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Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy

Aims Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different tr...

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Published in:British journal of clinical pharmacology 2022-01, Vol.88 (1), p.271-281
Main Authors: Pillai, Venkateswaran C., Shah, Mansi, Rytting, Erik, Nanovskaya, Tatiana N., Wang, Xiaoming, Clark, Shannon M., Ahmed, Mahmoud S., Hankins, Gary D. V., Caritis, Steve N., Venkataramanan, Raman
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cited_by cdi_FETCH-LOGICAL-c3600-5a6024b7713d30ab7d4003b3a82e5340e21a014ba89d5f0a7dbc0a764da554143
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container_title British journal of clinical pharmacology
container_volume 88
creator Pillai, Venkateswaran C.
Shah, Mansi
Rytting, Erik
Nanovskaya, Tatiana N.
Wang, Xiaoming
Clark, Shannon M.
Ahmed, Mahmoud S.
Hankins, Gary D. V.
Caritis, Steve N.
Venkataramanan, Raman
description Aims Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. Methods Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK‐based predictions with observed PK profiles. Results Predicted exposure (AUC0‐6h) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0‐6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. Conclusion A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure–response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.
doi_str_mv 10.1111/bcp.14960
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V. ; Caritis, Steve N. ; Venkataramanan, Raman</creator><creatorcontrib>Pillai, Venkateswaran C. ; Shah, Mansi ; Rytting, Erik ; Nanovskaya, Tatiana N. ; Wang, Xiaoming ; Clark, Shannon M. ; Ahmed, Mahmoud S. ; Hankins, Gary D. V. ; Caritis, Steve N. ; Venkataramanan, Raman</creatorcontrib><description>Aims Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. Methods Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK‐based predictions with observed PK profiles. Results Predicted exposure (AUC0‐6h) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0‐6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. Conclusion A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure–response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.14960</identifier><identifier>PMID: 34185331</identifier><language>eng</language><publisher>England</publisher><subject>Female ; Fetus ; Humans ; indomethacin ; Indomethacin - adverse effects ; Infant, Newborn ; Models, Biological ; physiologically based pharmacokinetics ; Pregnancy ; Pregnancy Trimester, Third ; Pregnancy Trimesters ; pregnant women</subject><ispartof>British journal of clinical pharmacology, 2022-01, Vol.88 (1), p.271-281</ispartof><rights>2021 British Pharmacological Society</rights><rights>2021 British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3600-5a6024b7713d30ab7d4003b3a82e5340e21a014ba89d5f0a7dbc0a764da554143</citedby><cites>FETCH-LOGICAL-c3600-5a6024b7713d30ab7d4003b3a82e5340e21a014ba89d5f0a7dbc0a764da554143</cites><orcidid>0000-0003-1893-3290</orcidid></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/34185331$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pillai, Venkateswaran C.</creatorcontrib><creatorcontrib>Shah, Mansi</creatorcontrib><creatorcontrib>Rytting, Erik</creatorcontrib><creatorcontrib>Nanovskaya, Tatiana N.</creatorcontrib><creatorcontrib>Wang, Xiaoming</creatorcontrib><creatorcontrib>Clark, Shannon M.</creatorcontrib><creatorcontrib>Ahmed, Mahmoud S.</creatorcontrib><creatorcontrib>Hankins, Gary D. V.</creatorcontrib><creatorcontrib>Caritis, Steve N.</creatorcontrib><creatorcontrib>Venkataramanan, Raman</creatorcontrib><title>Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aims Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. Methods Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK‐based predictions with observed PK profiles. Results Predicted exposure (AUC0‐6h) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0‐6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. Conclusion A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure–response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.