Extracellular and Intracellular Tenofovir DF and Emtricitabine Exposure in Mucosal Tissue after a Single Dose of Fixed-Dose TDF/FTC: Implications for Pre-exposure.

Extracellular and Intracellular Tenofovir DF and Emtricitabine Exposurein Mucosal Tissue after a Single Dose of

Fixed-Dose TDF/FTC: Implications for Pre-exposure Prophylaxis

Kristine B Patterson, Heather A Prince, Eric Kraft, Amanda Jones, Sunita Paul, Nicholas J Shaheen, Melissa Spacek, Paris E Heidt, Sunila Reddy, Jim Rooney,

Julie B Dumond, Myron S Cohen, and Angela DM Kashuba

University of North Carolina, Chapel Hill, NC USAGilead Sciences, Foster City, CA USA

Truvada® for preventionTenofovir disoproxil fumarate (TDF) + Emtricitabine (FTC)

Daily oral dosing of TDF +/- FTC being evaluated.

There are no PK data in mucosal tissue after a single oral dose of TDF and FTC.

Clinical trials evaluating EPISODIC ORAL dosing are being planned.

Objectives

Primary– To characterize tenofovir and emtricitabine

(TFV/FTC and TFV-DP/FTC-TP) exposure in multiple biological compartments in both men and women after a single oral dose of Truvada®.

Secondary– To analyze the decay characteristics (t1/2) of

TFV/FTC and TFV-DP/FTC-TP concentrations in multiple biological compartments in both men and women after a single oral dose of Truvada®.

Methods

Single site, open-label trial

Healthy HIV-negative men and women (ages 18-40)

– Comprehensive STD screening– Sexually abstinent– Using contraception

Single observed dose of Truvada®

Pharmacokinetic Sampling

Cervical (CT) and Vaginal Tissue (VT)

Rectal Tissue (RT)

Sampling Time (Days)

1 2 5 7 10 14

Blood Plasma (BP), PBMC, Cerv-Vag Fluid (CVF)

Analyses

Sample Analyses:– LC/MS/MS

– TFV and FTC: LLOQ 0.1 ng/mL– TFV-DP and FTC-TP: LLOQ 2-10 fmol

Data Analyses:– Non-compartmental PK (WinNonlin 6.0) (composite)

– Summary statistics (SAS 9.1.3)• AUC TFV and FTC: ng*days/mL or gm

• AUC TFV-DP and FTC-TP: fmol*days/106 cells or 0.2uL

• Penetration ratios (AUC Ratios); – CVF or tissue AUC 0-14d ÷ BP AUC 0-14d

Subject Demographics

Median (range) Females (n=7) Males (n=8)

Age (yrs) 22(21-25)

26(19-37)

BMI (kg/m2) 24.8(21.2-28.6)

23.5(18.8-28.1)

Race 6 White1 Black

5 White2 Asian

Emtricitabine

Time Post Dose (days)

0 2 4 6 8 10 12 14

FT

C C

once

ntra

tion

(ng/

mL)

0.1

1

10

100

Median Blood Plasma Concentrations Can Be Quantified Up to 14 Days Post-Dose

Tenofovir EmtricitabineTenofovir


0 2 4 6 8 10 12 14

TF

V C

once

ntra

tion

(ng/

mL)

0.1

1

10

100

AUC (ng*days/mL)

BP 89

t½(hr)

56 BP 60

AUC (ng*days/mL) t½(hr) 67

Tenofovir


0 2 4 6 8 10 12 14

TF

V C

on

cen

tra

tion

(n

g/m

L o

r n

g/g

)

0.1

1

10

100

1000

Emtricitabine


0 2 4 6 8 10 12 14F

TC

Co

nce

ntr

atio

n (

ng

/mL

or

ng

/g)

0.1

1

10

100

1000

Tenofovir Emtricitabine

rectal tissuerectal tissue

Median Rectal Tissue Concentrations Are Higher Than Blood Plasma Up to 14 Days Post-Dose

AUC

BP 89

AUCRT:BP

33

t½

42

56

RT 266BP 60

AUC AUCRT:BP

4.3

t½

8767

RT 2981

median

Time Post-Dose (days)

1 2 5 7 10 14FT

C-T

P (f

mol

/10

6 c

ells

or 0

.2uL

)

1

10

100

1000

Tenofovir Diphosphate Emtricitabine Triphosphate

Median Intracellular Rectal Tissue Concentrations Can Be Quantified 2-14 Days Post-Dose

