{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:10:16Z","timestamp":1791432616175,"version":"4.3.3"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T00:00:00Z","timestamp":1689120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir\/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P\u2010glycoprotein substrate).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PK was studied in 2 phase 1, open\u2010label, fixed\u2010sequence studies in healthy adults. Single oral doses of midazolam 2\u2009mg (<jats:italic>n<\/jats:italic>\u00a0=\u200912) or dabigatran 75\u2009mg (<jats:italic>n<\/jats:italic>\u00a0=\u200924) were administered alone and after steady state (i.e. \u22652\u2009days) of nirmatrelvir\/ritonavir 300\u2009mg\/100\u2009mg and ritonavir 100\u2009mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After administration of midazolam with nirmatrelvir\/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration\u2013time curve extrapolated to infinity (AUC<jats:sub>inf<\/jats:sub>) and maximum plasma concentration (C<jats:sub>max<\/jats:sub>) increased 14.3\u2010fold and 3.7\u2010fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5\u2010fold and 3.9\u2010fold increases in midazolam geometric mean AUC<jats:sub>inf<\/jats:sub> and C<jats:sub>max<\/jats:sub>, respectively. After administration of dabigatran with nirmatrelvir\/ritonavir (test) or alone (reference), dabigatran geometric mean AUC<jats:sub>inf<\/jats:sub> and C<jats:sub>max<\/jats:sub> increased 1.9\u2010fold and 2.3\u2010fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7\u2010fold increase in dabigatran geometric mean AUC<jats:sub>inf<\/jats:sub> and C<jats:sub>max<\/jats:sub>. Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir\/ritonavir or ritonavir alone, with a slightly higher dabigatran C<jats:sub>max<\/jats:sub> with nirmatrelvir\/ritonavir <jats:italic>vs<\/jats:italic>. ritonavir alone. Nirmatrelvir\/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Coadministration of midazolam or dabigatran with nirmatrelvir\/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir\/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran C<jats:sub>max<\/jats:sub> was slightly higher when coadministered with nirmatrelvir\/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15835","type":"journal-article","created":{"date-parts":[[2023,6,25]],"date-time":"2023-06-25T01:40:50Z","timestamp":1687657250000},"page":"3352-3363","source":"Crossref","is-referenced-by-count":24,"title":["Effects of nirmatrelvir\/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants"],"prefix":"10.1111","volume":"89","author":[{"given":"Donna S.","family":"Cox","sequence":"first","affiliation":[{"name":"Pfizer Inc. Global Product Development  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Rehman","sequence":"additional","affiliation":[{"name":"Pfizer Inc. Global Product Development  Andover Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahira","family":"Khan","sequence":"additional","affiliation":[{"name":"Pfizer Inc. Global Product Development  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Ginman","sequence":"additional","affiliation":[{"name":"Pfizer Inc. Global Product Development  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Salageanu","sequence":"additional","affiliation":[{"name":"Pfizer Inc. Global Product Development  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert R.","family":"LaBadie","sequence":"additional","affiliation":[{"name":"Pfizer Inc. Global Product Development  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katty","family":"Wan","sequence":"additional","affiliation":[{"name":"Pfizer Inc. Global Product Development  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharat","family":"Damle","sequence":"additional","affiliation":[{"name":"Pfizer Inc. Global Product Development  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,12]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"World Health Organization.WHO coronavirus (COVID\u201019) dashboard. 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