Meeting Update Jennifer Kiser, PharmD University of Colorado

14th International Workshop on Clinical Pharmacology of HIV Therapy April 24, 2013

Impressive Pipeline

Protease Inhibitors: Boceprevir Telaprevir Faldaprevir (BI 201335) Simeprevir (TMC435) ABT-450 ACH-1625 BMS-650032 (asunaprevir) GS-9451 GS-9256 MK-5172 RG7227 (danoprevir) ACH-2684

Kiser JJ, Flexner C. Annual Reviews in Pharmacology and Toxicology [In press]

NS5A Inhibitors: BMS-790052 (daclatasvir) ABT-267 GS-5885 GSK2336805 ACH-2928 IDX719 PPI-461 PPI-668

Nucleos(t)ide Inhibitors: Sofosbuvir (GS-7977) RG7128 (mericitabine) ALS-2158 ALS-2200 Non-Nucleoside Inhibitors: RG7790 (setrobuvir) BI 207127 Filibuvir GS 9190 (tegobuvir) VX-222 ABT-333 BMS-791325 GS-9669

BUT…. Persons with advanced liver disease are under-represented in clinical trials

Ongoing INF-free Trials Allowing or Exclusively Studying Persons with Advanced Liver Disease

DAA Combination Patient Population N NCT# Status

Daclatasvir + simeprevir ± RBV

Allows 1/3 F3 or F4 without decompensation

180 01628692 Ongoing, not recruiting

Sofosbuvir + simeprevir ± RBV

Allows half with F3 or F4 no decompensation

168 01466790 Ongoing, not recruiting

Sofosbuvir + RBV Pre-transplant CP ≤ 7 50 10559844 Enrollment complete

ABT450/r + ABT333 + ABT267 + RBV (TURQUOISE-II)

All cirrhotics CP ≤ 6 300 01704755 Recruiting

Sofosbuvir + RBV All cirrhotics including decompensation CP < 10, HVPG > 6

50 01687257 Recruiting

Sofosbuvir + RBV Post-transplant recurrence, 6 mo-12 yr post-transplant, excludes decompensation

40 01687270 Recruiting

www.clinicaltrials.gov

Major Themes Pre-Transplant

• P/R insufficient – 13-22% SVR • Lots of serious adverse events

with P/R + BOC or TVR – Anemia, infections, death

• Discussion about who the candidates are and how to manage them before and during treatment – Too risky, wait for new agents? – Complete an entire course of

treatment vs. treat for a certain period of time then transplant

• Interferon-free DAA combinations are needed

Post-Transplant • P/R insufficient – 1/3 SVR • Discussion about who the

candidates are and how to manage them before and during treatment

• Awaiting P/R + BOC or TVR SVR rates – forecast 50% SVR – EASL – Management of DDI with

immunosuppressants a challenge

• DAA combinations without interaction potential are needed

Pharmacology Topics

• Pre-Transplant – Effects of advanced liver disease on DAA

pharmacokinetics • Evaluate results of some hepatic impairment studies with

DAA in the context of these pathophysiologic features • Post-Transplant

– Managing immunosuppressant doses and dosing frequency with BOC and TVR

• Coilly A, EASL Late Breaker • Same considerations we tackled with HIV protease inhibitors

Features of Advanced Liver Disease which may Alter DAA PK

1. Hepatic enzyme expression and/or function 2. Membrane transporter expression and/or

function 3. Protein Binding 4. Portal-Systemic Shunting 5. Phosphorylation enzyme expression and/or

function 6. Renal Impairment 7. Reduced gastointestinal absorption

CYP Enzyme Expression and Function with Progressive Hepatic Impairment

Modified from figure by Branch RA, CPT 1998;64:462

CYP3A

ABT450/r Concentrations Increased with Moderate and Severe Hepatic Impairment

ABT450 is a CYP3A substrate reduced CYP3A expression may contribute to increased concentrations of ABT450

Khatri A, et al. AASLD 2012

Bile

NTCP

OATP1B1 OATP1B3* OATP2B1

Systemic Circulation Systemic Circulation

2. Transporter Expression in Liver Disease

OCT1 P-gp

MRP2 MRP3

MRP4

BCRP ABCG5/G8

BSEP

MDR3

Figure adapted from Oswald S. et al. Xenobiotica 2007;37(10-11):1171, 1Nakai K, et al. Drug Metab & Dispos 2008;36(9):1786,2Ogasawara K, et al. Drug Metabol PK 2010;25(2):190, 3Bonin S, et al. Mol Med 2002;8(6):318.

Sinusoidal Membrane Canalicular Membrane

?

Asunaprevir Increased with Moderate and Severe Hepatic Impairment

• Metabolized by CYP3A, substrate for OATP1B1 and OATP2B1

• AUC ↑ 9.8-fold and 32-fold in moderate and severe impairment

Eley T et al. AASLD 2012, #1873

3. Protein Binding

• Impaired production of plasma proteins results in decreased plasma binding of several drugs. – May also be a contribution of competition for binding

sites with endogenous substances and perhaps a reduction in the quality of protein

• For highly protein bound drugs (>90%), even

small changes in binding can have large effects on drug PK.

Verbeeck RK. Eur J Clin Pharmcol 2008;64:1147-1161

Daclatasvir Unbound Concentrations Unchanged in Hepatic Impairment

Bifano, M. 62nd AASLD 2011

~40%

Total concentrations appear lower, but free amount is unchanged.

↓~40%

4. Portal-Systemic Shunting DAA

Portal vein

Gut wall To feces

Metabolism Metabolism

Absorption

Bioavailability:

Liver

CYP

P-gp efflux

CYP CYP

CYP

CYP

CYP CYP CYP CYP

Portal vein Systemic circulation

Fraction extracted and metabolized (EH)

(Fraction escaping extraction): F = 1-EH

Summary

• Tremendous need for antiviral clinical pharmacology research in this patient population

• This meeting will continue to grow as new DAA reach the market – Workshop is a good place to review the data and

identify research needs in this special patient population