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Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability

•Developed & validated LC-MS/MS to detect T-CPT-11, NE-CPT-11, and SN-38 in plasma.•Reproducible SPE-HLB protocol robustly separated NE-CPT-11 from plasma.•Extensive studies performed to ensure NE-CPT-11 stability in plasma during storage.•Developed methods applied to clinical pharmacokinetic st...

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Published in:Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Analytical technologies in the biomedical and life sciences, 2024-09, Vol.1245, p.124273, Article 124273
Main Authors: Nair, Sreenath, Selvo, Nicholas S., Stolarski, Abigail, Klee, Brandon, Federico, Sara M., Stewart, Clinton F.
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Selvo, Nicholas S.
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Stewart, Clinton F.
description •Developed & validated LC-MS/MS to detect T-CPT-11, NE-CPT-11, and SN-38 in plasma.•Reproducible SPE-HLB protocol robustly separated NE-CPT-11 from plasma.•Extensive studies performed to ensure NE-CPT-11 stability in plasma during storage.•Developed methods applied to clinical pharmacokinetic study of Onivyde® in a pediatric patient.•First report of NE-CPT-11 concentrations in a pediatric patient with recurrent solid malignancy. Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 > 124.1 (CPT-11) and 393.0 > 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10–5000 ng/mL for T-CPT-11, 2.5–250 ng/mL for NE-CPT-11, and 1–500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. Finally, the LC-MS/MS methods were successfully applied in a phase I clinical pharmacokinetic study of nanoliposomal
doi_str_mv 10.1016/j.jchromb.2024.124273
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Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 &gt; 124.1 (CPT-11) and 393.0 &gt; 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10–5000 ng/mL for T-CPT-11, 2.5–250 ng/mL for NE-CPT-11, and 1–500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. 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B, Analytical technologies in the biomedical and life sciences, 2024-09, Vol.1245, p.124273, Article 124273</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c243t-62c0818e66380844363549a87a381db0e82413c8f4567148889bb541197500123</cites></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/39146822$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nair, Sreenath</creatorcontrib><creatorcontrib>Selvo, Nicholas S.</creatorcontrib><creatorcontrib>Stolarski, Abigail</creatorcontrib><creatorcontrib>Klee, Brandon</creatorcontrib><creatorcontrib>Federico, Sara M.</creatorcontrib><creatorcontrib>Stewart, Clinton F.</creatorcontrib><title>Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability</title><title>Journal of chromatography. B, Analytical technologies in the biomedical and life sciences</title><addtitle>J Chromatogr B Analyt Technol Biomed Life Sci</addtitle><description>•Developed &amp; validated LC-MS/MS to detect T-CPT-11, NE-CPT-11, and SN-38 in plasma.•Reproducible SPE-HLB protocol robustly separated NE-CPT-11 from plasma.•Extensive studies performed to ensure NE-CPT-11 stability in plasma during storage.•Developed methods applied to clinical pharmacokinetic study of Onivyde® in a pediatric patient.•First report of NE-CPT-11 concentrations in a pediatric patient with recurrent solid malignancy. Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 &gt; 124.1 (CPT-11) and 393.0 &gt; 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10–5000 ng/mL for T-CPT-11, 2.5–250 ng/mL for NE-CPT-11, and 1–500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. Finally, the LC-MS/MS methods were successfully applied in a phase I clinical pharmacokinetic study of nanoliposomal irinotecan (Onivyde®) in pediatric patients with recurrent solid malignancies or Ewing sarcoma.</description><subject>Adolescent</subject><subject>Bioanalysis</subject><subject>Camptothecin - administration &amp; dosage</subject><subject>Camptothecin - analogs &amp; derivatives</subject><subject>Camptothecin - blood</subject><subject>Camptothecin - pharmacokinetics</subject><subject>Child</subject><subject>Chromatography, Liquid - methods</subject><subject>Drug Stability</subject><subject>Female</subject><subject>Humans</subject><subject>Irinotecan - blood</subject><subject>Irinotecan - pharmacokinetics</subject><subject>LC-MS/MS</subject><subject>Limit of Detection</subject><subject>Linear Models</subject><subject>Liposomal irinotecan (CPT-11)</subject><subject>Liposomes - blood</subject><subject>Liposomes - chemistry</subject><subject>Male</subject><subject>Method validation</subject><subject>Neoplasms - blood</subject><subject>Neoplasms - drug therapy</subject><subject>Pharmacokinetics</subject><subject>Reproducibility of Results</subject><subject>SN-38</subject><subject>Tandem Mass Spectrometry - methods</subject><issn>1570-0232</issn><issn>1873-376X</issn><issn>1873-376X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqFkc1u1DAUhSMEoj_wCKC7ZJPBf0kcNghVQJEqEIJK7CzHudF45NiD7bSah-PdcDpTtqxsS9_1OfecqnpFyYYS2r7dbXZmG8M8bBhhYkOZYB1_Up1T2fGad-2vp-XedKQmjLOz6iKlHSG0Ix1_Xp3xnopWMnZe_fm-aJ9t1tneIYyYMc7Wl1fwECZwdh9SmLUDG60PGY32oP0IP77WXIIJ3qDP8YFPYD3snU6zhqTnvcMEU3EIZmvdGNHDvc1bSMHZEfIyh5jewW3CVUeDiYewj6tCLoZWankwkQOg3-qi82gGIWU9WGfz4UX1bNIu4cvTeVndfvr48-q6vvn2-cvVh5vaMMFz3TJDJJXYtlwSKQRveSN6LTvNJR0HgpIJyo2cRNN2VEgp-2FoBKV915TQGL-s3hz_LQ5_L5iymm0y6Jz2GJakOOl50wvWtAVtjqiJIaWIk9pHO-t4UJSotTm1U6fm1NqcOjZX5l6fJJZhxvHf1GNVBXh_BLAsemcxqmQsllxGG0toagz2PxJ_AW_Kr8Q</recordid><startdate>20240915</startdate><enddate>20240915</enddate><creator>Nair, Sreenath</creator><creator>Selvo, Nicholas S.