combatting zika virus infections: teaching old drugs new ......therapy for zika virus infections:...

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)