The Effect of Mild and Moderate Hepatic Impairment on Telaprevir Pharmacokinetics

B Adiwijaya, G Chandorkar, R van Heeswijk, L McNair, PY Kwo, S Gordon, and V Garg

6th International Workshop on the Clinical Pharmacology of Hepatitis Therapy June 22-23, 2011. Cambridge, MA. Author Disclosures

Drs. Adiwijaya and Garg are an employees and stock owners of Incorporated.

Dr. Chandorkar was an employee of Vertex at the time this work was performed and is a current stock holder. He is currently employed by and holds stock in Cubist Pharmaceuticals.

Dr. van Heeswijk is an employee of Tibotec BVBA, Belgium.

Dr. McNair was an employee of Vertex at the time this work was performed. She is currently employed by Equipoise Consulting.

Dr. Kwo has received consulting fees from Abbott, Anadys, Bayer, , Gilead, Merck, Novartis, Vertex; he also received fees for Non-CME/CE services directly from Bristol Myers Squibb, Gilead, Merck, and Roche; and contracted research funding from Abbott, Anadys, Bayer, Bristol Myers Squibb, Gilead, Merck, Novartis, Roche, and Vertex.

Dr. Gordon has received consulting fees from Achillion, Bristol-Myers Squibb, CVS Caremark, Gilead Pharmaceuticals, Merck, , Johnson and Johnson, and grant support from Abbott Pharmaceuticals, Anadys Pharmaceuticals, Bristol-Myers Squibb, Conatus, Eiger , Inc, Exalenz BioScience, Gilead Pharmaceuticals, GlaxoSmithKline, GlobeImmune, Intercept Pharmaceuticals, Merck, Roche Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, Zymogenetics, and served as a speaker/teacher for Bayer, Gilead, Roche, Merck and Vertex.

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Introduction

• Telaprevir (TVR) is an NS3/4A serine protease inhibitor of HCV1,2 • TVR is metabolized by CYP3A and non-CYP pathways • Based on animal data, biliary elimination is also likely • Patients with HCV-related advanced fibrosis have varying degrees of liver impairment that may affect drug metabolism3 – The effects of mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment on TVR PK was examined in cirrhotic volunteers

1Lin K, et al. Antimicrob Agents Chemother. 2004;48(12):4784–92; 2Perni RB, et al. Antimicrob Agents Chemother. 2006;50(3):899–909.3Seef LB, et al Hepatol. 2002;36(Suppl1):S35-S36.

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Study Design

Three volunteer groups: .Healthy, N=10 .Child-Pugh A (CPA), N=10 .Child-Pugh B (CPB), N=10

TVR 750 mg TVR 750 TVR 750 mg single dose mg q8h single dose Day 1 Days 2-5 Day 6

24h PK sampling Pre-dose PK samples 24h PK sampling

All TVR doses were administered with food

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Safety

• Early discontinuation due to adverse events (AEs):

Healthy volunteers .rash, pruritus (n=1) .edema (n=1)

CPA volunteers .erythema (n=1) .pruritus, rash, erythema, (n=1)

• In CPB volunteers, no discontinuations or serious AEs related to study reported.

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Median Plasma Concentrations of TVR after a Single Dose of 750 mg (Day 1)

2000 )

l Healthy m / 1500 GLS Mean Ratio (90% CI)

g CPA

1 n

(

y CPB c

a CPA n

D 1000 Cmax 0.82 (0.62, 1.08)

o n

c AUC8h 0.89 (0.66, 1.22)

a r

i

i d

v 500 CPB

e e

r Cmax 0.59 (0.45, 0.78)

M p

AUC8h 0.63 (0.47, 0.86) a

l 0

e t

0 5 10 15 20 25 Nominal Relative Time (h)

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Telaprevir Plasma Concentration – Time Profiles on Day 6

) 3500 l

Healthy m

/ 3000 GLS Mean Ratio (90% CI)

g 6

n CPA

(

y 2500 c

a CPB CPA

n D

o 2000 Cmax 0.90 (0.72, 1.10)

n

c

a r

i AUC 0.85 (0.70, 1.02)

i 1500 8h d

v

e

e r

M CPB

p 1000 a l Cmax 0.51 (0.41, 0.63)

e 500 t AUC8h 0.54 (0.43, 0.66) 0 0 5 10 15 20 25 Nominal Relative Time (h)

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Median Plasma Concentrations of TVR after a Single Dose of 750 mg (Day 1)

10000 )

l 4000

m 2000 Median Parameters /

g 1000 1 HV CPB n

( 500 y

300 T (h) 4.45 6.97 c

a 1/2 n D Vz/F (L) 375 592

o 100 n

c 50 CL/F (L/h) 60 65

a

r

i

i d

v 20 Healthy

e e

r 10 M p CPA

5 a

l 3 e

t CPB 1 0 5 10 15 20 25 Nominal Relative Time (h)

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Median Plasma Concentrations of TVR after Multiple Doses of 750 mg q8h

4000

) 2000 l

m 1000 /

g 500 6

n 300 Median Parameters

(

y c a HV CPB

n 100 D T (h) 6.45 7.43 o 1/2

50 n c V /F (L) 163 319 a 30

r z i

i Healthy d

v CL/F (L/h) 23 37 e e 10 r

M CPA

p 5 a

l 3

e CPB t 1 0 5 10 15 20 25 Nominal Relative Time (h)

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Possible Explanation for the Lowered Exposure in Hepatic Impairment

50

45

40

35

Albumin (g/L) Albumin 30

25

HV CPA CPB Child Pugh Classification 1 • Reduced binding to albumin and 1-acid glycoprotein (AAG) could increase the clearance and volume of distribution of TVR, leading to reduced total drug levels (without affecting the unbound levels of TVR) • Lowered bioavailability due to poor absorption 1Fraeyman NF et al; Br J Clin Pharmac. 1988;25,733-40.

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Conclusions

• The effect of mild hepatic impairment on telaprevir PK was not clinically significant – No dose modification is required in Child-Pugh A patients1 • Moderate hepatic impairment reduced the steady- state AUC of telaprevir by 46% – The appropriate dose of telaprevir in HCV- infected patients with moderate and severe hepatic impairment has not been determined; telaprevir is not recommended in these patients1

1INCIVEK™ U.S. Prescribing Information. Vertex Pharmaceuticals Incorporated.

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA Acknowledgements

We thank all study volunteers

Dr. Josef Waitzinger, AAI Deutschland GmbH & Co KG

Dr. Wolfgang Kratzer, Universitätsklinikum Universität Ulm

Jennifer Webster for study coordination, Kristin Stephan, PhD for medical writing and coordination support, both employees and stock owners of Vertex Pharmaceuticals Incorporated

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA