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Brincidofovir, the second medicine approved by the US Food and Drug Administration to treat smallpox, is metabolized by oxidative and hydrolytic pathways. The oxidative pathway is initiated by cytochrome P450 4F2 (CYP4F2), an enzyme lacking clinical probes for drug interaction studies. The aim of this work was to assess the impact of reduced activity CYP4F2 variants (rs2108622, C\/T and T\/T) on brincidofovir pharmacokinetics as a surrogate for drug inhibition.<\/jats:p><jats:p>Genotyping was performed on blood from healthy participants receiving oral (n\u00a0=\u00a0261) and intravenous (IV, n\u00a0=\u00a049) brincidofovir across 6 phase 1 trials. Plasma concentrations were measured by validated liquid chromatography tandem mass spectrometry methods.<\/jats:p><jats:p>After oral administration, subjects with the lowest activity CYP4F2 genotype (T\/T) had up to 36% higher AUC<jats:sub>inf<\/jats:sub> and 29% higher C<jats:sub>max<\/jats:sub> while subjects with the moderate activity CYP4F2 genotype (C\/T) had similar C<jats:sub>max<\/jats:sub> and AUC<jats:sub>inf<\/jats:sub> compared to those with the wild\u2010type genotype. Little to no increase in brincidofovir exposure parameters was observed following IV administration.<\/jats:p><jats:p>Based on the lack of significant increases in brincidofovir plasma concentrations in subjects with low activity CYP4F2, a clinically meaningful drug\u2013drug interaction is not expected with CYP4F2 inhibitor and brincidofovir coadministration.<\/jats:p>","DOI":"10.1002\/cpdd.1356","type":"journal-article","created":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T02:24:16Z","timestamp":1704335056000},"page":"288-296","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Utility of Cytochrome P450 4F2 Genotyping to Assess Drug Interaction Risk for Brincidovovir, a Cytochrome P450 4F2 Substrate"],"prefix":"10.1002","volume":"13","author":[{"given":"Tim","family":"Tippin","sequence":"first","affiliation":[{"name":"Chimerix, Inc.  Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamia","family":"Faison","sequence":"additional","affiliation":[{"name":"Certara  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virna","family":"Schuck","sequence":"additional","affiliation":[{"name":"Ribon Therapeutics  Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Dunn","sequence":"additional","affiliation":[{"name":"Chimerix, Inc.  Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Odin","family":"Naderer","sequence":"additional","affiliation":[{"name":"Chimerix, Inc.  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