</creator><creator>Stolarski, Abigail</creator><creator>Klee, Brandon</creator><creator>Federico, Sara M.</creator><creator>Stewart, Clinton F.</creator><general>Elsevier B.V</general><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></search><sort><creationdate>20240915</creationdate><title>Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability</title><author>Nair, Sreenath ; Selvo, Nicholas S. ; Stolarski, Abigail ; Klee, Brandon ; Federico, Sara M. ; Stewart, Clinton F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c243t-62c0818e66380844363549a87a381db0e82413c8f4567148889bb541197500123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adolescent</topic><topic>Bioanalysis</topic><topic>Camptothecin - administration &amp; dosage</topic><topic>Camptothecin - analogs &amp; derivatives</topic><topic>Camptothecin - blood</topic><topic>Camptothecin - pharmacokinetics</topic><topic>Child</topic><topic>Chromatography, Liquid - methods</topic><topic>Drug Stability</topic><topic>Female</topic><topic>Humans</topic><topic>Irinotecan - blood</topic><topic>Irinotecan - pharmacokinetics</topic><topic>LC-MS/MS</topic><topic>Limit of Detection</topic><topic>Linear Models</topic><topic>Liposomal irinotecan (CPT-11)</topic><topic>Liposomes - blood</topic><topic>Liposomes - chemistry</topic><topic>Male</topic><topic>Method validation</topic><topic>Neoplasms - blood</topic><topic>Neoplasms - drug therapy</topic><topic>Pharmacokinetics</topic><topic>Reproducibility of Results</topic><topic>SN-38</topic><topic>Tandem Mass Spectrometry - methods</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nair, Sreenath</creatorcontrib><creatorcontrib>Selvo, Nicholas S.</creatorcontrib><creatorcontrib>Stolarski, Abigail</creatorcontrib><creatorcontrib>Klee, Brandon</creatorcontrib><creatorcontrib>Federico, Sara M.</creatorcontrib><creatorcontrib>Stewart, Clinton F.</creatorcontrib><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><jtitle>Journal of chromatography. B, Analytical technologies in the biomedical and life sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nair, Sreenath</au><au>Selvo, Nicholas S.</au><au>Stolarski, Abigail</au><au>Klee, Brandon</au><au>Federico, Sara M.</au><au>Stewart, Clinton F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability</atitle><jtitle>Journal of chromatography. B, Analytical technologies in the biomedical and life sciences</jtitle><addtitle>J Chromatogr B Analyt Technol Biomed Life Sci</addtitle><date>2024-09-15</date><risdate>2024</risdate><volume>1245</volume><spage>124273</spage><pages>124273-</pages><artnum>124273</artnum><issn>1570-0232</issn><issn>1873-376X</issn><eissn>1873-376X</eissn><abstract>•Developed &amp; validated LC-MS/MS to detect T-CPT-11, NE-CPT-11, and SN-38 in plasma.•Reproducible SPE-HLB protocol robustly separated NE-CPT-11 from plasma.•Extensive studies performed to ensure NE-CPT-11 stability in plasma during storage.•Developed methods applied to clinical pharmacokinetic study of Onivyde® in a pediatric patient.•First report of NE-CPT-11 concentrations in a pediatric patient with recurrent solid malignancy. Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 &gt; 124.1 (CPT-11) and 393.0 &gt; 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10–5000 ng/mL for T-CPT-11, 2.5–250 ng/mL for NE-CPT-11, and 1–500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. Finally, the LC-MS/MS methods were successfully applied in a phase I clinical pharmacokinetic study of nanoliposomal irinotecan (Onivyde®) in pediatric patients with recurrent solid malignancies or Ewing sarcoma.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>39146822</pmid><doi>10.1016/j.jchromb.2024.124273</doi></addata></record>
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identifier ISSN: 1570-0232
ispartof Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2024-09, Vol.1245, p.124273, Article 124273
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source Elsevier
subjects Adolescent
Bioanalysis
Camptothecin - administration & dosage
Camptothecin - analogs & derivatives
Camptothecin - blood
Camptothecin - pharmacokinetics
Child
Chromatography, Liquid - methods
Drug Stability
Female
Humans
Irinotecan - blood
Irinotecan - pharmacokinetics
LC-MS/MS
Limit of Detection
Linear Models
Liposomal irinotecan (CPT-11)
Liposomes - blood
Liposomes - chemistry
Male
Method validation
Neoplasms - blood
Neoplasms - drug therapy
Pharmacokinetics
Reproducibility of Results
SN-38
Tandem Mass Spectrometry - methods
title Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability
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