PittsburghV1, Main, Exploration, bibRecord, 003644

Correlation between Compartmental Tenofovir Concentrations and an Ex Vivo Rectal Biopsy Model of Tissue Infectibility in the RMP-02/MTN-006 Phase 1 Study

Identifieur interne : 003644 ( Main/Exploration ); précédent : 003643; suivant : 003645

Correlation between Compartmental Tenofovir Concentrations and an Ex Vivo Rectal Biopsy Model of Tissue Infectibility in the RMP-02/MTN-006 Phase 1 Study

Auteurs : Nicola Richardson-Harman [États-Unis] ; Craig W. Hendrix [États-Unis] ; Namandjé N. Bumpus [États-Unis] ; Christine Mauck [États-Unis] ; Ross D. Cranston [États-Unis] ; Kuo Yang [États-Unis] ; Julie Elliott [États-Unis] ; Karen Tanner [États-Unis] ; Ian Mcgowan [États-Unis] ; Angela Kashuba [États-Unis] ; Peter A. Anton [États-Unis]

Source :

PLoS ONE [ 1932-6203 ] ; 2014.

RBID : PMC:4211741

Descripteurs français

KwdFr :
- Administration par voie orale, Administration par voie rectale, Adulte, Biopsie, Cellulose (), Cellulose (analogues et dérivés), Crèmes, mousses et gels vaginaux (), Femelle, Gels, Humains, Infections à VIH (), Jeune adulte, Mâle, Méthode en double aveugle, Rectum (), Relation dose-effet des médicaments, Ténofovir (administration et posologie), Ténofovir (pharmacocinétique).
MESH :
- administration et posologie : Ténofovir.
- analogues et dérivés : Cellulose.
- pharmacocinétique : Ténofovir.
- Administration par voie orale, Administration par voie rectale, Adulte, Biopsie, Cellulose, Crèmes, mousses et gels vaginaux, Femelle, Gels, Humains, Infections à VIH, Jeune adulte, Mâle, Méthode en double aveugle, Rectum, Relation dose-effet des médicaments.

English descriptors

KwdEn :
- Administration, Oral, Administration, Rectal, Adult, Biopsy, Cellulose (analogs & derivatives), Cellulose (chemistry), Dose-Response Relationship, Drug, Double-Blind Method, Female, Gels, HIV Infections (prevention & control), Humans, Male, Rectum (drug effects), Tenofovir (administration & dosage), Tenofovir (pharmacokinetics), Vaginal Creams, Foams, and Jellies (chemistry), Young Adult.
MESH :
- chemical , administration & dosage : Tenofovir.
- chemical , analogs & derivatives : Cellulose.
- chemical , chemistry : Cellulose, Vaginal Creams, Foams, and Jellies.
- drug effects : Rectum.
- chemical , pharmacokinetics : Tenofovir.
- prevention & control : HIV Infections.
- Administration, Oral, Administration, Rectal, Adult, Biopsy, Dose-Response Relationship, Drug, Double-Blind Method, Female, Gels, Humans, Male, Young Adult.

Abstract

Objectives

This study was designed to assess the dose-response relationship between tissue, blood, vaginal and rectal compartment concentrations of tenofovir (TFV) and tenofovir diphosphate (TFVdp) and ex vivo rectal HIV suppression following oral tenofovir disoproxil fumarate (TDF) and rectal administration of TFV 1% vaginally-formulated gel.

Design

Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females.

Methods

Eighteen participants received a single 300 mg exposure of oral TDF and were then randomized 2∶1 to receive a single then seven-daily rectal exposures of TFV 1% gel (40 mg TFV per 4 ml gel application) or hydroxyethyl-cellulose (HEC) placebo gel. Blood and rectal biopsies were collected for pharmacokinetic TDF and TFVdp analyses and ex vivo HIV-1 challenge.

Results

There was a significant fit for the TFVdp dose-response model for rectal tissue (p = 0.0004), CD4⁺_MMC (p<0.0001), CD4⁻_MMC (p<0.0001), and Total_MMC (p<0.0001) compartments with r² ranging 0.36–0.64. Higher concentrations of TFVdp corresponded with lower p24, consistent with drug-mediated virus suppression. The single oral treatment failed to provide adequate compartment drug exposure to reach the EC₅₀ of rectal tissue TFVdp predicted to be necessary to suppress HIV in rectal tissue. The EC₅₀ for CD4⁺_MMC was within the single topical treatment range, providing evidence that a 1% topical, vaginally-formulated TFV gel provided in-vivo doses predicted to provide for 50% efficacy in the ex vivo assay. The 7-daily topical TFV gel treatment provided TFVdp concentrations that reached EC₉₀ biopsy efficacy for CD4⁻_MMC, CD4⁺_MMC and Total_MMC compartments.

