Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study

Nicola Richardson-Harman; Craig W. Hendrix; Namandjé N. Bumpus; Christine Mauck; Ross D. Cranston; Kuo Yang; Julie Elliott; Karen Tanner; Ian McGowan; Angela Kashuba; Peter A. Anton

doi:10.1371/journal.pone.0111507

Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study

Nicola Richardson-Harman, Craig W. Hendrix, Namandjé N. Bumpus, Christine Mauck, Ross D. Cranston, Kuo Yang, Julie Elliott, Karen Tanner, Ian McGowan, Angela Kashuba, Peter A. Anton

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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), CD42 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.

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.

Original language	English (US)
Article number	e111507
Journal	PloS one
Volume	9
Issue number	10
DOIs	https://doi.org/10.1371/journal.pone.0111507
State	Published - Oct 28 2014

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
General

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Richardson-Harman, N., Hendrix, C. W., Bumpus, N. N., Mauck, C., Cranston, R. D., Yang, K., Elliott, J., Tanner, K., McGowan, I., Kashuba, A., & Anton, P. A. (2014). Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study. PloS one, 9(10), [e111507]. https://doi.org/10.1371/journal.pone.0111507

Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study. / Richardson-Harman, Nicola; Hendrix, Craig W.; Bumpus, Namandjé N.; Mauck, Christine; Cranston, Ross D.; Yang, Kuo; Elliott, Julie; Tanner, Karen; McGowan, Ian; Kashuba, Angela; Anton, Peter A.

In: PloS one, Vol. 9, No. 10, e111507, 28.10.2014.

Research output: Contribution to journal › Article › peer-review

Richardson-Harman, N, Hendrix, CW , Bumpus, NN, Mauck, C, Cranston, RD, Yang, K, Elliott, J, Tanner, K, McGowan, I, Kashuba, A & Anton, PA 2014, 'Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study', PloS one, vol. 9, no. 10, e111507. https://doi.org/10.1371/journal.pone.0111507

Richardson-Harman, Nicola ; Hendrix, Craig W. ; Bumpus, Namandjé N. ; Mauck, Christine ; Cranston, Ross D. ; Yang, Kuo ; Elliott, Julie ; Tanner, Karen ; McGowan, Ian ; Kashuba, Angela ; Anton, Peter A. / Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study. In: PloS one. 2014 ; Vol. 9, No. 10.

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title = "Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study",

abstract = "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), CD42 MMC (p<0.0001), and TotalMMC (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 TotalMMC 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.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.",

author = "Nicola Richardson-Harman and Hendrix, {Craig W.} and Bumpus, {Namandj{\'e} N.} and Christine Mauck and Cranston, {Ross D.} and Kuo Yang and Julie Elliott and Karen Tanner and Ian McGowan and Angela Kashuba and Anton, {Peter A.}",

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T1 - Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study

AU - Richardson-Harman, Nicola

AU - Hendrix, Craig W.

AU - Bumpus, Namandjé N.

AU - Mauck, Christine

AU - Cranston, Ross D.

AU - Yang, Kuo

AU - Elliott, Julie

AU - Tanner, Karen

AU - McGowan, Ian

AU - Kashuba, Angela

AU - Anton, Peter A.

PY - 2014/10/28

Y1 - 2014/10/28

N2 - 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), CD42 MMC (p<0.0001), and TotalMMC (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 TotalMMC 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.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.

AB - 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), CD42 MMC (p<0.0001), and TotalMMC (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 TotalMMC 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.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.

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