{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T22:27:57Z","timestamp":1778797677029,"version":"3.51.4"},"reference-count":15,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006483","name":"AbbVie","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100006483","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The immunosuppressive agents sirolimus and everolimus are sensitive CYP3A4 substrates with narrow therapeutic index. Ritonavir is a strong CYP3A inhibitor. A phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the co\u2010administration of sirolimus or everolimus with the ritonavir\u2010containing 3D regimen of the direct\u2010acting antiviral agents ombitasvir, ritonavir\u2010boosted paritaprevir, and dasabuvir in healthy subjects. This study had two independent arms, each with a two\u2010period, single\u2010sequence, crossover study design. A single dose of sirolimus 2\u00a0mg (<jats:italic>N<\/jats:italic>\u00a0=\u00a012) or everolimus 0.75\u2009mg (<jats:italic>N<\/jats:italic>\u00a0=\u00a012) was administered in Period 1. In Period 2, multiple doses of the 3D regimen (ombitasvir\/paritaprevir\/ritonavir 25\/150\/100\u2009mg once daily and dasabuvir 250\u2009mg twice daily) were administered for 34 or 28\u2009days, with a single dose of sirolimus 0.5\u00a0mg or everolimus 0.75\u2009mg co\u2010administered on Day 15. Following co\u2010administration with the 3D regimen, the sirolimus dose\u2010normalized maximum observed blood concentration (C<jats:sub>max<\/jats:sub>) and area under the blood concentration\u2013time curve from time zero to infinity (AUC<jats:sub>inf<\/jats:sub>) increased to 6.4\u2010fold and 38\u2010fold, respectively. Following co\u2010administration with the 3D regimen, the everolimus C<jats:sub>max<\/jats:sub> and AUC<jats:sub>inf<\/jats:sub> increased to 4.7\u2010fold and 27\u2010fold, respectively. Sirolimus and everolimus half\u2010lives increased from 96 to 249\u2009h, and 42 to 118\u2009h, respectively. There were no major safety or tolerability issues in this study. The ritonavir\u2010containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and\/or frequency modification when co\u2010administered with each other.<\/jats:p>","DOI":"10.1002\/prp2.1024","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T15:08:05Z","timestamp":1669216085000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of a <scp>ritonavir\u2010containing<\/scp> regimen on the pharmacokinetics of sirolimus or everolimus in healthy adult subjects"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-474X","authenticated-orcid":false,"given":"Jiuhong","family":"Zha","sequence":"first","affiliation":[{"name":"AbbVie Inc. (Clinical Pharmacology)  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Jiang","sequence":"additional","affiliation":[{"name":"AbbVie Inc. (Data and Statistical Sciences)  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betty B.","family":"Yao","sequence":"additional","affiliation":[{"name":"AbbVie Inc. (General Medicine)  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E.","family":"Cohen","sequence":"additional","affiliation":[{"name":"AbbVie Inc. (General Medicine)  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8102-7795","authenticated-orcid":false,"given":"David C.","family":"Carter","sequence":"additional","affiliation":[{"name":"AbbVie Inc. (Clinical Pharmacology)  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-0449","authenticated-orcid":false,"given":"Rajeev M.","family":"Menon","sequence":"additional","affiliation":[{"name":"AbbVie Inc. (Clinical Pharmacology)  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"European Association for the Study of the liver.Recommendations on treatment of hepatitis C2015.http:\/\/www.easl.eu\/research\/our\u2010contributions\/clinical\u2010practice\u2010guidelines\/detail\/recommendations\u2010on\u2010treatment\u2010of\u2010hepatitis\u2010c\u20102015\/report\/1."},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/lt.22410"},{"key":"e_1_2_12_4_1","unstructured":"Rapamune (sirolimus) [US package insert].PfizerAugust 2019."},{"key":"e_1_2_12_5_1","unstructured":"Zortress (Everolimus) [US Package Insert].NovartisAugust 2018."},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_2_12_7_1","unstructured":"Fact sheet for healthcare providers: emergency use authorization for paxlovid (nirmatrelvir tablets; ritonavir tablets). Pfizer Inc. April2022.https:\/\/www.fda.gov\/media\/155050\/download(Accessed on June 5 2022)."},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"issue":"1","key":"e_1_2_12_9_1","first-page":"S1","article-title":"THE CONCISE GUIDE TO PHARMACOLOGY 2019\/20: Introduction and other protein targets","volume":"176","author":"Alexander SPH","year":"2019","journal-title":"Br J Pharmacol"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25653"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.253"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270005275368"},{"key":"e_1_2_12_13_1","unstructured":"Viekira Pak (ombitasvir paritaprevir and ritonavir tablets; dasabuvir tablets) [US package insert].AbbVie Inc. December 2019."},{"key":"e_1_2_12_14_1","unstructured":"Viekirax (Ombitasvir\/Paritaprevir\/Ritonavir Tablets) [Summary of Product Characteristics].AbbVie Deutschland GmbH & Co. KG March2021https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/viekirax\u2010epar\u2010product\u2010information_en.pdf."},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.074518"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.01.026"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.1024","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.1024","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.1024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T17:01:21Z","timestamp":1692550881000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.1024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,23]]},"references-count":15,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1002\/prp2.1024"],"URL":"https:\/\/doi.org\/10.1002\/prp2.1024","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,23]]},"assertion":[{"value":"2022-09-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01024"}}