Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide
Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols. Mice and dogs received IV IPM daily for 3 day...
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| Veröffentlicht in: | Cancer chemotherapy and pharmacology 2005-02, Vol.55 (2), p.143-151 |
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| creator | GERMANN, N URIEN, S RODGERS, Andrew H RATTERREE, Marion STRUCK, Robert F WAUD, William R SEROTA, David G BASTIAN, Gerard JURSIC, Branko S MORGAN, Lee Roy |
| description | Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols.
Mice and dogs received IV IPM daily for 3 days. Single-day dosing-oral and IV-to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared.
For mice, the LD(10) for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87-134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T(1/2beta) was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses ( |
| doi_str_mv | 10.1007/s00280-004-0894-y |
| format | Article |
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Mice and dogs received IV IPM daily for 3 days. Single-day dosing-oral and IV-to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared.
For mice, the LD(10) for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87-134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T(1/2beta) was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T(1/2alpha) 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T(1/2) was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation.
Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m(2) with a clearance of 39.5 l/h, and a T(1/2) of 1 h 45 min for a 70-kg patient.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-004-0894-y</identifier><identifier>PMID: 15592722</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Dogs ; Female ; Lethal Dose 50 ; Macaca mulatta ; Male ; Maximum Tolerated Dose ; Medical sciences ; Mice ; Mice, Inbred C3H ; Pharmacology. Drug treatments ; Phosphoramide Mustards - pharmacokinetics ; Phosphoramide Mustards - toxicity ; Protein Binding ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Cancer chemotherapy and pharmacology, 2005-02, Vol.55 (2), p.143-151</ispartof><rights>2005 INIST-CNRS</rights><rights>Copyright Springer-Verlag 2005</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-8d6fc74f0a1800c137590dcb21cb4fb1ff80ab2bbbb01facfd71ee083936fa253</citedby><cites>FETCH-LOGICAL-c356t-8d6fc74f0a1800c137590dcb21cb4fb1ff80ab2bbbb01facfd71ee083936fa253</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16436992$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15592722$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GERMANN, N</creatorcontrib><creatorcontrib>URIEN, S</creatorcontrib><creatorcontrib>RODGERS, Andrew H</creatorcontrib><creatorcontrib>RATTERREE, Marion</creatorcontrib><creatorcontrib>STRUCK, Robert F</creatorcontrib><creatorcontrib>WAUD, William R</creatorcontrib><creatorcontrib>SEROTA, David G</creatorcontrib><creatorcontrib>BASTIAN, Gerard</creatorcontrib><creatorcontrib>JURSIC, Branko S</creatorcontrib><creatorcontrib>MORGAN, Lee Roy</creatorcontrib><title>Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><description>Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols.
Mice and dogs received IV IPM daily for 3 days. Single-day dosing-oral and IV-to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared.
For mice, the LD(10) for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87-134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T(1/2beta) was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T(1/2alpha) 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T(1/2) was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation.
Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m(2) with a clearance of 39.5 l/h, and a T(1/2) of 1 h 45 min for a 70-kg patient.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Dogs</subject><subject>Female</subject><subject>Lethal Dose 50</subject><subject>Macaca mulatta</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphoramide Mustards - pharmacokinetics</subject><subject>Phosphoramide Mustards - toxicity</subject><subject>Protein Binding</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpFkMtKAzEUhoMoWqsP4EYGwZ2jJ5e5LaV4g4IbXYczmcRGZpoxScW-vbEdMHAICd__H_gIuaBwSwGquwDAasgBRA51I_LtAZlRwVl6CX5IZsCFyIsKxAk5DeETEkg5PyYntCgaVjE2I3HhhhE9Rvuts9Fr1du1Vdhn0f1Y5Xr3sc1w3WXjCv2A04czmQ1uXLmQxuNgO50NmxDRdzdZXOkM1a5v0BFb19uodxHjgtnBZ-TIYB_0-XTPyfvjw9viOV--Pr0s7pe54kUZ87orjaqEAaQ1gKK8KhroVMuoaoVpqTE1YMvadIAaVKarqNZQ84aXBlnB5-Rq3zt697XRIcpPt_HrtFIyykXTVAmdE7qHlHcheG3k6O2AfispyD_Ncq9ZJnvyT7PcpszlVLxpB939JyavCbieAAzJpvG4Vjb8c6XgZdMw_gtPeIjn</recordid><startdate>20050201</startdate><enddate>20050201</enddate><creator>GERMANN, N</creator><creator>URIEN, S</creator><creator>RODGERS, Andrew H</creator><creator>RATTERREE, Marion</creator><creator>STRUCK, Robert F</creator><creator>WAUD, William R</creator><creator>SEROTA, David G</creator><creator>BASTIAN, Gerard</creator><creator>JURSIC, Branko S</creator><creator>MORGAN, Lee Roy</creator><general>Springer</general><general>Springer Nature B.V</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>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20050201</creationdate><title>Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide</title><author>GERMANN, N ; URIEN, S ; RODGERS, Andrew H ; RATTERREE, Marion ; STRUCK, Robert F ; WAUD, William R ; SEROTA, David G ; BASTIAN, Gerard ; JURSIC, Branko S ; MORGAN, Lee Roy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-8d6fc74f0a1800c137590dcb21cb4fb1ff80ab2bbbb01facfd71ee083936fa253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Dogs</topic><topic>Female</topic><topic>Lethal Dose 50</topic><topic>Macaca mulatta</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphoramide Mustards - pharmacokinetics</topic><topic>Phosphoramide Mustards - toxicity</topic><topic>Protein Binding</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GERMANN, N</creatorcontrib><creatorcontrib>URIEN, S</creatorcontrib><creatorcontrib>RODGERS, Andrew H</creatorcontrib><creatorcontrib>RATTERREE, Marion</creatorcontrib><creatorcontrib>STRUCK, Robert F</creatorcontrib><creatorcontrib>WAUD, William R</creatorcontrib><creatorcontrib>SEROTA, David G</creatorcontrib><creatorcontrib>BASTIAN, Gerard</creatorcontrib><creatorcontrib>JURSIC, Branko S</creatorcontrib><creatorcontrib>MORGAN, Lee Roy</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>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GERMANN, N</au><au>URIEN, S</au><au>RODGERS, Andrew H</au><au>RATTERREE, Marion</au><au>STRUCK, Robert F</au><au>WAUD, William R</au><au>SEROTA, David G</au><au>BASTIAN, Gerard</au><au>JURSIC, Branko S</au><au>MORGAN, Lee Roy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2005-02-01</date><risdate>2005</risdate><volume>55</volume><issue>2</issue><spage>143</spage><epage>151</epage><pages>143-151</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols.
Mice and dogs received IV IPM daily for 3 days. Single-day dosing-oral and IV-to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared.
For mice, the LD(10) for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87-134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T(1/2beta) was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T(1/2alpha) 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T(1/2) was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation.
Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m(2) with a clearance of 39.5 l/h, and a T(1/2) of 1 h 45 min for a 70-kg patient.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>15592722</pmid><doi>10.1007/s00280-004-0894-y</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Antineoplastic agents Biological and medical sciences Dogs Female Lethal Dose 50 Macaca mulatta Male Maximum Tolerated Dose Medical sciences Mice Mice, Inbred C3H Pharmacology. Drug treatments Phosphoramide Mustards - pharmacokinetics Phosphoramide Mustards - toxicity Protein Binding Rats Rats, Sprague-Dawley |
| title | Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide |
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