Conclusion

The TFVdp MMC compartment (CD4+, CD4− and Total) provided the best surrogate for biopsy infectibility and the 7-daily topical TFV gel treatment provided the strongest PK profile for HIV suppression.

ClinicalTrials.gov NCT00984971.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211741

DOI: 10.1371/journal.pone.0111507
PubMed: 25350130
PubMed Central: 4211741

Affiliations:

Le document en format XML

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 Rectal Biopsy Model of Tissue Infectibility in the RMP-02/MTN-006 Phase 1 Study</title>
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<author><name sortKey="Kashuba, Angela" sort="Kashuba, Angela" uniqKey="Kashuba A" first="Angela" last="Kashuba">Angela Kashuba</name>
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<term>Administration, Rectal</term>
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<term>Cellulose (chemistry)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Double-Blind Method</term>
<term>Female</term>
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<term>Administration par voie rectale</term>
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<term>Cellulose ()</term>
<term>Cellulose (analogues et dérivés)</term>
<term>Crèmes, mousses et gels vaginaux ()</term>
<term>Femelle</term>
<term>Gels</term>
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<term>Infections à VIH ()</term>
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<term>Relation dose-effet des médicaments</term>
<term>Ténofovir (administration et posologie)</term>
<term>Ténofovir (pharmacocinétique)</term>
</keywords>
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</keywords>
<keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Ténofovir</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Rectum</term>
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<term>Administration, Rectal</term>
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<term>Biopsy</term>
<term>Dose-Response Relationship, Drug</term>
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<term>Female</term>
<term>Gels</term>
<term>Humans</term>
<term>Male</term>
<term>Young Adult</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Administration par voie orale</term>
<term>Administration par voie rectale</term>
<term>Adulte</term>
<term>Biopsie</term>
<term>Cellulose</term>
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<term>Jeune adulte</term>
<term>Mâle</term>
<term>Méthode en double aveugle</term>
<term>Rectum</term>
<term>Relation dose-effet des médicaments</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Objectives</title>
<p>This study was designed to assess the dose-response relationship between tissue, blood, vaginal and rectal compartment concentrations of tenofovir (TFV) and tenofovir diphosphate (TFVdp) and <italic>ex vivo</italic>
 rectal HIV suppression following oral tenofovir disoproxil fumarate (TDF) and rectal administration of TFV 1% vaginally-formulated gel.</p>
</sec>
<sec><title>Design</title>
<p>Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females.</p>
</sec>
<sec><title>Methods</title>
<p>Eighteen participants received a single 300 mg exposure of oral TDF and were then randomized 2∶1 to receive a single then seven-daily rectal exposures of TFV 1% gel (40 mg TFV per 4 ml gel application) or hydroxyethyl-cellulose (HEC) placebo gel. Blood and rectal biopsies were collected for pharmacokinetic TDF and TFVdp analyses and <italic>ex vivo</italic>
 HIV-1 challenge.</p>
</sec>
<sec><title>Results</title>
<p>There was a significant fit for the TFVdp dose-response model for rectal tissue (<italic>p</italic>
 = 0.0004), CD4<sup>+</sup>
<sub>MMC</sub>
 (<italic>p</italic>
<0.0001), CD4<sup>−</sup>
<sub>MMC</sub>
 (<italic>p</italic>
<0.0001), and Total<sub>MMC</sub>
 (<italic>p</italic>
<0.0001) compartments with <italic>r<sup>2</sup>
</italic>
 ranging 0.36–0.64. Higher concentrations of TFVdp corresponded with lower p24, consistent with drug-mediated virus suppression. The single oral treatment failed to provide adequate compartment drug exposure to reach the EC<sub>50</sub>
 of rectal tissue TFVdp predicted to be necessary to suppress HIV in rectal tissue. The EC<sub>50</sub>
 for CD4<sup>+</sup>
<sub>MMC</sub>
 was within the single topical treatment range, providing evidence that a 1% topical, vaginally-formulated TFV gel provided <italic>in-vivo</italic>
