Case #1. Pharmacology and Drug Interactions of Newer Direct-Acting Antivirals

Transcription

1 Pharmacology and Drug Interactions of Newer Direct-Acting Antivirals Charles W. Flexner, MD Professor of Medicine, Pharmacology, and International Health The Johns Hopkins University School of Medicine Baltimore, Maryland EDITED: Learning Objectives After attending this presentation, learners will be able to: Discuss the pharmacology and pharmacokinetics of new direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection Recognize the potential for clinically significant drug-drug interactions of new DAAs for HCV infection Slide 3 of 46 Case #1 Slide 4 of 46 Boston, MA: October 14, 2014, IAS USA Page 1 of 15

2 A 60 y.o. man with stage 2 fibrosis Slide 5 of year-old Caucasian man with HCV 1b infection. He was diagnosed at least 11 years ago. Liver biopsies in 2000 and 2008 (stage 2/4 fibrosis). HAV and HBV vaccinated; no ETOH; no IDU; HIV neg; HBsAg neg PMH: high cholesterol, seasonal rhinitis, and HTN Meds: HCTZ 25 mg Atorvastatin 20 mg Fluticasone spray each nostril QD year-round A 60 y.o. man with stage 2 fibrosis You decide to treat this patient. What kind of drug interactions might you expect if his treatment regimen contains sofosbuvir? Meds: HCTZ 25 mg Atorvastatin 20 mg Fluticasone spray each nostril QD year-round Slide 6 of 46 Slide 7 of 46 Audience Question #1 Boston, MA: October 14, 2014, IAS USA Page 2 of 15

3 Slide 8 of 46 Which of the following statements best describes the PK of sofosbuvir? 1. Higher plasma sofosbuvir concentrations are associated with more-rapid clearance of HCV. 2. plasma concentrations are of no value in predicting clinical outcomes. 3. increases intracellular ribavirintriphosphate and subsequent risk of anemia. 4. Ritonavir increases plasma sofosbuvir concentrations (AUC) by an average of 34%. 5. What the heck is sofosbuvir? Metabolism and PK Slide 9 of 46 Enriched (>98%) for the more potent of two diastereomers. Rapidly taken up by the liver and converted to the intracellular monophosphate. Sofia et al., J Med Chem 2010;53:7202 The intracellular triphosphate is the active anabolite. Very little SOF reaches the systemic circulation. Most of what can be measured is a metabolite, GS Renal excretion, P-gp substrate, but no known CYP interactions. Plasma PK is an oral prodrug; very little can be measured in the plasma and it is cleared quite rapidly. The main SOF-associated metabolite that can be measured in the plasma is its uridine nucleoside metabolite GS Slide 10 of 46 Alanine metabolite Uridine Nucleoside GS Lawitz et al., AAC 2013;57:1209 Boston, MA: October 14, 2014, IAS USA Page 3 of 15

4 metabolism Slide 11 of 46 GS-007 Nucleoside Systemic circulation Portal vein First-pass metabolism 007-MP metabolism Slide 12 of 46 Portal vein First-pass metabolism 007-MP GS-007 Nucleoside Systemic circulation 007-DP 007-TP Active metabolite Slide 13 of 46 What is the drug interaction potential of sofosbuvir? Boston, MA: October 14, 2014, IAS USA Page 4 of 15

5 Audience Question #2 Slide 14 of 46 Which statement best describes the interactions between sofosbuvir and Cyclosporine A? 1. decreases the CyA AUC. 2. increases the CyA AUC. 3. CyA does not alter sofosbuvir PK. 4. CyA decreases the sofosbuvir AUC. 5. CyA increases the sofosbuvir AUC. Slide 15 of 46 and Cyclosporine A Slide 16 of 46 CyA increases the SOF AUC in healthy volunteers by 4-fold (353%). However, the AUC of the major metabolite in plasma, GS , is unchanged. Possible clinical significance is unclear. Could represent inhibition of cellular uptake of SOF by CyA. The CyA AUC is not altered by SOF. - Mathias et al., AASLD 2012; abstract 1869 Boston, MA: October 14, 2014, IAS USA Page 5 of 15

