Innovazione farmacologica e farmacologia clinica Francesco - - PowerPoint PPT Presentation

Innovazione farmacologica e farmacologia clinica

PostGraduate School Clinical Pharmacology

Francesco Scaglione, MD, PhD

Department of Medical Biotechnology and Translational Medicine School of medicine Postgradute School of clinical pharmacology University of Milan,Italy

Milestones Achieved, Miles to Go Milestones Achieved, Miles to Go

60 80 100 %) %) 1986 1986 1998 1998 2001 2001 2002 2002 54 54-

• 56%

56%

Strader et al. Hepatology; 39:1147-1171

20 40 SVR (% SVR (% IFN IFN 6 m 6 m IFN/RBV IFN/RBV 6 m 6 m PEG PEG-

• IFN

IFN /RBV /RBV 12 m 12 m IFN IFN 12 m 12 m IFN/RBV IFN/RBV 12 m 12 m PEG PEG-

• IFN

IFN 12 m 12 m 6% 6% 16% 16% 34% 34% 42% 42% 39% 39%

Sustained Viral Response Rates with Sustained Viral Response Rates with PEG PEG-

• IFN /RBV

IFN /RBV

76% 76%-

• 82%

82% 76% 76%-

• 82%

82%

Genotype Non Genotype Non-

• 1

1 Genotype 1 Genotype 1

Strader et al. Strader et al. Hepatology Hepatology; 39:1147 ; 39:1147-

• 1171

1171

42% 42%-

• 46%

46% 42% 42%-

• 46%

46%

The importance of viral kinetics

5 6 7 8 CV RNA Non-response (NR) Slow response with relapse Therapy 1 2 3 4 1 2 3 4 12 24 48 72 Time (wks) Log (10) HC Early virologic response (EVR) Rapid virologic response (RVR)

Scott J and Gretch DR. JAMA 2007.

Mechanism of Action: Interferon

Interferon alfa HCV IFN receptors JAK Viral RNA

Protein

HCV replicative complex

Assembly HCV virions

OAS: activates antiviral RNAses

Biologic response modifier

STAT STAT1 IRF9 ISGF3 ISRE ISG mRNA

kinase R

Adenosine deaminase 2',5'oligoadenylate synthetase

Adapted from Hoofnagle J. NEJM 2006

PKR: inactivates viral ptn translation ADA: edits viral RNA

• 1.5

1.5

• 1.0

1.0

• 0.5

0.5 0.0 0.0 +0.5 +0.5

Average HCV RNA level reduction (log IU/ml) Average HCV RNA level reduction (log IU/ml)

Effect of IFN-α

• 5.0

5.0

• 4.5

4.5

• 4.0

4.0

• 3.5

3.5

• 3.0

3.0

• 2.5

2.5

• 2.0

2.0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 22 22 24 24 26 26 28 28

Days Days

Group C: IFN Group C: IFN-

• α

α 3 MU tiw 3 MU tiw Group A: untreated Group A: untreated

(Pawlotsky et al., Gastroenterology 2004;126:703-14)

inosine- monophospate- dehydrogenase (IMPDH),

• 1.5

1.5

• 1.0

1.0

• 0.5

0.5 0.0 0.0 +0.5 +0.5

Average HCV RNA level reduction (log IU/ml) Average HCV RNA level reduction (log IU/ml)

Effect of IFN-α/Ribavirin

• 5.0

5.0

• 4.5

4.5

• 4.0

4.0

• 3.5

3.5

• 3.0

3.0

• 2.5

2.5

• 2.0

2.0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 22 22 24 24 26 26 28 28

Days Days

Group D: IFN Group D: IFN-

• α

α 3 MU tiw + ribavirin 1.0 3 MU tiw + ribavirin 1.0-

• 1.2 g qd

1.2 g qd Group C: IFN Group C: IFN-

• α

α 3 MU tiw 3 MU tiw Group A: untreated Group A: untreated

(Pawlotsky et al., Gastroenterology 2004;126:703-14) slide courtesy of JM Pawlotsky

e…il futuro ? HIV! Abbiamo imparato tutto da qui !

HIV protease

…..il futuro è cominciato!!

