16 in a multiple‐dose study [6 mg kg−1 day−1 once daily for 5 days or twice daily (12 mg kg−1 day−1) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed.
Results
The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg−1 day−1) in the multiple‐dose study. Orally administered mizoribine reached peak concentrations within 2–3 h and was eliminated mostly via the kidney (65–100% of dose) with a 3‐h half‐life. Only the 12 mg kg−1 day−1 group achieved trough concentrations that were within the therapeutic window.
Conclusions
Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6–12 mg kg−1 day−1 range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.</description><subject>Administration, Oral</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Humans</subject><subject>Immunoglobulins - drug effects</subject><subject>immunosuppression</subject><subject>Immunosuppressive Agents - administration & dosage</subject><subject>Immunosuppressive Agents - adverse effects</subject><subject>Immunosuppressive Agents - pharmacokinetics</subject><subject>Kidney Transplantation</subject><subject>Lymphocytes - drug effects</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>mizoribine</subject><subject>Pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>renal transplant</subject><subject>Ribonucleosides - administration & dosage</subject><subject>Ribonucleosides - adverse effects</subject><subject>Ribonucleosides - pharmacokinetics</subject><subject>safety</subject><subject>Treatment Outcome</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS0EokPhFZA3sCLBP3HiLECCEX9SJZCAtfE4140HJ57amdKw4hF4Rp4Ehxm1sMMbWz7fPffaByFMSUnzerotKa9FwSgTJSOkLglrmra8uoVW18JttCKc1IVggp6geyltCaGc1uIuOqENaetaViv05aO2MM1P8BQ8RL1x3k0z1mOHd72OgzbhqxthcibhYHHvznuIv3787EICPLjvIbpN1rEbcQ_aT_2MB-0BXwa_HyeAmO6jO1b7BA-O-yn6_PrVp_Xb4uz9m3frF2eFEbVsixZkZakB1jJLKtIC53YjSKcF7fILWsk5Adm0LN90trZZktawlkorO11pfoqeH3x3-80AnYFxitqrXXSDjrMK2ql_ldH16jxcKsYIZ4Jkg8dHgxgu9pAmNbhkwHs9Qtgn1Sy_2bAmg_IAmhhSimCvm1CilnjUVi0pqCUFtcSj_sSjrnLpw7-HvCk85pGBR0dAJ6O9jXo0Lt1wUkhZ1TRzzw7cN-dh_u8B1Mv1h-XEfwPY5K8G</recordid><startdate>200704</startdate><enddate>200704</enddate><creator>Stypinski, Daria</creator><creator>Obaidi, Mohammad</creator><creator>Combs, Michelle</creator><creator>Weber, Meg</creator><creator>Stewart, Adrian J.</creator><creator>Ishikawa, Hiroaki</creator><general>Blackwell Publishing Ltd</general><general>Blackwell Science</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><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200704</creationdate><title>Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers</title><author>Stypinski, Daria ; Obaidi, Mohammad ; Combs, Michelle ; Weber, Meg ; Stewart, Adrian J. ; Ishikawa, Hiroaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5689-9e84f1ce292f0409e33fb50da51d52598330e8792da5df6f50d8fc2918f8da4a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Administration, Oral</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Humans</topic><topic>Immunoglobulins - drug effects</topic><topic>immunosuppression</topic><topic>Immunosuppressive Agents - administration & dosage</topic><topic>Immunosuppressive Agents - adverse effects</topic><topic>Immunosuppressive Agents - pharmacokinetics</topic><topic>Kidney Transplantation</topic><topic>Lymphocytes - drug effects</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>mizoribine</topic><topic>Pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>renal transplant</topic><topic>Ribonucleosides - administration & dosage</topic><topic>Ribonucleosides - adverse effects</topic><topic>Ribonucleosides - pharmacokinetics</topic><topic>safety</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stypinski, Daria</creatorcontrib><creatorcontrib>Obaidi, Mohammad</creatorcontrib><creatorcontrib>Combs, Michelle</creatorcontrib><creatorcontrib>Weber, Meg</creatorcontrib><creatorcontrib>Stewart, Adrian J.</creatorcontrib><creatorcontrib>Ishikawa, Hiroaki</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><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stypinski, Daria</au><au>Obaidi, Mohammad</au><au>Combs, Michelle</au><au>Weber, Meg</au><au>Stewart, Adrian J.</au><au>Ishikawa, Hiroaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2007-04</date><risdate>2007</risdate><volume>63</volume><issue>4</issue><spage>459</spage><epage>468</epage><pages>459-468</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><coden>BCPHBM</coden><abstract>Aims
Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at ≥0.5 but <3 µg ml−1. It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2–5 mg kg−1 day−1. The safety, tolerability and pharmacokinetics from two clinical trials of higher‐dose mizoribine treatments in healthy male volunteers are presented.
Methods
Forty‐eight healthy White male nonsmokers participated in two randomized, double‐blind, placebo‐controlled trials: 32 in a single‐dose study (3, 6, 9 and 12 mg kg−1) and 16 in a multiple‐dose study [6 mg kg−1 day−1 once daily for 5 days or twice daily (12 mg kg−1 day−1) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed.
Results
The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg−1 day−1) in the multiple‐dose study. Orally administered mizoribine reached peak concentrations within 2–3 h and was eliminated mostly via the kidney (65–100% of dose) with a 3‐h half‐life. Only the 12 mg kg−1 day−1 group achieved trough concentrations that were within the therapeutic window.
Conclusions
Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6–12 mg kg−1 day−1 range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>17096684</pmid><doi>10.1111/j.1365-2125.2006.02779.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Oral Adolescent Adult Biological and medical sciences Dose-Response Relationship, Drug Double-Blind Method Humans Immunoglobulins - drug effects immunosuppression Immunosuppressive Agents - administration & dosage Immunosuppressive Agents - adverse effects Immunosuppressive Agents - pharmacokinetics Kidney Transplantation Lymphocytes - drug effects Male Medical sciences Middle Aged mizoribine Pharmacokinetics Pharmacology. Drug treatments renal transplant Ribonucleosides - administration & dosage Ribonucleosides - adverse effects Ribonucleosides - pharmacokinetics safety Treatment Outcome |
| title | Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers |
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