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National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

High maraviroc concentrations in rectal secretions after oral dosing do not prevent rectal SHIV transmission in macaques Ivana Massud , Wutyi Aung, Amy Martin, Shanon Bachman, James Mitchell, Frank Deyounks, Ellen Kersh, Chou-Pong Pau, Walid Heneine, J. Gerardo García-Lerma.

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National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

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  1. High maraviroc concentrations in rectal secretions after oral dosing do not prevent rectal SHIV transmission in macaques IvanaMassud, Wutyi Aung, Amy Martin, Shanon Bachman, James Mitchell, Frank Deyounks, Ellen Kersh, Chou-Pong Pau, Walid Heneine, J. Gerardo García-Lerma Laboratory Branch, Division of HIV/AIDS Prevention, CDC Disclaimer: The findings and conclusions in this presentation are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of HIV/AIDS Prevention

  2. Pharmacokinetic profile of maraviroc in rhesus macaques 100000 Plasma Rectal secretions 10000 1000 Maraviroc (ng/ml) 100 10 1 0 24 48 72 96 120 144 168 Hours Blood plasma Rectal secretions Macaques Humans* T max 24 n.a n.a C max 12,748 n.a n.a AUC0-24h 131,164 n.a n.a AUC0-48h 339,772 n.a n.a T max 2 1.6 2 C max 451 412 503 AUC0-24h 1,685 1,680 1,950 *PK parameters in human studies measured over 12h. Brown et al., JID 2010; Dumond et al., J AIDS 2009 Division of HIV/AIDS Prevention Single dose PK 12 rhesus macaques MVC (44 mg/kg) given orally by gavage Blood and secretions collected over time National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

  3. Efficacy of MVC against rectal SHIV transmission Design SHIV162p3 MVC MVC Weekly rectal exposures to low doses (10 TCID50) of SHIV162p3 (R5 tropic) Treated(n=6) -24h +2h Untreated controls (n=4) Results MVC in secretions MVC in tissues Maraviroc (n = 6) 3000 100 Real-time controls (n = 4) 100000 2500 75 10000 2000 Historical controls (n = 35) Tissue MVC (ng/g) 1000 Percent survival 1500 ng/ml 50 100 1000 25 10 500 1 0 0 0 2 4 6 8 10 12 14 ILN Vag ALN MLN Ileum Rectal Rectal Vaginal Jejunum N. of rectal exposures Division of HIV/AIDS Prevention National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

  4. Summary • Similar PK profile with 44 mg/kg MVC in macaques and 300 mg in humans • No prophylactic efficacy with the doses and regimen used • Poster WEPDC0105 • Long (2.5 days) half-life of MVC bound to CCR5 in PBMCs • Similar IC50 in rhesus and human PBMCs • No evidence of selection of low frequency X4 variants from the infecting pool • Low (10-20%) protein binding in rectal secretions • High stability of protein-bound and free MVC in secretions

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