TWICE DAILY ADMINISTRATION OF TENOFOVIR ALAFENAMIDE IN COMBINATION WITH RIFAMPIN:

POTENTIAL FOR TENOFOVIR ALAFENAMIDE USE IN HIV-TB COINFECTION

J.M. Custodio, S. West, J. Lutz, A. Vu, D. Xiao, S. Collins, M. Das, B.P. Kearney, A. Mathias

Abstract PS13/4

TWICE DAILY ADMINISTRATION OF TENOFOVIR ALAFENAMIDE IN COMBINATION WITH RIFAMPIN: POTENTIAL FOR TENOFOVIR ALAFENAMIDE USE IN HIV-TB COINFECTION

TAF is a substrate of human drug transportersRIF is commonly used in a multi-drug regimen for TBRIF is potent inducer and associated with DDI

DDI Mechanism TAF RIF

Drug transportersP-gp/BCRP Substrate Inducer

OATP1B1/1B3 Substrate Inducer

To evaluate the PK of TAF, TFV-DP, and plasma TFV, following co-administration of TAF BID with RIF 600 mg OD vs TAF OD

Custodio K, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PS13/4.

STUDY DESIGN

Phase 1, open-label, parallel-design, multiple-dose, single center study in healthy subjects

3

TAF QD administered as Bictegravir/Emtricitabine/TAF QD; TAF BID administered as Bictegravir/Emtricitabine/TAF BID

Custodio K, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PS13/4.

TAF 25 mg QD Cohort 1n=26

Intensive plasma PK sampling

Day1

Day28

Cohort 2n=26

600 mg RIF

TAF 25 mg BID600 mg RIF

Discharge

Intensive plasma PK sampling

Day1

Day28

Day35

RESULTS: TAF PLASMA PK = 15% REDUCTION

Custodio K, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PS13/4.

TAF PK Mean (%CV)

TAF QD n=26 (ref)

TAF BID + RIFn=26 (test)

GLSM Ratio 90% CI

AUC0-24 (ng•h/mL) 345 (52) 290 (48) 85.8 (69.7, 106)

Cmax (ng/mL) 471 (72) 207 (64) 44.1 (33.2, 58.7)

0 4 8 12 16 20 24

Mea

n (S

D) T

AFC

onc

(ng/

mL)

Time (h)

TAF BID + RIFTAF QD

1000

100

10

1

0.1

0.01

RESULTS: PLASMA TFV PK = 30% REDUCTION

Custodio K, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PS13/4.

TAF PK Mean (%CV)

TAF QD n=26 (ref)

TAF BID + RIFn=26 (test)

GLSM Ratio 90% CI

AUC0-24 (ng•h/mL) 348 (20) 277 (19) 79.9 (73.1, 87.3)

0 4 8 12 16 20 24

Mea

n (S

D) T

FVC

onc

(ng/

mL)

Time (h)

TAF BID + RIFTAF QD

100

10

1

RESULTS: TFV-DP PK = 24% REDUCTION

Custodio K, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PS13/4.

TFV-DP PK GLSM Ratio (90% CI)

AUC0-24 (fmol•h/106 cells) 76.3 (58.7, 99.2)

Conclusions: TAF plus RIF was well toleratedNo Grade 3 / 4 AEs or lab changesPD evaluations in patients with TB and HIV needed

Historical Steady-State TFV-DP datawith TDF 300 mg: 85-222 fmol/106 cells1-3

0 4 8 12 16 20 24

Mea

n (9

5% C

I) TF

V-D

P (fm

ol/1

06ce

lls

Time (h)

TAF BID + RIFTAF QD1000

10

1

10

100

1