Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema
[Display omitted] HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people...
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| Veröffentlicht in: | European journal of pharmaceutics and biopharmaceutics 2019-05, Vol.138, p.23-29 |
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| container_title | European journal of pharmaceutics and biopharmaceutics |
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| creator | Hoang, Thuy Date, Abhijit A. Ortiz, Jairo Ortiz Young, Ting-Wei Bensouda, Sabrine Xiao, Peng Marzinke, Mark Rohan, Lisa Fuchs, Edward J. Hendrix, Craig Gumber, Sanjeev Villinger, Francois Cone, Richard A. Hanes, Justin Ensign, Laura M. |
| description | [Display omitted]
HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people to adhere to treatment regimens that require significant behavioral changes and daily discipline. An alternative approach to PrEP is to focus on strategies that fit in to normal, and even desirable, sexual behaviors, such as the use of cleansing enemas by men who have sex with men (MSM) prior to receptive anal intercourse (RAI). Here, we describe preclinical efforts toward optimizing a tenofovir (TFV)-based enema formulation for rectal PrEP. Using a murine model, we compared the plasma and tissue pharmacokinetics of TFV and various TFV prodrugs, including tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and hexadecyloxypropyl tenofovir (CMX157), after dosing as enema formulations with varying osmolality and ion content. We observed that the enema vehicle composition played a more important role than the TFV prodrug properties in achieving rapid and therapeutically relevant tenofovir diphosphate (TFV-DP) concentrations in mouse colorectal tissue. Our results support the next steps, which are further preclinical (non-human primate) and clinical development of a hypo-osmolar TFV enema product for rectal PrEP. |
| doi_str_mv | 10.1016/j.ejpb.2018.05.030 |
| format | Article |
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HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people to adhere to treatment regimens that require significant behavioral changes and daily discipline. An alternative approach to PrEP is to focus on strategies that fit in to normal, and even desirable, sexual behaviors, such as the use of cleansing enemas by men who have sex with men (MSM) prior to receptive anal intercourse (RAI). Here, we describe preclinical efforts toward optimizing a tenofovir (TFV)-based enema formulation for rectal PrEP. Using a murine model, we compared the plasma and tissue pharmacokinetics of TFV and various TFV prodrugs, including tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and hexadecyloxypropyl tenofovir (CMX157), after dosing as enema formulations with varying osmolality and ion content. We observed that the enema vehicle composition played a more important role than the TFV prodrug properties in achieving rapid and therapeutically relevant tenofovir diphosphate (TFV-DP) concentrations in mouse colorectal tissue. Our results support the next steps, which are further preclinical (non-human primate) and clinical development of a hypo-osmolar TFV enema product for rectal PrEP.</description><identifier>ISSN: 0939-6411</identifier><identifier>EISSN: 1873-3441</identifier><identifier>DOI: 10.1016/j.ejpb.2018.05.030</identifier><identifier>PMID: 29802984</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Adenine - analogs & derivatives ; Adenine - pharmacology ; Administration, Rectal ; Animals ; Anti-HIV Agents - pharmacology ; Anti-Infective Agents - pharmacology ; Enema - methods ; Fleet ; HIV Infections - drug therapy ; HIV-1 - drug effects ; Homosexuality, Male ; Hypotonic ; Male ; Mice ; Organophosphates - pharmacology ; Organophosphonates - pharmacology ; Pre-Exposure Prophylaxis - methods ; Prodrugs - pharmacology ; Rectal douche ; Rectal gel ; Rectum - drug effects ; Sexual and Gender Minorities ; Sodium bicarbonate ; Tenofovir - pharmacology</subject><ispartof>European journal of pharmaceutics and biopharmaceutics, 2019-05, Vol.138, p.23-29</ispartof><rights>2018 Elsevier B.V.</rights><rights>Copyright © 2018 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-c46d120158fbc6d169731fa39196a7ec55703d8b4c98dce1c1176f2309a8a14b3</citedby><cites>FETCH-LOGICAL-c455t-c46d120158fbc6d169731fa39196a7ec55703d8b4c98dce1c1176f2309a8a14b3</cites><orcidid>0000-0001-9048-2717 ; 0000-0002-5696-8665</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0939641118304764$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29802984$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hoang, Thuy</creatorcontrib><creatorcontrib>Date, Abhijit A.