national center for hiv/aids, viral hepatitis, std, and tb prevention
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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. - PowerPoint PPT PresentationTRANSCRIPT
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB PreventionDivision of HIV/AIDS Prevention
High maraviroc concentrations in rectal secretions after oral dosing do not prevent rectal SHIV transmission in macaquesIvana Massud, Wutyi Aung, Amy Martin, Shanon Bachman, James Mitchell, Frank Deyounks, Ellen Kersh, Chou-Pong Pau, Walid Heneine, J. Gerardo García-Lerma
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
Laboratory Branch, Division of HIV/AIDS Prevention, CDC
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB PreventionDivision of HIV/AIDS Prevention
Pharmacokinetic profile of maraviroc in rhesus macaques
Single dose PK- 12 rhesus macaques- MVC (44 mg/kg) given
orally by gavage- Blood and secretions
collected over time
PlasmaRectal secretions
0 24 48 72 96 120 144 1681
10
100
1000
10000
100000
HoursM
arav
iroc
(ng/
ml)
Macaques Humans*
T max
24n.an.a
C max
12,748n.an.a
AUC0-24h
131,164n.an.a
AUC0-48h
339,772n.an.a
T max
21.62
C max
451412503
AUC0-24h
1,6851,6801,950
Blood plasma Rectal secretions
*PK parameters in human studies measured over 12h. Brown et al., JID 2010; Dumond et al., J AIDS 2009
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB PreventionDivision of HIV/AIDS Prevention
Historicalcontrols (n = 35)
Real-time controls (n = 4)
N. of rectal exposures0 2 4 6 8 10 12 14
0
25
50
75
100
Per
cent
sur
viva
lEfficacy of MVC against rectal SHIV transmissionDesign
Treated (n=6)
SHIV162p3MVCMVC
-24h +2hWeekly rectal exposures to low doses (10 TCID50) of SHIV162p3 (R5 tropic)Untreated
controls (n=4)Results
Maraviroc (n = 6)ng
/ml
Rectal
Vagin
al1
10
100
1000
10000
100000
MVC in secretions
Tiss
ue M
VC
(ng/
g)
MLN ALN ILN VagRec
tal
Jejun
umIle
um0
500
1000
1500
2000
2500
3000MVC in tissues
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 PBMCsSimilar IC50 in rhesus and human PBMCsNo evidence of selection of low frequency X4 variants from
the infecting poolLow (10-20%) protein binding in rectal secretionsHigh stability of protein-bound and free MVC in secretions