 doses predicted to provide for 50% efficacy in the <italic>ex vivo</italic>
 assay. The 7-daily topical TFV gel treatment provided TFVdp concentrations that reached EC<sub>90</sub>
 biopsy efficacy for CD4<sup>−</sup>
<sub>MMC</sub>
, CD4<sup>+</sup>
<sub>MMC</sub>
 and Total<sub>MMC</sub>
 compartments.</p>
</sec>
<sec><title>Conclusion</title>
<p>The TFVdp MMC compartment (CD4+, CD4− and Total) provided the best surrogate for biopsy infectibility and the 7-daily topical TFV gel treatment provided the strongest PK profile for HIV suppression.</p>
</sec>
<sec><title></title>
<p>ClinicalTrials.gov <ext-link ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov/ct2/show/NCT00984971">NCT00984971.</ext-link>
</p>
</sec>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Abner, Sr" uniqKey="Abner S">SR Abner</name>
</author>
<author><name sortKey="Guenthner, Pc" uniqKey="Guenthner P">PC Guenthner</name>
</author>
<author><name sortKey="Guarner, J" uniqKey="Guarner J">J Guarner</name>
</author>
<author><name sortKey="Hancock, Ka" uniqKey="Hancock K">KA Hancock</name>
</author>
<author><name sortKey="Cummins, Je" uniqKey="Cummins J">JE Cummins</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Batman, Pa" uniqKey="Batman P">PA Batman</name>
</author>
<author><name sortKey="Fleming, Sc" uniqKey="Fleming S">SC Fleming</name>
</author>
<author><name sortKey="Sedgwick, Pm" uniqKey="Sedgwick P">PM Sedgwick</name>
</author>
<author><name sortKey="Macdonald, Tt" uniqKey="Macdonald T">TT MacDonald</name>
</author>
<author><name sortKey="Griffin, Ge" uniqKey="Griffin G">GE Griffin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fischetti, L" uniqKey="Fischetti L">L Fischetti</name>
</author>
<author><name sortKey="Barry, Sm" uniqKey="Barry S">SM Barry</name>
</author>
<author><name sortKey="Hope, Tj" uniqKey="Hope T">TJ Hope</name>
</author>
<author><name sortKey="Shattock, Rj" uniqKey="Shattock R">RJ Shattock</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Greenhead, P" uniqKey="Greenhead P">P Greenhead</name>
</author>
<author><name sortKey="Hayes, P" uniqKey="Hayes P">P Hayes</name>
</author>
<author><name sortKey="Watts, Ps" uniqKey="Watts P">PS Watts</name>
</author>
<author><name sortKey="Laing, Kg" uniqKey="Laing K">KG Laing</name>
</author>
<author><name sortKey="Griffin, Ge" uniqKey="Griffin G">GE Griffin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hladik, F" uniqKey="Hladik F">F Hladik</name>
</author>
<author><name sortKey="Doncel, Gf" uniqKey="Doncel G">GF Doncel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Anton, Pa" uniqKey="Anton P">PA Anton</name>
</author>
<author><name sortKey="Cranston, Rd" uniqKey="Cranston R">RD Cranston</name>
</author>
<author><name sortKey="Kashuba, A" uniqKey="Kashuba A">A Kashuba</name>
</author>
<author><name sortKey="Hendrix, Cw" uniqKey="Hendrix C">CW Hendrix</name>
</author>
<author><name sortKey="Bumpus, Nn" uniqKey="Bumpus N">NN Bumpus</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Anton, Pa" uniqKey="Anton P">PA Anton</name>
</author>
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</author>
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</author>
<author><name sortKey="Khanukhova, E" uniqKey="Khanukhova E">E Khanukhova</name>
</author>
<author><name sortKey="Dennis, R" uniqKey="Dennis R">R Dennis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Richardson Harman, N" uniqKey="Richardson Harman N">N Richardson-Harman</name>
</author>
<author><name sortKey="Mauck, C" uniqKey="Mauck C">C Mauck</name>
</author>
<author><name sortKey="Mcgowan, I" uniqKey="Mcgowan I">I McGowan</name>
</author>
<author><name sortKey="Anton, P" uniqKey="Anton P">P Anton</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tien, D" uniqKey="Tien D">D Tien</name>
</author>
<author><name sortKey="Schnaare, Rl" uniqKey="Schnaare R">RL Schnaare</name>
</author>
<author><name sortKey="Kang, F" uniqKey="Kang F">F Kang</name>
</author>
<author><name sortKey="Cohl, G" uniqKey="Cohl G">G Cohl</name>
</author>
<author><name sortKey="Mccormick, Tj" uniqKey="Mccormick T">TJ McCormick</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hendrix, Cw" uniqKey="Hendrix C">CW Hendrix</name>
</author>
<author><name sortKey="Chen, Ba" uniqKey="Chen B">BA Chen</name>
</author>
<author><name sortKey="Guddera, V" uniqKey="Guddera V">V Guddera</name>
</author>
<author><name sortKey="Hoesley, C" uniqKey="Hoesley C">C Hoesley</name>
</author>
