combatting zika virus infections: teaching old drugs new ......therapy for zika virus infections:...
TRANSCRIPT
Combatting Zika Virus Infections:
Teaching Old Drugs New Tricks
Ashley Brown, Ph. D.
Program Director & Assistant Professor
Institute for Therapeutic Innovation
Research and Academic Center at Lake Nona
Orlando, FL
Project team
Funding: Florida Department of Health (7ZK30)
Antiviral Pharmacodynamics Laboratory(College of Medicine)
Dr. Ashley BrownDr. Camilly
Pires de Mello
Mathematical Modeling Team(College of Pharmacy)
Dr. Jürgen Bulitta
Xun TaoDr. Tae Hwan
Kim
UF Emerging pathogens instituteDr. John Lednicky
Optimize Antiviral Therapy• What is the minimal effective dose of a drug and
how often do we need to give that drug to maximize viral suppression and prevent resistance.
• Antiviral therapies for Zika virus DO NOT exist!
• Drug Repurposing Strategy: New use for existing drug(s).• Safety and Pharmacokinetics (drug metabolism) profiles are defined
• Formulation and bulk manufacturing process are complete
Focused on Antiviral Agents with Broad-Spectrum Activity
Ribavirin Interferon-Alfa Favipiravir
Antiviral Evaluation Methods[0]: Control [1] [2]
[3] [4] [5]
Medium with varying concentrations of drug
Three drugs:- Favipiravir,- Ribavirin, and - Interferon
evaluated as single agent therapy and as all two drug combinations.
Zika virus
Single Agent Therapy Results
Combination Therapy Results
Clinically Achievable Concentrations
1 1 0 1 0 0 1 0 0 0 1 0 0 0 0
2
4
6
8
1 0
F a v ip ira v ir + In te r fe ro n -a lfa
[ IF N ] ( IU /m L )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0
0 u M
3 1 .2 5 u M
6 2 .5 u M
1 2 5 u M
2 5 0 u M
5 0 0 u M
[F A V ]
1 1 0 1 0 0 1 0 0 0 1 0 0 0 0
2
4
6
8
1 0
F a v ip ira v ir + In te r fe ro n -a lfa
[ IF N ] ( IU /m L )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0
0 u M
3 1 .2 5 u M
6 2 .5 u M
1 2 5 u M
2 5 0 u M
5 0 0 u M
[F a v ip ira v ir]
[Interferon-alfa] (IU/ml)
Combination Therapy Results
0 .1 1 1 0 1 0 0 1 0 0 0
2
4
6
8
1 0
F a v ip ira v ir + R ib a v ir in
[R B V ] (u g /m L )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0
0 u M
3 1 .2 5 u M
6 2 .5 u M
1 2 5 u M
2 5 0 u M
5 0 0 u M
[F A V ]
0 .1 1 1 0 1 0 0 1 0 0 0
2
4
6
8
1 0
In te r fe ro n -A lfa + R ib a v ir in
[R B V ] (u g /m L )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0
0 IU /m l
1 IU /m l
1 0 IU /m l
1 0 0 IU /m l
1 0 0 0 IU /m l
1 0 ,0 0 0 IU /m l
[ IF N ]
Which dose – how often – for how long? Answered via mathematical modeling
Characterize viral burden over time in the presence of drug treatment
Model excellently described the data
0 1 2 3 4
2
4
6
8
1 0
F a v ip ira v ir A lo n e
T im e (d a y s )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0 u M
6 2 .5 u M
1 2 5 u M
2 5 0 u M
5 0 0 u M
0 1 2 3 4
2
4
6
8
1 0
In te r fe ro n -a lfa A lo n e
T im e (d a y s )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0 IU /m l
1 IU /m l
1 0 IU /m l
1 0 0 IU /m l
1 0 0 0 IU /m l
1 0 ,0 0 0 IU /m l
0 1 2 3 4
2
4
6
8
1 0
R ib a v ir in A lo n e
T im e (d a y s )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0 u g /m l
0 .1 u g /m l
1 u g /m l
1 0 u g /m l
1 0 0 u g /m l
1 0 0 0 u g /m l
1 1 0 1 0 0 1 0 0 0 1 0 0 0 0
2
4
6
8
1 0
F a v ip ira v ir + In te r fe ro n -a lfa
[ In te r fe ro n -a lfa ] ( IU /m L )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0
0 u M
3 1 .2 5 u M
6 2 .5 u M
1 2 5 u M
2 5 0 u M
5 0 0 u M
[F a v ip ira v ir]
0 .1 1 1 0 1 0 0 1 0 0 0
2
4
6
8
1 0
F a v ip ira v ir + R ib a v ir in
[R ib a v ir in ] ( g /m L )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0
0 u M
3 1 .2 5 u M
6 2 .5 u M
1 2 5 u M
2 5 0 u M
5 0 0 u M
[F a v ip ira v ir]
1 1 0 1 0 0 1 0 0 0 1 0 0 0 0
2
4
6
8
1 0
R B V + IF N C o m b o th e ra p y
[ In te r fe ro n -a lfa ] ( IU /m L )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
0
0 u g /m l
0 .1 u g /m l
1 u g /m l
1 0 u g /m l
1 0 0 u g /m l
1 0 0 0 u g /m l
[R ib a v ir in ]
Simulating drug effects for combination therapyBlood Drug Concentrations in Man are dynamic due to metabolic processes
Concentration-TimeProfiles Associated With Clinical Regimens
0 2 4 6 8 1 0
0
1 0 0
2 0 0
3 0 0
4 0 0
In te r fe ro n -A lfa
T im e (D a y s )
[IF
N]
(IU
/ml)
0 2 4 6 8 1 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
F a v ip ir a v ir
T im e (D a y s )
[FA
V]
(M
)
In f lu e n z a R e g im e n
(L o w e r D o s e )
E b o la R e g im e n
(H ig h e r D o s e )
Favipiravir + Interferon-Alfa shows promise as a Therapy for Zika Virus Infections: What Next?Experimentally Validate the Model Simulations Predicting Antiviral Effect
0 2 4 6 8 1 0
0
1 0 0
2 0 0
3 0 0
4 0 0
In te r fe ro n -A lfa
T im e (D a y s )
[IF
N] (
IU/m
l)
0 2 4 6 8 1 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
F a v ip ir a v ir
T im e (D a y s )
[F
AV
] (
M)
In f lu e n z a R e g im e n
(L o w e r D o s e )
E b o la R e g im e n
(H ig h e r D o s e )+
0 2 4 6 8 1 0
0
2
4
6
8
1 0
E ffe c t o f F a v ip ira v ir + In te r fe ro n -A lfa
o n Z ik a V iru s R e p lic a t io n
T im e (d a y s )
Vir
al
Bu
rd
en
(L
og
10
PF
U/m
l)
N o T re a tm e n t
F a v ip ira v ir In flu e n z a R e g im e n
+ In te r fe ro n -A lfa
F a v ip ira v ir E b o la R e g im e n
+ In te r fe ro n -A lfa
Future Directions
• Determine whether antiviral treatment allows for the emergence of viruses that contain mutations conferring resistance to treatment (currently under investigation).
• Continue to evaluate other promising repurposed agents against Zika virus as single agent therapy and in combination.
• Optimize dosage regimens for new promising agents.
Funding: Florida Department of Health (7ZK30)