Direct Acting Antivirals (DAAs) Specifically Targeted Antiviral Therapy for Hepatitis C (STAT-C)

–Telaprevir –Boceprevir

The Hepatitis C Genome The Hepatitis C Genome

HCV Polyprotein

C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

NS3 Protease NS3 Protease domain domain NS5B RNA NS5B RNA-

• dependent

dependent RNA polymerase RNA polymerase NS3 Helicase NS3 Helicase domain domain NS3 Bifunctional NS3 Bifunctional protease / helicase protease / helicase

The protease cleaves the HCV polyprotein The protease cleaves the HCV polyprotein chain, initiating replication chain, initiating replication

NS3/4A Protease NS4B NS5A NS5B NS2 P7 E2 E1 C

Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

Protease inhibitors prevents cleavage of the Protease inhibitors prevents cleavage of the polyprotein chain, preventing viral replication polyprotein chain, preventing viral replication

Boceprevir and Telaprevir Protease inhibitor binds to protease Downstream cleavage is halted Protease

Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

Zhang J et al.Hepatology 2005;42:535A. Farmacocinetica Il cuore dall’azione dei farmaci

BOCEPREVIR T max T 1/2 1-2,5 h 7-15 h

Pharmacokinetic parameters of plasma telaprevir

BOCEPREVIR T max T 1/2 1-2,5 h 7-15 h

Journal of Viral Hepatitis, 2012, 19, e112–e119

Attenzione alle interazioni!

Drug Boceprevir Telaprevir cyclosporine 2.7 4.6

!

Tacrolimus 17 70 Midazolam 6.3 3.4 iv 9 os Atorvastatin 2.3 7.9

! !

Specifically pecifically T Targeted argeted A Antiviral ntiviral T Therapies herapies for H for HC CV (STAT V (STAT-

• C)

C)

Protease Protease Inhibition Inhibition Polymerase Polymerase Inhibition Inhibition

Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

The final enzyme cleaved from the HCV polyprotein, The final enzyme cleaved from the HCV polyprotein, the polymerase is critical to RNA replication the polymerase is critical to RNA replication

Replicated RNA NS5B HCV replicase RNA template

Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

Inhibition of the polymerase halts viral replication Inhibition of the polymerase halts viral replication downstream downstream

NS5B Polymerase inhibitor HCV replicase RNA template

Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

Evolution of HCV genotype 1 treatment

ate (%)

42– 54% 59– 75%

DAA

60 80 100

• 1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–82
• 3. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55
• 5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A
• 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon DAA: direct-acting antiviral SVR: sustained virologic response

SVR ra

2– 7%

IFN1

16– 28%

IFN + RBV1 Peg-IFN + RBV2–4 DAA + Peg- IFN + RBV5–8

20 4 1990 2000 2010 2020

The importance of viral kinetics

5 6 7 8 CV RNA Non-response (NR) Slow response with relapse Therapy 1 2 3 4 1 2 3 4 12 24 48 72 Time (wks) Log (10) HC Early virologic response (EVR) Rapid virologic response (RVR)

Scott J and Gretch DR. JAMA 2007.

Pharmacokinetic parameters of plasma telaprevir

telaprevir PK

Days

20 40 60 80 100 10 20 30

AUC

telaprevir PK

Days

20 40 60 80 100 1 2 3 4

Cmax Cmin

Journal of Viral Hepatitis, 2012, 19, e112–e119

No Correlation of SVR With Plasma PK

Tx-Experienced Tx-Naive Median, Quartiles Data from RESPOND-2 and SPRINT-2.

AUC=area under the concentration-time curve; Cmin=minimum observed plasma concentration; PK=pharmacokinetic; SVR=sustained virologic response.

No SVR (n=29) SVR (n=87) No SVR (n=29) SVR (n=87)

Paradigm of HCV Diagnosis and Treatment

Treated1 Treated but failed1 Diagnosed but not treated1 Not diagnosed2

1. Evon DM, et al. Dig Dis Sci. 2007;52(11):3251-3258. 2. McHutchison JG, Bacon BR. Am J Manag Care. 2005;11(10 suppl):S286-S295.

Grazie per l’attenzione !