<author><name sortKey="Justman, J" uniqKey="Justman J">J Justman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Anton, Pa" uniqKey="Anton P">PA Anton</name>
</author>
<author><name sortKey="Elliott, J" uniqKey="Elliott J">J Elliott</name>
</author>
<author><name sortKey="Poles, Ma" uniqKey="Poles M">MA Poles</name>
</author>
<author><name sortKey="Mcgowan, Im" uniqKey="Mcgowan I">IM McGowan</name>
</author>
<author><name sortKey="Matud, J" uniqKey="Matud J">J Matud</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fletcher, Ps" uniqKey="Fletcher P">PS Fletcher</name>
</author>
<author><name sortKey="Elliott, J" uniqKey="Elliott J">J Elliott</name>
</author>
<author><name sortKey="Grivel, Jc" uniqKey="Grivel J">JC Grivel</name>
</author>
<author><name sortKey="Margolis, L" uniqKey="Margolis L">L Margolis</name>
</author>
<author><name sortKey="Anton, P" uniqKey="Anton P">P Anton</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Richardson Harman, N" uniqKey="Richardson Harman N">N Richardson-Harman</name>
</author>
<author><name sortKey="Lackman Smith, C" uniqKey="Lackman Smith C">C Lackman-Smith</name>
</author>
<author><name sortKey="Fletcher, Ps" uniqKey="Fletcher P">PS Fletcher</name>
</author>
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</author>
<author><name sortKey="Bremer, Jw" uniqKey="Bremer J">JW Bremer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Glatting, G" uniqKey="Glatting G">G Glatting</name>
</author>
<author><name sortKey="Kletting, P" uniqKey="Kletting P">P Kletting</name>
</author>
<author><name sortKey="Reske, Sn" uniqKey="Reske S">SN Reske</name>
</author>
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<author><name sortKey="Ring, C" uniqKey="Ring C">C Ring</name>
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</biblStruct>
<biblStruct><analytic><author><name sortKey="Yang, K H" uniqKey="Yang K">K-H Yang</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Tebit, Dm" uniqKey="Tebit D">DM Tebit</name>
</author>
<author><name sortKey="Ndembi, N" uniqKey="Ndembi N">N Ndembi</name>
</author>
<author><name sortKey="Weinberg, A" uniqKey="Weinberg A">A Weinberg</name>
</author>
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</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Caroline du Nord</li>
<li>Maryland</li>
<li>Pennsylvanie</li>
<li>Virginie</li>
</region>
<settlement><li>Chapel Hill (Caroline du Nord)</li>
<li>Pittsburgh</li>
</settlement>
<orgName><li>Université de Caroline du Nord à Chapel Hill</li>
<li>Université de Pittsburgh</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Maryland"><name sortKey="Richardson Harman, Nicola" sort="Richardson Harman, Nicola" uniqKey="Richardson Harman N" first="Nicola" last="Richardson-Harman">Nicola Richardson-Harman</name>
</region>
<name sortKey="Anton, Peter A" sort="Anton, Peter A" uniqKey="Anton P" first="Peter A." last="Anton">Peter A. Anton</name>
<name sortKey="Bumpus, Namandje N" sort="Bumpus, Namandje N" uniqKey="Bumpus N" first="Namandjé N." last="Bumpus">Namandjé N. Bumpus</name>
<name sortKey="Cranston, Ross D" sort="Cranston, Ross D" uniqKey="Cranston R" first="Ross D." last="Cranston">Ross D. Cranston</name>
<name sortKey="Elliott, Julie" sort="Elliott, Julie" uniqKey="Elliott J" first="Julie" last="Elliott">Julie Elliott</name>
<name sortKey="Hendrix, Craig W" sort="Hendrix, Craig W" uniqKey="Hendrix C" first="Craig W." last="Hendrix">Craig W. Hendrix</name>
<name sortKey="Kashuba, Angela" sort="Kashuba, Angela" uniqKey="Kashuba A" first="Angela" last="Kashuba">Angela Kashuba</name>
<name sortKey="Mauck, Christine" sort="Mauck, Christine" uniqKey="Mauck C" first="Christine" last="Mauck">Christine Mauck</name>
<name sortKey="Mcgowan, Ian" sort="Mcgowan, Ian" uniqKey="Mcgowan I" first="Ian" last="Mcgowan">Ian Mcgowan</name>
<name sortKey="Tanner, Karen" sort="Tanner, Karen" uniqKey="Tanner K" first="Karen" last="Tanner">Karen Tanner</name>
<name sortKey="Yang, Kuo" sort="Yang, Kuo" uniqKey="Yang K" first="Kuo" last="Yang">Kuo Yang</name>
</country>
</tree>
</affiliations>
</record>

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Correlation between Compartmental Tenofovir Concentrations and an Ex Vivo Rectal Biopsy Model of Tissue Infectibility in the RMP-02/MTN-006 Phase 1 Study

Correlation between Compartmental Tenofovir Concentrations and an Ex Vivo Rectal Biopsy Model of Tissue Infectibility in the RMP-02/MTN-006 Phase 1 Study

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