AUC

RT 6,495PBMC 10,813

AUC Ratio t½

4556

RT 199PBMC 10,832

AUC AUC Ratio

NA

t½

6787NA


1 2 5 7 10 14

TF

V-D

P (

fmol

/10

6 c

ells

or

0.2u

L)

1

10

100

1000

10000


1 2 5 7 10 14

TF

V-D

P (

fmol

/10

6 c

ells

or

0.2u

L)

1

10

100

1000

10000

median


1 2 5 7 10 14

FTC

-TP

(fm

ol/1

06 c

ells

or 0

.2uL

)

1

10

100

1000

10000

Emtricitabine


0 2 4 6 8 10 12 14F

TC

Co

nce

ntr

atio

n (

ng

/mL

)0.1

1

10

100

1000

Tenofovir


0 2 4 6 8 10 12 14

TF

V C

on

cen

tra

tion

(n

g/m

L)

0.1

1

10

100

1000


cervicovaginal fluid

cervicovaginal fluid

Median Cervicovaginal Fluid Concentrations Are Higher Than Blood Plasma Up to 14 Days Post-Dose

AUC

CVF 233BP 89

AUCCVF:BP

2.6

t½

5356

CVF 2520BP 60

AUC AUCCVF:BP

42

t½

4367

Emtricitabine


0 2 4 6 8 10 12 14

FT

C C

once

ntra

tion

(ng/

mL

or n

g/g)

0.1

1

10

100

1000

Tenofovir


0 2 4 6 8 10 12 14

TF

V C

on

cen

tra

tion

(n

g/m

L o

r n

g/g

)

0.1

1

10

100

1000


Vaginal and Cervical Tissue Concentrations Are Similar To, or Higher Than, Blood Plasma

Up to 14 Days Post-Dose

AUCCT 510

AUC Ratio5.8

t½

24AUC AUC Ratio

CT 2496 42t½

57VT 50BP 89

11056

VT 419BP 60

3267

0.6 7

cervical tissue

vaginal tissue

cervical tissue

vaginal tissue

median


1 2 5 7 10 14F

TC

-TP

(fm

ol/1

06 c

ells

or

0.2u

L)

1

10

100

1000

Cervical TissueVaginal Tissue


1 2 5 7 10 14

TF

V-D

P (

fmo

l/106 c

ells

or

0.2

uL

)

1

10

100

1000

Cervical TissueVaginal Tissue

Tenofovir Diphosphate Emtricitabine Triphosphate

Median Intracellular Vaginal and Cervical Tissue Concentrations Can Be Detected 1-14 Days Post-Dose

AUCCT 132

AUC Ratio

NA

t½

NA148

AUC AUC RatioCT 167

NA

t½

NANAVT 1171

PBMC 10,813 43VT 1492PBMC 10,832 86


1 2 5 7 10 14

TF

V-D

P (

fmol

/106 c

ells

or

0.2u

L)

1

10

100

1000

10000

median


1 2 5 7 10 14

FT

C-T

P (

fmol

/10

6 cel

ls o

r 0.

2uL)

1

10

100

1000

10000

Summary and Implications

• Preferential penetration of TFV/FTC seen in this study supports quantification of other ARVs in all mucosal tissues as part of early development strategies for oral PrEP.

• Differential drug terminal elimination (“Tail”) emphasizes consideration for combination therapy esp. episodic dosing.

TFV TFV-DP FTC FTC-TPBlood, PBMCs 14 d 14 d 14 d 10 d

Rectal Tissue AUC RT:BP

3314 d

-14 d

4.314 d

-2 d

Cervicovaginal Fluid AUC CVF:BP

2.614 d

4214 d

Vaginal TissueAUC VT:BP

0.614 d

-14 d

710 d

-2 d

Cervical TissueAUC CT:BP

5.87 d

-14 d

4210 d

-1 d

Acknowledgements

Study Volunteers

Gilead Sciences

UNC CFAR Clinical Pharmacology and Analytical Chemistry Laboratory (P30 AI50410)

National Institute of Health (K23 AI077355)

UNC Clinical Translational Research Center

(RR025747)

Extracellular and Intracellular Tenofovir DF and Emtricitabine Exposure in Mucosal Tissue after a Single Dose of Fixed-Dose TDF/FTC: Implications for Pre-exposure.

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