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Drug Exposure and Correlates of Oral and Topical ARV Protection. Microbicides and PrEP : Back to Basics Wednesday July 25, 2012 ADM Kashuba. Drug Exposure Predicts Efficacy SC or PO tenofovir±emtricitabine Multiple Routes of Viral Challenge. Vaginal Challenge TFV 30mg/kg/d SC Otten 2000. - PowerPoint PPT Presentation
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Drug Exposure and Correlates of Oral and Topical ARV Protection
Microbicides and PrEP: Back to BasicsWednesday July 25, 2012
ADM Kashuba
Drug Exposure Predicts Efficacy SC or PO tenofovir±emtricitabineMultiple Routes of Viral Challenge
Vaginal ChallengeTFV 30mg/kg/d SC
Otten 2000
NoProtection
Mon
key
Pla
sma C
on
cen
trati
on
R
ela
tive
to H
um
an
Exp
osu
re
PartialProtection
FullProtection
Rectal ChallengeTFV 22mg/kg/d PO
Subbarao 2006
Rectal ChallengeTFV 22 + FTC 20mg/kg/d SC
Garcia Lerma 2008
Rectal ChallengeTFV 22 + FTC 20mg/kg/d PO
Garcia Lerma 2010Rectal Challenge
TFV 10mg/kg/d POVan Rompay 2006
Oral ChallengeTFV 10mg/kg/d POVan Rompay 2006
Oral ChallengeTFV .04 mg/kg/d POVan Rompay 2002
Oral ChallengeTFV .02 mg/kg/d POVan Rompay 2006
Oral ChallengeTFV 30 mg/kg/d SCVan Rompay 2001
Oral ChallengeTFV 30 mg/kg/d SCVan Rompay 1998
IV ChallengeTFV 30 mg/kg/d SC
Tsai 1995
100
X3X
“Low
er”
Adherence Predicts EfficacyDrugs only Work If They Are Used: HPTN 052
Immediate ArmDelayed Arm (not on ART)Delayed Arm (on ART)
Cohen et al. MOAXO102, 6th IAS Conference, Rome, Italy, 2011
90%
Efficacy with Modest Adherence to TDF/FTC in MSM (iPrEx)
TFV-DP
CONC
iPrExCase-Control
Analysis
STRAND(Directly-Observed TDF
Dosing )
Cases Controls 2 doses/w
k
4 doses/w
k
7 doses/w
k
N 48 144 21 21 22
% drug detecte
d
8% 44%
56% < 2 doses/w
k;
18% in range of
daily dosing
100% 100% 100%
Anderson, Liu et al. CROI 2012???
Infection with (Seemingly) Good Adherence (Partners PrEP)
Donnell et al. CROI 2012
Detectable Drug Conc.
Cases (TDF=17,
TDF/FTC=12)Cohort (n=198)
Seroconversion Visits All visits
TDF arm 6/17 31% 363/437 83%
TDF/FTC arm 3/12 25% 375/466 81%
TF
V P
lasm
a C
on
cen
tratio
n (n
g/m
L)
>4
0n
g/m
L
Visit Months0 3 6 9 12 15 18 21 24 27 30
???
The Relationship Between Pharmacokinetics (drug exposure) & Pharmacodynamics (drug target) Can Alter The Importance of Adherence
Minimum Effective Concentration
Days
Conc
entr
ation
Q Day
Q Week
The Principles of PrEP
TDF vs TFV 1% Gel in WomenConcentrations Differ With Formulation
Time Post-Dose (hr)
0 4 8 12 16 20 24
Conc
entra
tion
(ng/
mL)
101
102
103
104
105
106
107
TFV 1% Gel Vaginal Lumen
TDF Tablet Vaginal Lumen
Schwartz et al PloS One, 2011; Dumond et al AIDS 2008
100-1000x
Abdool-Karim et al, Lancet 2011
Place
bo gel
TFV G
el ≤ 1
,000n
g/mL
TFV Gel > 1,000ng/mL
Do different formulations act differently? Are target concentrations different for topical versus systemic delivery?
Chuchuen et al M2011
Lumen
Tissue
Regional
Lymph NodesPlasma
TFV 1% Gel
TDF vs TFV 1% Gel in Women
Lumen,Tissue,
Regional Lymph Nodes
Plasma
TDF 300mg
MUSCULARIS
TDF/FTC and Colorectal TissueARV Concentrations Differ Compared to Cervicovaginal Tissue
Time Post-Single Dose of Truvada (days)
1 2 3 4 5 6 7
Ten
ofo
vir
and
Em
tric
itab
ine
Tis
sue
Con
cent
ratio
ns
(ng/
mg)
10-1
100
101
102
103
104
1 2 3 4 5 6 7
Patterson et al Sci Transl Med, 2011
FTC Rectal Tissue
FTC Vaginal Tissue
TFV Rectal Tissue
TFV Vaginal Tissue
Implications for Efficacious Dosing
Depending on Surface to be
Protected
At 24h:Colorectal TFV-DP
~200 fmol/mgVaginal TFV-DP
~1 fmol/mg
TFV DP Homogenate Comparison ~30min Post-Dose
Oral Dose Single Rectal Dose Multiple Rectal Dose
TV
F D
P T
issu
e H
om
og
en
ate
C
on
cen
tra
tion
(fm
ol/m
g)
100
101
102
103
104
105
N detectable 7/18 10/12 12/12
TDF vs TFV 1% Gel in Colorectal TissueConcentrations Less Divergent With Different Formulations?
Anton et al CROI 2011
30min
30min
30min
24hPatterson et al 2011
ORAL DOSE TOPICAL DOSE
Minimum Effective Concentration
Days
Conc
entr
ation
Oral TDF Dosing for Cervicovaginal Protection Requires high daily (eg>80%) adherence
Oral TDF/FTC Dosing for Colorectal ProtectionTopical TFV Dosing for Cervicovaginal Protection
Less than Daily Adherence May Provide Protection (≤ 2x/wk; BAT24)
An Intricate Relationship Exists Between Pharmacokinetics, Pharmacodynamics, and Adherence in PrEP
To be determined: Effect of inflammation & other physiologic factors on PK-PD-Adherence
Relationship; Relationship Between Drug Exposure and MEC for New Drugs in Vaginal Rings,
LAIs, etc