</description><subject>Female</subject><subject>Fetus</subject><subject>Humans</subject><subject>indomethacin</subject><subject>Indomethacin - adverse effects</subject><subject>Infant, Newborn</subject><subject>Models, Biological</subject><subject>physiologically based pharmacokinetics</subject><subject>Pregnancy</subject><subject>Pregnancy Trimester, Third</subject><subject>Pregnancy Trimesters</subject><subject>pregnant women</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp1kLtOw0AQRVcIREKg4AeQWwonM96HkxIiXlIEKaC2Zh8mC_HaWhuh_D0OBjqmmLkjHd3iMHaOMMV-Zto0UxQLBQdsjFzJNMNMHrIxcFCpzCSO2EnbvgEgRyWP2YgLnEvOccwe19FZbzpfh6Quk4o6FwNtEwo2KV3Xp2ZDsSJTv_vgOm_aPeaDrSvXbcj40D9JE91roGB2p-yopG3rzn7uhL3c3jwv79PV093D8mqVGq4AUkkKMqHzHLnlQDq3AoBrTvPMSS7AZUiAQtN8YWUJlFtt-q2EJSkFCj5hl0OviXXbRlcWTfQVxV2BUOydFL2T4ttJz14MbPOhK2f_yF8JPTAbgE-_dbv_m4rr5Xqo_AJfzWrq</recordid><startdate>202201</startdate><enddate>202201</enddate><creator>Pillai, Venkateswaran C.</creator><creator>Shah, Mansi</creator><creator>Rytting, Erik</creator><creator>Nanovskaya, Tatiana N.</creator><creator>Wang, Xiaoming</creator><creator>Clark, Shannon M.</creator><creator>Ahmed, Mahmoud S.</creator><creator>Hankins, Gary D. V.</creator><creator>Caritis, Steve N.</creator><creator>Venkataramanan, Raman</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0003-1893-3290</orcidid></search><sort><creationdate>202201</creationdate><title>Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy</title><author>Pillai, Venkateswaran C. ; Shah, Mansi ; Rytting, Erik ; Nanovskaya, Tatiana N. ; Wang, Xiaoming ; Clark, Shannon M. ; Ahmed, Mahmoud S. ; Hankins, Gary D. 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V.</creatorcontrib><creatorcontrib>Caritis, Steve N.</creatorcontrib><creatorcontrib>Venkataramanan, Raman</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pillai, Venkateswaran C.</au><au>Shah, Mansi</au><au>Rytting, Erik</au><au>Nanovskaya, Tatiana N.</au><au>Wang, Xiaoming</au><au>Clark, Shannon M.</au><au>Ahmed, Mahmoud S.</au><au>Hankins, Gary D. V.</au><au>Caritis, Steve N.</au><au>Venkataramanan, Raman</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2022-01</date><risdate>2022</risdate><volume>88</volume><issue>1</issue><spage>271</spage><epage>281</epage><pages>271-281</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><abstract>Aims Indomethacin is used for the treatment of preterm labour, short cervices and idiopathic polyhydramnios during pregnancy. Few studies have described the pharmacokinetics (PK) of indomethacin during pregnancy. This study aimed to determine maternal and fetal PK of indomethacin during different trimesters of pregnancy using physiologically based PK (PBPK) modelling and simulations. Methods Full PBPK simulations were performed in nonpregnant subjects and pregnant subjects from each trimester of pregnancy at steady state using Simcyp's healthy volunteers and pregnancy PBPK model, respectively. The fetal exposures were predicted using a fetoplacental pregnancy PBPK model. The models were verified by comparing PBPK‐based predictions with observed PK profiles. Results Predicted exposure (AUC0‐6h) and clearance of indomethacin in nonpregnant women and pregnant women are similar to the clinical observations. AUC0‐6h of indomethacin is approximately 14, 24 and 32% lower, consistent with 18, 34 and 52% higher clearance in the first, second and third trimesters of pregnancy, respectively, compared to nonpregnant women. Predicted fetal plasma exposures increased by approximately 30% from the second trimester to the third trimester of pregnancy. Conclusion A mechanistic PBPK model adequately described the maternal and the fetal PK of indomethacin during pregnancy. As the pregnancy progresses, a modest decrease (≤32%) in systemic exposures in pregnant women and a 33% increase in fetal exposures to indomethacin were predicted. Higher fetal exposures in the third trimester of pregnancy may pose safety risks to the fetus. Additional studies are warranted to understand the exposure–response relationship and provide appropriate dosing recommendations during pregnancy that consider both safety and efficacy.</abstract><cop>England</cop><pmid>34185331</pmid><doi>10.1111/bcp.14960</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-1893-3290</orcidid><oa>free_for_read</oa></addata></record>
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subjects Female
Fetus
Humans
indomethacin
Indomethacin - adverse effects
Infant, Newborn
Models, Biological
physiologically based pharmacokinetics
Pregnancy
Pregnancy Trimester, Third
Pregnancy Trimesters
pregnant women
title Prediction of maternal and fetal pharmacokinetics of indomethacin in pregnancy
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