</creatorcontrib><creatorcontrib>Ortiz, Jairo Ortiz</creatorcontrib><creatorcontrib>Young, Ting-Wei</creatorcontrib><creatorcontrib>Bensouda, Sabrine</creatorcontrib><creatorcontrib>Xiao, Peng</creatorcontrib><creatorcontrib>Marzinke, Mark</creatorcontrib><creatorcontrib>Rohan, Lisa</creatorcontrib><creatorcontrib>Fuchs, Edward J.</creatorcontrib><creatorcontrib>Hendrix, Craig</creatorcontrib><creatorcontrib>Gumber, Sanjeev</creatorcontrib><creatorcontrib>Villinger, Francois</creatorcontrib><creatorcontrib>Cone, Richard A.</creatorcontrib><creatorcontrib>Hanes, Justin</creatorcontrib><creatorcontrib>Ensign, Laura M.</creatorcontrib><title>Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema</title><title>European journal of pharmaceutics and biopharmaceutics</title><addtitle>Eur J Pharm Biopharm</addtitle><description>[Display omitted]
HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people to adhere to treatment regimens that require significant behavioral changes and daily discipline. An alternative approach to PrEP is to focus on strategies that fit in to normal, and even desirable, sexual behaviors, such as the use of cleansing enemas by men who have sex with men (MSM) prior to receptive anal intercourse (RAI). Here, we describe preclinical efforts toward optimizing a tenofovir (TFV)-based enema formulation for rectal PrEP. Using a murine model, we compared the plasma and tissue pharmacokinetics of TFV and various TFV prodrugs, including tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and hexadecyloxypropyl tenofovir (CMX157), after dosing as enema formulations with varying osmolality and ion content. We observed that the enema vehicle composition played a more important role than the TFV prodrug properties in achieving rapid and therapeutically relevant tenofovir diphosphate (TFV-DP) concentrations in mouse colorectal tissue. Our results support the next steps, which are further preclinical (non-human primate) and clinical development of a hypo-osmolar TFV enema product for rectal PrEP.</description><subject>Adenine - analogs & derivatives</subject><subject>Adenine - pharmacology</subject><subject>Administration, Rectal</subject><subject>Animals</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Anti-Infective Agents - pharmacology</subject><subject>Enema - methods</subject><subject>Fleet</subject><subject>HIV Infections - drug therapy</subject><subject>HIV-1 - drug effects</subject><subject>Homosexuality, Male</subject><subject>Hypotonic</subject><subject>Male</subject><subject>Mice</subject><subject>Organophosphates - pharmacology</subject><subject>Organophosphonates - pharmacology</subject><subject>Pre-Exposure Prophylaxis - methods</subject><subject>Prodrugs - pharmacology</subject><subject>Rectal douche</subject><subject>Rectal gel</subject><subject>Rectum - drug effects</subject><subject>Sexual and Gender Minorities</subject><subject>Sodium bicarbonate</subject><subject>Tenofovir - pharmacology</subject><issn>0939-6411</issn><issn>1873-3441</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtLxDAUhYMoOj7-gAvJUhdTkyZtUxFhmBkfoCii65Cmt2OGtilJLfjvTRkV3bjIA3LOF-45CB1TElFC0_N1BOuuiGJCRUSSiDCyhSZUZGzKOKfbaEJylk9TTuke2vd-TQjhWSJ20V6cCxIWnyC3gAFq2zXQ9thW2IHuVY2hhUZh5XFjtLOF0aYEfLp4Xs4ezi7wU1DVpjU6KDtnVw68NwNgD3WwG9uOJIV7aG1lB-NGUeneVxvsIdqpVO3h6Os8QK_Xy5f57fT-8eZuPrufap4kfdjTkobZElEVOlzTPGO0Uiyneaoy0EmSEVaKgutclBqopjRLq5iRXAlFecEO0NWG270XDQRJ2ztVy86ZRrkPaZWRf19a8yZXdpApj0XKWADEG0CIwHsH1Y-XEjk2INdybECODUiSyNBAMJ38_vXH8h15EFxuBBBmHww46bWBVkNpxvBlac1__E9Capnf</recordid><startdate>20190501</startdate><enddate>20190501</enddate><creator>Hoang, Thuy</creator><creator>Date, Abhijit A.</creator><creator>Ortiz, Jairo Ortiz</creator><creator>Young, Ting-Wei</creator><creator>Bensouda, Sabrine</creator><creator>Xiao, Peng</creator><creator>Marzinke, Mark</creator><creator>Rohan, Lisa</creator><creator>Fuchs, Edward J.</creator><creator>Hendrix, Craig</creator><creator>Gumber, Sanjeev</creator><creator>Villinger, Francois</creator><creator>Cone, Richard A.</creator><creator>Hanes, Justin</creator><creator>Ensign, Laura M.