Pharmacologic Considerations when using DAAs in Cirrhosis

Jennifer J. Kiser, PharmD Assistant Professor

University of Colorado Denver 1st International Workshop on the Optimal Use of DAAs in

Liver Transplant Patients 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 cirrhosis are under-represented in clinical trials

• Limited numbers of patients with cirrhosis were included in BOC and TVR registration trials, and tolerability to triple therapy in cirrhotics in practice has been poor.

• Persons with decompensated cirrhosis are technically ineligible for interferon-based therapies.

• Interferon free treatments that are safe and efficacious in persons with advanced liver disease are desperately needed.

• There is a hesitation to study DAA in persons with advanced liver disease, however these are the patients in greatest need of treatment.

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

How can we safely use DAA in Persons with Advanced Liver Disease?

• Need to determine the optimal drug doses and combinations

• Achieved through a comprehensive understanding of the pharmacokinetics and physiologic features of advanced liver disease which may influence DAA pharmacokinetics

Goals

1. Discuss potential pathophysiologic features of advanced liver disease that might influence DAA pharmacokinetics.

2. Evaluate results of some hepatic impairment studies with DAA in the context of these pathophysiologic features.

3. Identify pharmacology-related research needs in this patient population.

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. Phosphorylation enzyme expression and/or

function 5. Portal-Systemic Shunting 6. Renal Impairment 7. Reduced gastointestinal absorption

1. Hepatic Enzyme Expression and Function

• Phase I metabolism (e.g., oxidation) affected earlier in disease severity – e.g., cytochrome P450 (CYP) enzymes – BUT declines are isoform-specific

• Phase II metabolism affected later in disease

severity – e.g., glucuronidation, sulfation, acetylation,

methylation, glutathione conjugation, amino acid conjugation

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

CYP Enzyme Expression and Function with Progressive Hepatic Impairment

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

CYP3A

Simeprevir Concentrations Increased in Moderate Hepatic Impairment

• Simeprevir is a CYP3A substrate

• AUC ↑ 2.62-fold in persons with moderate hepatic impairment relative to those with normal hepatic impairment

• More data at EASL 2013

Sekar V, et al. EASL 2011

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. Phosphorylation enzyme expression and/or function

• Nucleos(t)ide analogs undergo intracellular phosphorylation by host enzymes to the active form

• No data to support or refute alterations in phosphorylation due to advanced liver disease, but biologic plausibility

NDPK NMPK Adenosine kinase cN-II nucleotidase

Sofosbuvir

GS-566500

GS-566500 Sofosbuvir

Hepatocyte Plasma

GS-606965

Made from: Mathias A, et al. 63rd AASLD, Nov 9-13, 2012, abstract 1869, Sofia MJ, et al. J. Med. Chem. 2010, 53, 7202-7218, Murakami E, et al. J Biol Chem 2010;285:34337.

uridine MP DP TP

GS-331007 uridine

GS-461203 GS-606965

uridine MP

GS-331007 uridine

ACTIVE FORM

hCE1,CatA

HINT1

Sofosbuvir in Hepatic Impairment Child Pugh B (n=8) Child Pugh C (n=8) Controls (n=8)

Sofosbuvir AUC 1350 (59) 1380 (52) 538.1 (39)

AUC Ratio vs. Controls 2.25 (1.35, 3.75) 2.44 (1.58, 3.76)

GS-331007 AUC 12561 (57) 12211 (63) 9639 (19)

AUC Ratio vs. Controls 1.18 (0.84, 1.64) 1.09 (0.73, 1.62)

Lawitz E, et al. EASL 2012, #1130

5. 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

Portal-Systemic Shunting Effects on Drug Pharmacokinetics

Increased bioavailability and thus plasma exposures due to shunting

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

Shunting Effects on DAA

• Shunting may contribute to PK alterations for all DAA, but those with lowest bioavailability likely to be most affected.

• Bioavailability for most DAA not in public domain.

Enzyme Expression and Function Transporter Expression and Function

Protein Binding Portal-Systemic Shunting

Phosphorylation

Summary and Questions • Results of DAA PK hepatic impairment trials highlight the

need for mechanistic explanations for PK results – If we understand why the PK is altered this will guide what we

do next…..

• Role for physiologic-based pharmacokinetic modeling? – Johnson TV, et al. Clin PK 2010;49(3):189-206.

• Role for therapeutic drug monitoring? – Plasma correlate with hepatocyte concentrations?

• Other ideas for pharmacology research needs in this

patient population?