twice daily administration of tenofovir ...twice daily administration of tenofovir alafenamide in...
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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