Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants
Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate...
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| Veröffentlicht in: | Journal of clinical pharmacology 2020-01, Vol.60 (1), p.16-27 |
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| creator | Hammer, Gregory B. Maxwell, Lynne G. Taicher, Brad M. Visoiu, Mihaela Cooper, David S. Szmuk, Peter Pheng, Leng Hong Gosselin, Nathalie H. Lu, Jia Devarakonda, Krishna |
| description | Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients ( |
| doi_str_mv | 10.1002/jcph.1508 |
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This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted‐versus‐observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration‐versus‐time profiles in the active and placebo groups. Terminal elimination half‐life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment‐emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/jcph.1508</identifier><identifier>PMID: 31448420</identifier><language>eng</language><publisher>England: American College of Clinical Pharmacology</publisher><subject>Acetaminophen ; Acetaminophen - administration & dosage ; Acetaminophen - adverse effects ; Acetaminophen - pharmacokinetics ; Acetaminophen - therapeutic use ; acute postoperative pain ; Adolescents ; Analgesics ; Analgesics, Non-Narcotic - administration & dosage ; Analgesics, Non-Narcotic - adverse effects ; Analgesics, Non-Narcotic - pharmacokinetics ; Analgesics, Non-Narcotic - therapeutic use ; Babies ; Blood levels ; Continuing Education: Pediatric Pharmacology ; Dose-Response Relationship, Drug ; Female ; Humans ; Infant ; Infant, Newborn ; Infants ; Infusions, Intravenous ; Intravenous administration ; Male ; Neonates ; Newborn babies ; Opioids ; Pain ; Pain Management ; Pain, Postoperative - drug therapy ; Pain, Postoperative - metabolism ; Patients ; Pharmacodynamics ; Pharmacokinetics ; Postoperative period ; Randomization ; Rectum ; Surgery ; Treatment Outcome</subject><ispartof>Journal of clinical pharmacology, 2020-01, Vol.60 (1), p.16-27</ispartof><rights>2019 Mallinckrodt. published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology</rights><rights>2020 American College of Clinical Pharmacology</rights><rights>2019 American College of Clinical Pharmacology</rights><rights>2019 Mallinckrodt. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.</rights><rights>2020, The American College of Clinical Pharmacology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5928-2f0fdc21935957635825d3c9274353ba7f1376a98fcbb9244158acdc66ea43983</citedby><cites>FETCH-LOGICAL-c5928-2f0fdc21935957635825d3c9274353ba7f1376a98fcbb9244158acdc66ea43983</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%2Fjcph.1508$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcph.1508$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31448420$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hammer, Gregory B.</creatorcontrib><creatorcontrib>Maxwell, Lynne G.</creatorcontrib><creatorcontrib>Taicher, Brad M.</creatorcontrib><creatorcontrib>Visoiu, Mihaela</creatorcontrib><creatorcontrib>Cooper, David S.</creatorcontrib><creatorcontrib>Szmuk, Peter</creatorcontrib><creatorcontrib>Pheng, Leng Hong</creatorcontrib><creatorcontrib>Gosselin, Nathalie H.</creatorcontrib><creatorcontrib>Lu, Jia</creatorcontrib><creatorcontrib>Devarakonda, Krishna</creatorcontrib><title>Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants</title><title>Journal of clinical pharmacology</title><addtitle>J Clin Pharmacol</addtitle><description>Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted‐versus‐observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration‐versus‐time profiles in the active and placebo groups. Terminal elimination half‐life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment‐emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.</description><subject>Acetaminophen</subject><subject>Acetaminophen - administration & dosage</subject><subject>Acetaminophen - adverse effects</subject><subject>Acetaminophen - pharmacokinetics</subject><subject>Acetaminophen - therapeutic use</subject><subject>acute postoperative pain</subject><subject>Adolescents</subject><subject>Analgesics</subject><subject>Analgesics, Non-Narcotic - administration & dosage</subject><subject>Analgesics, Non-Narcotic - adverse effects</subject><subject>Analgesics, Non-Narcotic - pharmacokinetics</subject><subject>Analgesics, Non-Narcotic - therapeutic use</subject><subject>Babies</subject><subject>Blood levels</subject><subject>Continuing Education: Pediatric Pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Infants</subject><subject>Infusions, Intravenous</subject><subject>Intravenous administration</subject><subject>Male</subject><subject>Neonates</subject><subject>Newborn babies</subject><subject>Opioids</subject><subject>Pain</subject><subject>Pain Management</subject><subject>Pain, Postoperative - drug therapy</subject><subject>Pain, Postoperative - metabolism</subject><subject>Patients</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Postoperative period</subject><subject>Randomization</subject><subject>Rectum</subject><subject>Surgery</subject><subject>Treatment Outcome</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp9ktuKFDEQhoMo7rh64QtIwCsvejfHPtwIw6DuyKKDh-uQSSd2ZruTNknPMr6CL23aGRcFNQRCVb76q5IqAJ5idIERIpc7NXYXmKP6HlhgzknBSsTugwVCDS5IhdAZeBTjDiFcMo4fgjOKGasZQQvw_YN0rR_sN93CjR-nXibrHdx0MgxS-RvrdLIKLp3sD9FGmGn4URqdDtAbuHYpyL12fopwqXSSg3V-7LSDxofsmZLOqjH5UYcsvM-WtA7m_U57J5M-Cq6dkS7Fx-CBkX3UT07nOfj8-tWn1VVx_f7NerW8LhRvSF0Qg0yrCG4ob3hVUl4T3lLVkIpRTreyMphWpWxqo7bbhjCGeS1Vq8pSS0abmp6Dl0fdcdoOulV6fkUvxmAHGQ7CSyv-vHG2E1_8XpRNRRFmWeD5SSD4r5OOSez8FPIXRUEoqSnHGPFMvThSKvgYgzZ3GTASc9_E3Dcx9y2zz34v6Y781agMFEfg1vdJh3jTT7c6iE7LPnV_FWT_4VFeLM9FQRDJU5GtYnbRHHZ5CrO9Pvy7YPF2tbn6megHPOfEaA</recordid><startdate>202001</startdate><enddate>202001</enddate><creator>Hammer, Gregory B.