6 and Tacrolimus TAC increases the SOF AUC by only 13% Unlikely to be clinically significant No effect of SOF on the TAC AUC. Slide 17 of 46 - Mathias et al., AASLD 2012; abstract 1869 Slide 18 of 46 sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir Drug Interaction Potential of Slide 19 of 46 Like HIV NRTIs, sofosbuvir has a low potential for clinically significant drug-drug interactions. There are few concomitant meds absolutely contraindicated for administration with SOF in the current package insert for sofosbuvir. Mainly P-gp inducers Tipranavir is the only excluded ARV Boston, MA: October 14, 2014, IAS USA Page 6 of 15

7 Slide 20 of 46 Other HCV polymerase inhibitors Slide 21 of 46 Cytidine prodrug of PSI-6130 Converted inside hepatocytes to two different active metabolites: 6130-TP GS007-TP (!) aka GS007 Mericitabine Ma et al., J Biol Chem 2007; 282: Slide 22 of 46 Mericitabine Slower decay rate than other HCV DAAs Disappointing clinical activity compared to sofosbuvir No resistance detected in clinical trials Guedj et al., Hepatology 2012;55:1031 Boston, MA: October 14, 2014, IAS USA Page 7 of 15

8 Why isn t mericitabine as potent as sofosbuvir??? Slide 23 of 46 aka GS007 Mericitabine Slide 24 of 46 Ma et al., J Biol Chem 2007; 282: Mericitabine Slide 25 of 46 Conversion of PSI to 6130-MP by deoxycytidine kinase may be a slow conversion, and therefore rate aka GS007 limiting. Both 6130-TP and 007-TP may accumulate in hepatocytes more slowly than 007-TP - Ma et al., J Biol Chem 2007; 282: with sofosbuvir. - Guedj et al., Hepatology 2012;55:1031 Boston, MA: October 14, 2014, IAS USA Page 8 of 15

9 Slide 26 of 46 What about other DAAs? Slide 27 of 46 Case #1 revisited A 60 y.o. man with stage 2 fibrosis Slide 28 of year-old Caucasian man with HCV 1b infection. He was diagnosed at least 11 years ago. Liver biopsies in 2000 and 2008 (stage 2/4 fibrosis). HAV and HBV vaccinated; no ETOH; no IDU; HIV neg; HBsAg neg PMH: high cholesterol, seasonal rhinitis, and HTN Meds: HCTZ 25 mg Atorvastatin 20 mg Fluticasone spray each nostril QD year-round Boston, MA: October 14, 2014, IAS USA Page 9 of 15

10 A 60 y.o. man with stage 2 fibrosis You decide to treat this patient. What kind of drug interactions might you expect if his treatment regimen contains simeprevir? Meds: HCTZ 25 mg Atorvastatin 20 mg Fluticasone spray each nostril QD year-round Slide 29 of 46 Slide 30 of 46 Drug interaction potential of newer HCV protease inhibitors Slide 31 of 46 Audience Question #3 Boston, MA: October 14, 2014, IAS USA Page 10 of 15

11 Slide 32 of 46 Which statement best describes the drug interaction potential of simeprevir? 1. Simeprevir is a potent CYP 3A4 inducer. 2. Simeprevir is a potent CYP 3A4 inhibitor. 3. Simeprevir is a CYP 3A4 substrate. 4. Simeprevir PK is not altered by ritonavir. 5. All of the above are true. Slide 33 of 46 Effect of simeprevir on the PK of ARVs Effect of simeprevir on CYP 3A4 (A) Intestine drug metabolized Slide 34 of 46 CYP3A4 Gut lumen Simeprevir Drug Enterocyte (B) Intestine inhibition Gut lumen Inhibition CYP3A4 Drug X CYP3A4 Inhibitor Enterocyte Ouwerkerk-Mahadevan S EASL 2014 Boston, MA: October 14, 2014, IAS USA Page 11 of 15

