Pharmacologic Considerations when using DAAs in Cirrhosis

Transcription

1 Pharmacologic Considerations when using DAAs in Cirrhosis Jennifer J. Kiser, PharmD Assistant Professor University of Colorado Denver 1 st International Workshop on the Optimal Use of DAAs in Liver Transplant Patients April 24, 2013

2 Impressive Pipeline Protease Inhibitors: Boceprevir Telaprevir Faldaprevir (BI ) Simeprevir (TMC435) ABT-450 ACH-1625 BMS (asunaprevir) GS-9451 GS-9256 MK-5172 RG7227 (danoprevir) ACH-2684 NS5A Inhibitors: BMS (daclatasvir) ABT-267 GS-5885 GSK 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 Filibuvir GS 9190 (tegobuvir) VX-222 ABT-333 BMS GS-9669 Kiser JJ, Flexner C. Annual Reviews in Pharmacology and Toxicology [In press]

3 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.

4 Ongoing INF-free Trials Allowing or Exclusively Studying Persons with Advanced Liver Disease DAA Combination Patient Population N NCT# Status Daclatasvir + simeprevir ± RBV Sofosbuvir + simeprevir ± RBV Allows 1/3 F3 or F4 without decompensation Allows half with F3 or F4 no decompensation Ongoing, not recruiting Ongoing, not recruiting Sofosbuvir + RBV Pre-transplant CP Enrollment complete ABT450/r + ABT333 + ABT267 + RBV (TURQUOISE-II) Sofosbuvir + RBV Sofosbuvir + RBV All cirrhotics CP Recruiting All cirrhotics including decompensation CP < 10, HVPG > 6 Post-transplant recurrence, 6 mo-12 yr post-transplant, excludes decompensation Recruiting Recruiting

5 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

6 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.

7 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

8 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:

9 CYP Enzyme Expression and Function with Progressive Hepatic Impairment CYP3A Modified from figure by Branch RA, CPT 1998;64:462

10 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

11 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

12 2. Transporter Expression in Liver Disease Systemic Circulation Systemic Circulation NTCP BCRP? ABCG5/G8 OATP1B1 OATP1B3* OATP2B1 MRP2 Bile BSEP MRP3 MRP4 OCT1 P-gp MDR3 Sinusoidal Membrane Canalicular Membrane Figure adapted from Oswald S. et al. Xenobiotica 2007;37(10-11):1171, 1 Nakai K, et al. Drug Metab & Dispos 2008;36(9):1786, 2 Ogasawara K, et al. Drug Metabol PK 2010;25(2):190, 3 Bonin S, et al. Mol Med 2002;8(6):318.

13 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

14 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:

15 Daclatasvir Unbound Concentrations Unchanged in Hepatic Impairment ~40% ~40 % Bifano, M. 62 nd AASLD 2011 Total concentrations appear lower, but free amount is unchanged.

16 4. Phosphorylation enzyme expression and/or function Nucleos(t)ide analogs undergo intracellular phosphorylation by host enzymes to the active form Adenosine kinase cn-ii nucleotidase NMPK NDPK No data to support or refute alterations in phosphorylation due to advanced liver disease, but biologic plausibility

17 Plasma Sofosbuvir Sofosbuvir Hepatocyte GS hce1,cata GS GS ACTIVE FORM GS HINT1 GS uridine MP TP DP uridine MP GS uridine GS uridine Made from: Mathias A, et al. 63 rd AASLD, Nov 9-13, 2012, abstract 1869, Sofia MJ, et al. J. Med. Chem. 2010, 53, , Murakami E, et al. J Biol Chem 2010;285:34337.

18 Sofosbuvir in Hepatic Impairment Child Pugh B (n=8) Child Pugh C (n=8) Controls (n=8) Sofosbuvir AUC 1350 (59) 1380 (52) (39) AUC Ratio vs. Controls 2.25 (1.35, 3.75) 2.44 (1.58, 3.76) GS AUC (57) (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

19 DAA 5. Portal-Systemic Shunting Portal vein Liver CYP Absorption efflux P-gp Portal vein Metabolism CYP CYP CYP CYP CYP CYP CYP CYP Metabolism Bioavailability: Systemic circulation (Fraction escaping extraction): F = 1-E H To feces Gut wall Fraction extracted and metabolized (E H )

20 Portal-Systemic Shunting Effects on Drug Pharmacokinetics Increased bioavailability and thus plasma exposures due to shunting Verbeeck RK. Eur J Clin Pharmcol 2008;64:

21 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.

22 Enzyme Expression and Function Transporter Expression and Function Protein Binding Portal-Systemic Shunting Phosphorylation

23 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): Role for therapeutic drug monitoring? Plasma correlate with hepatocyte concentrations? Other ideas for pharmacology research needs in this patient population?