</creator><creator>Maxwell, Lynne G.</creator><creator>Taicher, Brad M.</creator><creator>Visoiu, Mihaela</creator><creator>Cooper, David S.</creator><creator>Szmuk, Peter</creator><creator>Pheng, Leng Hong</creator><creator>Gosselin, Nathalie H.</creator><creator>Lu, Jia</creator><creator>Devarakonda, Krishna</creator><general>American College of Clinical Pharmacology</general><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>202001</creationdate><title>Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants</title><author>Hammer, Gregory B. ; Maxwell, Lynne G. ; Taicher, Brad M. ; Visoiu, Mihaela ; Cooper, David S. ; Szmuk, Peter ; Pheng, Leng Hong ; Gosselin, Nathalie H. ; Lu, Jia ; Devarakonda, Krishna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5928-2f0fdc21935957635825d3c9274353ba7f1376a98fcbb9244158acdc66ea43983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetaminophen</topic><topic>Acetaminophen - administration & dosage</topic><topic>Acetaminophen - adverse effects</topic><topic>Acetaminophen - pharmacokinetics</topic><topic>Acetaminophen - therapeutic use</topic><topic>acute postoperative pain</topic><topic>Adolescents</topic><topic>Analgesics</topic><topic>Analgesics, Non-Narcotic - administration & dosage</topic><topic>Analgesics, Non-Narcotic - adverse effects</topic><topic>Analgesics, Non-Narcotic - pharmacokinetics</topic><topic>Analgesics, Non-Narcotic - therapeutic use</topic><topic>Babies</topic><topic>Blood levels</topic><topic>Continuing Education: Pediatric Pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Humans</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Infants</topic><topic>Infusions, Intravenous</topic><topic>Intravenous administration</topic><topic>Male</topic><topic>Neonates</topic><topic>Newborn babies</topic><topic>Opioids</topic><topic>Pain</topic><topic>Pain Management</topic><topic>Pain, Postoperative - drug therapy</topic><topic>Pain, Postoperative - metabolism</topic><topic>Patients</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Postoperative period</topic><topic>Randomization</topic><topic>Rectum</topic><topic>Surgery</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hammer, Gregory B.</creatorcontrib><creatorcontrib>Maxwell, Lynne G.</creatorcontrib><creatorcontrib>Taicher, Brad M.</creatorcontrib><creatorcontrib>Visoiu, Mihaela</creatorcontrib><creatorcontrib>Cooper, David S.</creatorcontrib><creatorcontrib>Szmuk, Peter</creatorcontrib><creatorcontrib>Pheng, Leng Hong</creatorcontrib><creatorcontrib>Gosselin, Nathalie H.</creatorcontrib><creatorcontrib>Lu, Jia</creatorcontrib><creatorcontrib>Devarakonda, Krishna</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hammer, Gregory B.</au><au>Maxwell, Lynne G.</au><au>Taicher, Brad M.</au><au>Visoiu, Mihaela</au><au>Cooper, David S.</au><au>Szmuk, Peter</au><au>Pheng, Leng Hong</au><au>Gosselin, Nathalie H.</au><au>Lu, Jia</au><au>Devarakonda, Krishna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>J Clin Pharmacol</addtitle><date>2020-01</date><risdate>2020</risdate><volume>60</volume><issue>1</issue><spage>16</spage><epage>27</epage><pages>16-27</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><abstract>Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted‐versus‐observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration‐versus‐time profiles in the active and placebo groups. Terminal elimination half‐life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment‐emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.</abstract><cop>England</cop><pub>American College of Clinical Pharmacology</pub><pmid>31448420</pmid><doi>10.1002/jcph.1508</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acetaminophen Acetaminophen - administration & dosage Acetaminophen - adverse effects Acetaminophen - pharmacokinetics Acetaminophen - therapeutic use acute postoperative pain Adolescents Analgesics Analgesics, Non-Narcotic - administration & dosage Analgesics, Non-Narcotic - adverse effects Analgesics, Non-Narcotic - pharmacokinetics Analgesics, Non-Narcotic - therapeutic use Babies Blood levels Continuing Education: Pediatric Pharmacology Dose-Response Relationship, Drug Female Humans Infant Infant, Newborn Infants Infusions, Intravenous Intravenous administration Male Neonates Newborn babies Opioids Pain Pain Management Pain, Postoperative - drug therapy Pain, Postoperative - metabolism Patients Pharmacodynamics Pharmacokinetics Postoperative period Randomization Rectum Surgery Treatment Outcome |
| title | Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants |
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