12 Slide 35 of 46 Slide 36 of 46 Slide 37 of 46 Boston, MA: October 14, 2014, IAS USA Page 12 of 15

13 Slide 38 of 46 Drug interaction potential of other new HCV DAAs Slide 39 of 46 PIs NS5A inhibitors Cyclophilin inhibitors NRTI NS5B NNRTI Approved Boceprevir Telaprevir Simeprevir Phase 3 Phase 2 Phase 1 Faldaprevir Asunaprevir ABT 450r MK 5172 Danoprevir GS 9451 Vaniprevir GS 9256 ACH1625 MK 6325 MK 2748 ABT 493 Daclatasvir Alisporivir Ledipasvir Ombitasvir MK 8742 GSK SCY 635 Mericitabine IDX 184 VX 135 GS 5816 ABT 530 IDX 719 MK 8326 Dasabuvir Tegobuvir ABT 072 BI VX 222 GS 9669 PF BMS GSK IDX 375 Adapted from Weiser, Drug Discov Today: Tech 2012 Drug interactions of DAAs with ARVs Slide 40 of 46 Kiser et al., Nature Rev Gastro Hep 2013 Boston, MA: October 14, 2014, IAS USA Page 13 of 15

14 Drug interactions of DAAs with ARVs Slide 41 of 46 Kiser et al., Nature Rev Gastro Hep 2013 Drug interactions of DAAs with ARVs Slide 42 of 46 Kiser et al., Nature Rev Gastro Hep 2013 Drug interactions of DAAs with ARVs Slide 43 of 46 Kiser et al., Nature Rev Gastro Hep 2013 Boston, MA: October 14, 2014, IAS USA Page 14 of 15

15 Slide 44 of 46 VICTIM of DDI PERPETRATOR of DDI DDI potential Inhibits CYP 3A4, PgP, OATP1B1/2 Telaprevir TLP Substrate for CYP 3A4, PgP Significant? Protein binding Substrate for aldoketoreductase, Inhibits CYP 3A4, PgP, OCT 1&2 Boceprevir Significant CYP 3A4, PgP, BCRP Inhibits OATP1B1, MRP2 Simeprevir Substrate for CYP 3A4, PgP Moderate Mild inhibitor gut CYP 3A4, PgP cathepsin A, esterases, kinases Weak inhibitor of gut PgP & BCRP Low PgP & BCRP substrate (parent) Primarily excreted unchanged (>98% Weak inhibitor of PgP/BCRP, Ledipasvir? faeces), PgP / BCRP substrate?oatp1b1/3 Weak inhibitor PgP/BCRP (gut), ABT450r Substrate for CYP 3A4, PgP, OATP1B1/3?OATP1B1/3 Ombitasvir Substrate for PgP, BCRP Moderate to Weak inhibitor of UGT1A1 (ABT-267) (CYP 3A4 ) Significant (RTV) Dasabuvir Substrate of CYP 2C8 > 3A4 > 2D6, Weak inhibitor of UGT1A1 (ABT-333) Substrate of PgP, BCRP Daclatasvir Substrate for CYP 3A4, PgP Inhibits OATP1B1/3 & PgP Moderate Inhibits CYP2D6 (mod) & OATP1B1/3 Substrate for OATP1B1/2B1 Asunaprevir (weak),?bcrp,? CYP 3A4 Weak CYP3A4 inducer Substrate for CYP 3A4, PgP, OATP1B1 Inhibitor of CYP 3A4, 2C9, UGT1A1, Faldaprevir Moderate & MRP2 Probably inhibits OATP1B1/3, MRP2 MK-5172 Substrate for CYP 3A4, PgP,? OATP1B1 Inhibits CYP 2C8, weak inhibitor of UGT1A1,? BCRP Moderate MK-8742 Substrate for CYP 3A4, PgP,?OATP1B1 weak inhibitor of UGT1A1 Moderate Conclusions Slide 45 of 46 In general, newer DAAs have much less potential for clinically significant drug-drug interactions than telaprevir and boceprevir. Nucleoside polymerase inhibitors like sofosbuvir have the lowest potential for clinically significant DDIs. Simeprevir is not a significant P450 inhibitor or inducer, but is still susceptible to DDIs caused by inhibitors or inducers of CYP 3A4. Which statement best describes the PK of sofosbuvir? 1. Higher plasma sofosbuvir concentrations are associated with more-rapid clearance of HCV. 2. plasma concentrations are of no value in predicting clinical outcomes. 3. increases intracellular ribavirintriphosphate and subsequent risk of anemia. 4. Ritonavir increases plasma sofosbuvir concentrations (AUC) by an average of 34%. 5. What the heck is sofosbuvir? Slide 46 of 46 Boston, MA: October 14, 2014, IAS USA Page 15 of 15