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