gs-9350: a pharmacoenhancer without anti-hiv activity aa mathias, p german, m lee, c callebaut, l...
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GS-9350: A Pharmacoenhancer Withoutanti-HIV Activity
AA Mathias, P German, M Lee, C Callebaut, L Xu, L Tsai, B Murray, H Liu,K Yale, D Warren and BP Kearney
Gilead SciencesFoster City, CA, USA
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• Potent, irreversible (mechanism-based) inhibition of CYP3A
• No anti-HIV activity
Keys to Pharmacoenhancement
GS-9350 RTV
kinact (min-1) 0.44 0.23
KI (µM) 0.94 0.26mean of 5 experiments
Antiviral Assay EC50 (M) GS-9350 RTV Fold-difference
- w/o human serum
- 40% human serum
> 30
> 90
0.015
0.060
> 2000
> 1500mean of > 5 experiments
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• Greater CYP450 enzyme inhibition specificity
• Less induction of drug metabolizing enzymes and transporters
Keys to Pharmacoenhancement
1 100
20
40
60
80
100
RTV
GS-9350
hPXR Activation
Concentration (µM)
Re
sp
on
se
(%
Em
ax)
Induction of Hepatocyte CYP3A4 mRNA
mean + SD, n=3
0
20
40
60
80
100
120
1 µM 3 µM 10 µM 30 µM Rifampicin
GS-9350
% M
ax
imu
m
mean ± SD, n=3
CYP450 enzyme IC50
(µM)1A2 2B6 2C8 2C9 2C19 2D6 3A*
GS-9350 >25 2.8 30 >25 >25 9.2 0.2
RTV >25 2.9 5.5 4.4 >25 2.8 0.2
* midazolam 1’-hydroxylase (no preincubation)mean of 3 experiments conducted in duplicate
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• Reduced potential for lipid abnormalities
• Improved physicochemical properties
Keys to Pharmacoenhancement
Drug
Adipocyte Function Assays
Inhibition of Normal LipidAccumulation (EC50 µM)
% Inhibition of GlucoseUptake @ 10µM
RTV 16 55
GS-9350 > 30 9.5
ATV > 30 1.1
Aqueous Solubility (g/mL)
GS-9350 RTV Fold-difference
pH 7.4 75 ~ 2.0 35
pH 2.2 > 6500 3.1 > 2100
mean of 5 experiments /assay
mean of 2 experiments conducted in duplicate
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Study GS-216-0101
• Evaluate GS-9350 safety, tolerability, PK and PD (anti-CYP3A activity)
– Double-blind, double-dummy, active and placebo controlled study in HIV(-) subjects
• 3 dose-escalation cohorts: 50, 100 and 200mg tablets (N = 12 /cohort)
• RTV 100mg & dual placebo (each N = 3 /cohort)
– Single and multiple dose PK, safety and tolerability
– Steady-state PD: change from pre-treatment PK of “metabolic probe” oral midazolam
50 mg Single
Dose PK
50 mgx 14 Days
PK/PD
100 mg Single
Dose PK
100 mgx 14 Days
PK/PD
200 mgX 14 Days
PK/PD
Pre-treatment safety and PD assessments
Study drugs administered with food
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PK/PD Results
• GS-9350 exhibited non-linear increases in exposure with dose and time– Time- and dose-dependent PK consistent with mechanism-based inhibition
• GS-9350 achieved potent inhibition of CYP3A activity– Near-maximal inhibition achieved at ≥ 100mg
0 6 12 18 240.1
1
10
100
10002500
mean 95% CIn = 9 - 12
100mg200mg
50mg
RTV 100 mg GS-9350
Time (hr)
Ste
ad
y-s
tate
Dru
g C
on
cen
tra
tio
n (
ng
/mL
)
GS-9350 & RTV PK
0 6 12 18 240.1
1
10
100
10002500
mean 95% CIn = 9 - 12
100mg200mg
50mg
RTV 100 mg GS-9350
Time (hr)
Ste
ad
y-s
tate
Dru
g C
on
cen
tra
tio
n (
ng
/mL
)
GS-9350 & RTV PK
RTV
- 95%
50 mg 100 mg 200 mg
- 88%
- 92%- 95%
GS-9350
Pre-treatment0
5
10
15
20
2550
75
100
Mid
azol
am C
L/F
(L/h
r)
GS-9350 & RTV PD(midazolam apparent clearance)
RTV
- 95%
50 mg 100 mg 200 mg
- 88%
- 92%- 95%
GS-9350
RTV
- 95%
RTV
- 95%
50 mg 100 mg 200 mg
