Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application

R. K. Malcolm, Deborah Lowry, P. Boyd, L. Geer, R. S. Veazey, L. Goldman, P. J. Klasse, R. J. Shattock, J. P. Moore

    Research output: Contribution to journal › Article

    12 Citations (Scopus)

    Abstract

    ObjectivesThis study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques.MethodsA vaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC–mass spectrometry.ResultsCMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration.ConclusionsThe study provides clear evidence for vaginal–rectal and rectal–vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products.
    LanguageEnglish
    Pages1325-1329
    JournalJournal of Antimicrobial Chemotherapy
    Volume69
    Issue number5
    DOIs
    Publication statusPublished - 1 May 2014

    Fingerprint

    Female Contraceptive Devices
    Macaca mulatta
    Oral Administration
    Pharmacokinetics
    Gels
    Intravaginal Administration
    Foams and Jellies Vaginal Creams
    Rectal Administration
    Silicone Elastomers
    Medroxyprogesterone Acetate
    Anti-Infective Agents
    Pharmaceutical Preparations
    HIV-1
    Mass Spectrometry
    High Pressure Liquid Chromatography
    HIV
    hydroxyethylcellulose
    Pre-Exposure Prophylaxis

    Keywords

    • HIV microbicides
    • vaginal HEC gels
    • vaginal rings
    • rectal gels
    • pre-exposure prophylaxis
    • PrEP
    • CMPD167

    Cite this

    Malcolm, R. K. ; Lowry, Deborah ; Boyd, P. ; Geer, L. ; Veazey, R. S. ; Goldman, L. ; Klasse, P. J. ; Shattock, R. J. ; Moore, J. P. / Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application. In: Journal of Antimicrobial Chemotherapy. 2014 ; Vol. 69, No. 5. pp. 1325-1329.
    @article{dc9ea4f7dd8f48099bf956a0baa88796,
    title = "Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application",
    abstract = "ObjectivesThis study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques.MethodsA vaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC–mass spectrometry.ResultsCMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration.ConclusionsThe study provides clear evidence for vaginal–rectal and rectal–vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products.",
    keywords = "HIV microbicides, vaginal HEC gels, vaginal rings, rectal gels, pre-exposure prophylaxis, PrEP, CMPD167",
    author = "Malcolm, {R. K.} and Deborah Lowry and P. Boyd and L. Geer and Veazey, {R. S.} and L. Goldman and Klasse, {P. J.} and Shattock, {R. J.} and Moore, {J. P.}",
    year = "2014",
    month = "5",
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    doi = "10.1093/jac/dkt506",
    language = "English",
    volume = "69",
    pages = "1325--1329",
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    Malcolm, RK, Lowry, D, Boyd, P, Geer, L, Veazey, RS, Goldman, L, Klasse, PJ, Shattock, RJ & Moore, JP 2014, 'Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application', Journal of Antimicrobial Chemotherapy, vol. 69, no. 5, pp. 1325-1329. https://doi.org/10.1093/jac/dkt506

    Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application. / Malcolm, R. K.; Lowry, Deborah; Boyd, P.; Geer, L.; Veazey, R. S.; Goldman, L.; Klasse, P. J.; Shattock, R. J.; Moore, J. P.

    In: Journal of Antimicrobial Chemotherapy, Vol. 69, No. 5, 01.05.2014, p. 1325-1329.

    Research output: Contribution to journal › Article

    TY - JOUR

    T1 - Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application

    AU - Malcolm, R. K.

    AU - Lowry, Deborah

    AU - Boyd, P.

    AU - Geer, L.

    AU - Veazey, R. S.

    AU - Goldman, L.

    AU - Klasse, P. J.

    AU - Shattock, R. J.

    AU - Moore, J. P.

    PY - 2014/5/1

    Y1 - 2014/5/1

    N2 - ObjectivesThis study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques.MethodsA vaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC–mass spectrometry.ResultsCMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration.ConclusionsThe study provides clear evidence for vaginal–rectal and rectal–vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products.

    AB - ObjectivesThis study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques.MethodsA vaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC–mass spectrometry.ResultsCMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration.ConclusionsThe study provides clear evidence for vaginal–rectal and rectal–vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products.

    KW - HIV microbicides

    KW - vaginal HEC gels

    KW - vaginal rings

    KW - rectal gels

    KW - pre-exposure prophylaxis

    KW - PrEP

    KW - CMPD167

    U2 - 10.1093/jac/dkt506

    DO - 10.1093/jac/dkt506

    M3 - Article

    VL - 69

    SP - 1325

    EP - 1329

    JO - Journal of Antimicrobial Chemotherapy

    T2 - Journal of Antimicrobial Chemotherapy

    JF - Journal of Antimicrobial Chemotherapy

    SN - 0305-7453

    IS - 5

    ER -

    Malcolm RK, Lowry D, Boyd P, Geer L, Veazey RS, Goldman L et al. Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application. Journal of Antimicrobial Chemotherapy. 2014 May 1;69(5):1325-1329. https://doi.org/10.1093/jac/dkt506

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