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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EPart 1 of A Dose-Ranging Study to Compare MK-1439 Plus TRUVADA\u00ae Versus Efavirenz Plus TRUVADA\u00ae in Human Immunodeficiency Virus-1 Infected Participants (MK-1439-007) [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01632345\u0026amp;atom=%2Fspmdc%2F14%2F28%2F21.atom\u0022\u003ENCT01632345\u003C\/a\u003E] examined the safety, tolerability, pharmacokinetics, and efficacy of 4 doses of doravirine (25, 50, 100, and 200 mg once daily) versus efavirenz, both taken with emtricitabine-tenofovir. The Part 1 efficacy and safety results demonstrated that all 4 doses of doravirine had potent antiretroviral activity and fewer drug-related adverse events than efavirenz [Morales-Ramirez et al. CROI 2014].\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHIV \u0026amp; AIDS\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInfectious Disease Clinical Trials\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHIV \u0026amp; AIDS\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInfectious Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInfectious Disease Clinical Trials\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003ECommonly used nonnucleoside reverse transcriptase inhibitors (NNRTIs) are associated with suboptimal efficacy or safety profiles. Doravirine is a novel, next-generation NNRTI in development for the treatment of HIV-1 infection. It is dosed once daily and has a rapid onset with a median T\u003Csub\u003Emax\u003C\/sub\u003E of 1 to 5 hours and an apparent terminal half-life of 11 to 19 hours. Doravirine is not expected to interact with proton pump inhibitors (PPIs) and can be dosed without regard to food intake.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EPart 1 of A Dose-Ranging Study to Compare MK-1439 Plus TRUVADA\u00ae Versus Efavirenz Plus TRUVADA\u00ae in Human Immunodeficiency Virus (HIV)-1 Infected Participants (MK-1439-007) [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01632345\u0026amp;atom=%2Fspmdc%2F14%2F28%2F21.atom\u0022\u003ENCT01632345\u003C\/a\u003E] examined the safety, tolerability, pharmacokinetics (PK), and efficacy of 4 doses of doravirine (25, 50, 100, and 200 mg once daily) versus efavirenz, both taken with emtricitabine-tenofovir. The Part 1 efficacy and safety results demonstrated that all 4 doses of doravirine had potent antiretroviral activity and fewer drug-related adverse events (AEs) than efavirenz [Morales-Ramirez et al. CROI 2014]. In this report, Matthew L. Rizk, PhD, Merck and Company, Inc., Whitehouse Station, New Jersey, USA, presented exposure-response analysis results from Part 1 of this dose-ranging study.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ESparse doravirine PK data, available from 167 of 208 enrolled patients, were pooled with densely sampled phase 1 PK data in a population PK model to obtain individual post-hoc estimates of steady-state PK parameters. Individual PK estimates and week 24 HIV-1 RNA (vRNA) were matched, and PK-pharmacodynamic (PD) trends were explored. Individual area under the curve (AUC) estimates were plotted against the predefined AE rate. Steady-state C\u003Csub\u003Etrough\u003C\/sub\u003E distributions were compared to in vitro C\u003Csub\u003Etrough\u003C\/sub\u003E targets for wild-type and various mutant HIV-1 strains.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe exposure-response analysis of efficacy showed that there was no trend between C\u003Csub\u003Etrough\u003C\/sub\u003E or AUC and the proportion of patients with undetectable HIV-1 RNA at week 24 (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). No difference in the PK-PD relationship between high and low-viral-load patients was observed.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/28\/21\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022HIV RNA vs steady-state Ctrough and AUC0\u0026#x2013;24 hr by baseline HIV RNA\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1469965719\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;HIV RNA vs steady-state C\u0026amp;lt;sub\u0026amp;gt;trough\u0026amp;lt;\/sub\u0026amp;gt; and AUC\u0026amp;lt;sub\u0026amp;gt;0\u0026#x2013;24 hr\u0026amp;lt;\/sub\u0026amp;gt; by baseline HIV RNA\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/28\/21\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/28\/21\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/28\/21\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11840\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EHIV RNA vs steady-state C\u003Csub\u003Etrough\u003C\/sub\u003E and AUC\u003Csub\u003E0\u201324 hr\u003C\/sub\u003E by baseline HIV RNA\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EAUC, area under the curve; SS, steady-state.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from ML Rizk, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-7\u0022\u003ENo apparent trend between AUC and the proportion of patients with central nervous system AEs, abnormal dreams, nausea, or diarrhea was observed. A logistic regression model found no significant relationship between AUC and nausea.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EComparison of steady-state C\u003Csub\u003Etrough\u003C\/sub\u003E distributions and in vitro C\u003Csub\u003Etrough\u003C\/sub\u003E targets for wild-type and mutant HIV-1 found that 25 mg through 200 mg doses of doravirine provided good coverage of wild-type virus, consistent with the clinical results (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E). The 100 mg dose provided better coverage (92.3%) of dual mutant strains [K103N\/Y181C] compared with 50 mg, which provided 69.5% coverage.\u003C\/p\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/11841\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/11841\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11841\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-9\u0022 class=\u0022first-child\u0022\u003ESimulated Percentage of Patients With Higher-Than-Target Steady-State C\u003Csub\u003E24\u003C\/sub\u003E hr for a Representative HIV-1 Patient Population Assuming Full Compliance\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EThe safety and efficacy results showed that all tested doses of doravirine were efficacious and safe and had numerically higher response rates and fewer drug-related AEs than efavirenz. Although all 4 doravirine doses underwent exposure-response analysis, the study primarily focused on the 50 mg and 100 mg doses. The analysis confirmed that there is no relationship between doravirine plasma levels and both efficacy and AE rates. Based on these results and the superior coverage of dual mutant HIV-1 strains [K103N\/Y181C], the 100 mg dose of doravirine was selected for Part 2 of the study (with additional enrollment at 100 mg doravirine vs efavirez) and for study in Phase 3.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/28\/21.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzm0z2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzm0z2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_tables.js?nzm0z2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}