</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9048-2717</orcidid><orcidid>https://orcid.org/0000-0002-5696-8665</orcidid></search><sort><creationdate>20190501</creationdate><title>Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema</title><author>Hoang, Thuy ; Date, Abhijit A. ; Ortiz, Jairo Ortiz ; Young, Ting-Wei ; Bensouda, Sabrine ; Xiao, Peng ; Marzinke, Mark ; Rohan, Lisa ; Fuchs, Edward J. ; Hendrix, Craig ; Gumber, Sanjeev ; Villinger, Francois ; Cone, Richard A. ; Hanes, Justin ; Ensign, Laura M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-c46d120158fbc6d169731fa39196a7ec55703d8b4c98dce1c1176f2309a8a14b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adenine - pharmacology</topic><topic>Administration, Rectal</topic><topic>Animals</topic><topic>Anti-HIV Agents - pharmacology</topic><topic>Anti-Infective Agents - pharmacology</topic><topic>Enema - methods</topic><topic>Fleet</topic><topic>HIV Infections - drug therapy</topic><topic>HIV-1 - drug effects</topic><topic>Homosexuality, Male</topic><topic>Hypotonic</topic><topic>Male</topic><topic>Mice</topic><topic>Organophosphates - pharmacology</topic><topic>Organophosphonates - pharmacology</topic><topic>Pre-Exposure Prophylaxis - methods</topic><topic>Prodrugs - pharmacology</topic><topic>Rectal douche</topic><topic>Rectal gel</topic><topic>Rectum - drug effects</topic><topic>Sexual and Gender Minorities</topic><topic>Sodium bicarbonate</topic><topic>Tenofovir - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hoang, Thuy</creatorcontrib><creatorcontrib>Date, Abhijit A.</creatorcontrib><creatorcontrib>Ortiz, Jairo Ortiz</creatorcontrib><creatorcontrib>Young, Ting-Wei</creatorcontrib><creatorcontrib>Bensouda, Sabrine</creatorcontrib><creatorcontrib>Xiao, Peng</creatorcontrib><creatorcontrib>Marzinke, Mark</creatorcontrib><creatorcontrib>Rohan, Lisa</creatorcontrib><creatorcontrib>Fuchs, Edward J.</creatorcontrib><creatorcontrib>Hendrix, Craig</creatorcontrib><creatorcontrib>Gumber, Sanjeev</creatorcontrib><creatorcontrib>Villinger, Francois</creatorcontrib><creatorcontrib>Cone, Richard A.</creatorcontrib><creatorcontrib>Hanes, Justin</creatorcontrib><creatorcontrib>Ensign, Laura M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of pharmaceutics and biopharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hoang, Thuy</au><au>Date, Abhijit A.</au><au>Ortiz, Jairo Ortiz</au><au>Young, Ting-Wei</au><au>Bensouda, Sabrine</au><au>Xiao, Peng</au><au>Marzinke, Mark</au><au>Rohan, Lisa</au><au>Fuchs, Edward J.</au><au>Hendrix, Craig</au><au>Gumber, Sanjeev</au><au>Villinger, Francois</au><au>Cone, Richard A.</au><au>Hanes, Justin</au><au>Ensign, Laura M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema</atitle><jtitle>European journal of pharmaceutics and biopharmaceutics</jtitle><addtitle>Eur J Pharm Biopharm</addtitle><date>2019-05-01</date><risdate>2019</risdate><volume>138</volume><spage>23</spage><epage>29</epage><pages>23-29</pages><issn>0939-6411</issn><eissn>1873-3441</eissn><abstract>[Display omitted]
HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people to adhere to treatment regimens that require significant behavioral changes and daily discipline. An alternative approach to PrEP is to focus on strategies that fit in to normal, and even desirable, sexual behaviors, such as the use of cleansing enemas by men who have sex with men (MSM) prior to receptive anal intercourse (RAI). Here, we describe preclinical efforts toward optimizing a tenofovir (TFV)-based enema formulation for rectal PrEP. Using a murine model, we compared the plasma and tissue pharmacokinetics of TFV and various TFV prodrugs, including tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and hexadecyloxypropyl tenofovir (CMX157), after dosing as enema formulations with varying osmolality and ion content. We observed that the enema vehicle composition played a more important role than the TFV prodrug properties in achieving rapid and therapeutically relevant tenofovir diphosphate (TFV-DP) concentrations in mouse colorectal tissue. Our results support the next steps, which are further preclinical (non-human primate) and clinical development of a hypo-osmolar TFV enema product for rectal PrEP.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>29802984</pmid><doi>10.1016/j.ejpb.2018.05.030</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-9048-2717</orcidid><orcidid>https://orcid.org/0000-0002-5696-8665</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of pharmaceutics and biopharmaceutics, 2019-05, Vol.138, p.23-29 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adenine - analogs & derivatives Adenine - pharmacology Administration, Rectal Animals Anti-HIV Agents - pharmacology Anti-Infective Agents - pharmacology Enema - methods Fleet HIV Infections - drug therapy HIV-1 - drug effects Homosexuality, Male Hypotonic Male Mice Organophosphates - pharmacology Organophosphonates - pharmacology Pre-Exposure Prophylaxis - methods Prodrugs - pharmacology Rectal douche Rectal gel Rectum - drug effects Sexual and Gender Minorities Sodium bicarbonate Tenofovir - pharmacology |
| title | Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema |
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