- 88%
- 92%- 95%
GS-9350
50 mg 100 mg 200 mg
- 88%
- 92%- 95%
GS-9350
Pre-treatment0
5
10
15
20
2550
75
100
Mid
azol
am C
L/F
(L/h
r)
GS-9350 & RTV PD(midazolam apparent clearance)
Pre-treatment0
5
10
15
20
2550
75
100
Mid
azol
am C
L/F
(L/h
r)
GS-9350 & RTV PD(midazolam apparent clearance)
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Study GS-236-0101
• Evaluate the relative bioavailability, PK and safety ofEVG/FTC/TDF/GS-9350 FDC tablet vs. EVG/r and FTC + TDF
– Open-label, partially-randomized, adaptive study design in HIV(-) subjects(N = 44)
• 100 mg starting GS-9350 dose → 75 or 150 mg GS-9350 containing FDC
EVG/FTC/TDF/GS-9350150/200/300/100mg
EVG + RTV 150mg + 100mg
FTC + TDF200mg + 300mg
EVG/FTC/TDF/GS-9350150/200/300/100mg
EVG + RTV150mg + 100mg
EVG/FTC/TDF/GS-9350150/200/300/150mg
Real-time GS-9350 & EVG PK analysis
Study drugs administered with food
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Mean (CV%)EVG PK (n = 42)
GS-9350 100mg FDC GS-9350 150mg FDC EVG + RTV 100mg
AUCtau (ng.hr/mL) 21100 (25.4) 27000 (29.4) 22500 (23.4)
Cmax (ng/mL) 2250 (26.3) 2660 (27.6) 2500 (32.1)
Ctau (ng/mL) 282 (60.4) 490 (52.9) 409 (40.5)
Elvitegravir PK
• GS-9350 effectively boosts EVG within FDC tablet
• High EVG trough concentrations maintained w/ GS-9350 150mg
– 11-fold above the protein binding-adjusted IC95 (44.5 ng/mL)
– Low within-subject variability (15% CV)
IC95
100 mg 150 mg RTV0
200
400
600
800
1000
1200
IC95
GS-9350Bars represent geometric mean ( 95% CI)
Elv
iteg
ravi
r C
tau (
ng
/mL
)
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• FTC and TFV exposures clinically equivalent
– FTC exposures increased 20% as FDC vs. FTC capsule
– TFV AUC bioequivalent as FDC or TDF tablet
EVG/FTC/TDF/GS-9350 150 mg FTC + TDF
Mean (CV%) PK(n = 42)
FTC TFV FTC TFV
AUCtau
(ng.hr/mL)11500 (19.3) 3010 (20.4) 9330 (22.1) 2550 (22.6)
Cmax (ng/mL) 1850 (22.5) 332 (28.9) 1600 (26.1) 252 (24.9)
Ctau (ng/mL) 101 (26.8) 65.0 (26.0) 80.1 (25.9) 52.0 (25.4)
FTC/TDF PK
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Safety Summary
• GS-9350 first-in-man, dose-ranging study– Single and multiple doses up to 200 mg well tolerated
– No drug-related Grade 3/4 laboratory abnormalities
– Single Grade 3 adverse event of discoordination (GS-9350 100mg)
– No changes or differences observed in serum lipids across treatments over 14 days
• Integrase FDC “Quad” tablet study– All treatments well tolerated
– Two Grade 3 adverse events• Single subject with drug-related ALT elevation (GS-9350 100mg FDC)• One subject with acute appendicitis
– No other drug-related Grade 3/4 laboratory abnormalities
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Conclusions
• GS-9350 is a potent, selective, mechanism-based CYP3A inhibitor that lacks anti-HIV activity and has limited effects on adipocyte function in vitro
• GS-9350 boosts CYP3A substrates comparable to RTV in humans
• EVG/FTC/TDF/GS-9350 FDC tablet achieves desired exposures of EVG, FTC and TFV
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GS-9350 & Ritonavir PK
Mean (CV%) PK(n = 42)
GS-9350 100mg FDC GS-9350 150mg FDC RTV 100mg
AUCtau (ng.hr/mL) 5150 (31.7) 10400 (35.2) 5750 (38.4)
Cmax (ng/mL) 855 (27.6) 1570 (29.7) 1030 (47.8)
Ctau (ng/mL) 7.6 (124) 22.7 (107) 37.6 (52.2)
0 6 12 18 241
10
100
1000
2500
EVG/FTC/TDF/GS-9350 100 mg
mean 95% CI
EVG/FTC/TDF/GS-9350 150 mg
EVG + RTV 100 mg
Time (hr)
Dru
g C
on
ce
ntr
ati
on
(n
g/m
L)