C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 1 of 15

Charles W. Flexner, MDProfessor of Medicine, Pharmacology,

and International HealthThe Johns Hopkins University School of Medicine

Baltimore, Maryland

Pharmacology andDrug Interactions of Newer

Direct-Acting Antivirals

EDITED: 10-07-14

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 3 of 46

Learning Objectives

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

After attending this presentation, learners will be able to:

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 4 of 46

Case #1

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 2 of 15

Slide 5 of 46

A 60 y.o. man with stage 2 fibrosis 60-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

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 6 of 46

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 7 of 46

AudienceQuestion #1

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 3 of 15

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. Sofosbuvir plasma concentrations are of no value in predicting clinical outcomes.

3. Sofosbuvir increases intracellular ribavirin-triphosphate and subsequent risk of anemia.

4. Ritonavir increases plasma sofosbuvirconcentrations (AUC) by an average of 34%.

5. What the heck is sofosbuvir?

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 9 of 46

Sofosbuvir Metabolism and PK Enriched (>98%) for the more potent of two diastereomers.

Rapidly taken up by the liver and converted to the intracellular monophosphate.

The intracellular triphosphate is the active anabolite.

Very little SOF reaches the systemic circulation.

Most of what can be measured is a metabolite, GS-331007. Renal excretion, P-gp substrate, but no known CYP interactions.

Sofia et al., J Med Chem 2010;53:7202

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 10 of 46

Sofosbuvir

Alaninemetabolite

UridineNucleosideGS-331007

Sofosbuvir Plasma PK

Sofosbuvir 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-331007.

- Lawitz et al., AAC 2013;57:1209

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 4 of 15

Slide 11 of 46

Sofosbuvir metabolism

GS-007

Sofosbuvir

007-MP

First-pass metabolism

Portal vein

Nucleoside

Systemic circulation

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 12 of 46

Sofosbuvir metabolism

GS-007

Sofosbuvir

007-MP

007-DP

007-TP

First-pass metabolism

Portal vein

Nucleoside

Systemic circulation

Active metabolite

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 13 of 46

What is the drug interaction potential of sofosbuvir?

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 5 of 15

Slide 14 of 46

AudienceQuestion #2

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 15 of 46

Which statement best describes the interactions between sofosbuvir and

Cyclosporine A?

1. Sofosbuvir decreases the CyA AUC.

2. Sofosbuvir increases the CyA AUC.

3. CyA does not alter sofosbuvir PK.

4. CyA decreases the sofosbuvir AUC.

5. CyA increases the sofosbuvir AUC.

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 16 of 46

Sofosbuvir and Cyclosporine A

CyA increases the SOF AUC in healthy volunteers by 4-fold (353%).

However, the AUC of the major metabolite in plasma, GS-331007, 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

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 6 of 15

Slide 17 of 46

Sofosbuvir and Tacrolimus

TAC increases the SOF AUC by only 13% Unlikely to be clinically significant

No effect of SOF on the TAC AUC.

- Mathias et al., AASLD 2012; abstract 1869

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 18 of 46

sofosbuvir

sofosbuvir

sofosbuvir

sofosbuvir

sofosbuvir

sofosbuvir

Sofosbuvir

Sofosbuvir

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 19 of 46

Drug Interaction Potential of Sofosbuvir

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

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 7 of 15

Slide 20 of 46

Other HCV polymerase inhibitors

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 21 of 46

Mericitabine• Cytidine prodrug of

PSI-6130

• Converted inside hepatocytes to two different active metabolites:

• 6130-TP

• GS007-TP (!)

Ma et al., J Biol Chem 2007; 282: 29812

aka GS007

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

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

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 8 of 15

Slide 23 of 46

Why isn’t mericitabine as potent as sofosbuvir???

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 24 of 46

Mericitabine

aka GS007

Ma et al., J Biol Chem 2007; 282: 29812

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 25 of 46

Mericitabine• Conversion of PSI-6130 to 6130-MP by deoxycytidinekinase may be a slow conversion, and therefore rate limiting.

• Both 6130-TP and 007-TP may accumulate in hepatocytes more slowly than 007-TP with sofosbuvir.

aka GS007

- Ma et al., J Biol Chem 2007; 282: 29812- Guedj et al., Hepatology 2012;55:1031

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 9 of 15

Slide 26 of 46

What about other DAAs?

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 27 of 46

Case #1 revisited

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 28 of 46

A 60 y.o. man with stage 2 fibrosis 60-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

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 10 of 15

Slide 29 of 46

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 30 of 46

Drug interaction potential of newer HCV protease inhibitors

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 31 of 46

AudienceQuestion #3

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 11 of 15

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

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 34 of 46

(A) Intestine – drug metabolized

(B) Intestine – inhibition

Drug

CYP3A4

Enterocyte

Gut lumen

Inhibitor

X

Inhibition

Enterocyte

Gut lumen

CYP3A4 Drug

CYP3A4

Simeprevir

Effect of simeprevir on CYP 3A4

Ouwerkerk-Mahadevan S EASL 2014

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 12 of 15

Slide 35 of 46

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 36 of 46

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 37 of 46

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 13 of 15

Slide 38 of 46

Drug interaction potential of other new HCV DAAs

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 39 of 46

Adapted from Weiser, Drug Discov Today: Tech 2012

PIs NS5A inhibitors Cyclophilininhibitors

NS5B

NRTI NNRTI

Approved Boceprevir

Telaprevir

Simeprevir

Sofosbuvir

Phase 3 Faldaprevir

Asunaprevir

ABT‐450r

MK‐5172

Daclatasvir

Ledipasvir

Ombitasvir

MK‐8742

Alisporivir Dasabuvir

Phase 2 Danoprevir

Vaniprevir

GS‐9451

GS‐9256

ACH1625

GSK‐2336805 SCY‐635 Mericitabine

IDX‐184

VX‐135

Tegobuvir

BI‐207127

GS‐9669

BMS‐791325

ABT‐072

VX‐222

PF‐868554

Phase 1 MK‐6325

MK‐2748

ABT‐493

GS‐5816

ABT‐530

IDX‐719

MK‐8326

GSK‐625433

IDX‐375

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 40 of 46

Drug interactions of DAAs with ARVs

Kiser et al., Nature Rev Gastro Hep 2013

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 14 of 15

Slide 41 of 46

Drug interactions of DAAs with ARVs

Kiser et al., Nature Rev Gastro Hep 2013

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 42 of 46

Drug interactions of DAAs with ARVs

Kiser et al., Nature Rev Gastro Hep 2013

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 43 of 46

Drug interactions of DAAs with ARVs

Kiser et al., Nature Rev Gastro Hep 2013

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

C. W. Flexner, MD

Boston, MA: October 14, 2014, IAS–USA Page 15 of 15

Slide 44 of 46

ABT450r Substrate for CYP 3A4, PgP, OATP1B1/3 Weak inhibitor PgP/BCRP (gut), ?OATP1B1/3

MK-5172 Substrate for CYP 3A4, PgP, ? OATP1B1

Inhibits CYP 2C8, weak inhibitor of UGT1A1, ? BCRP Moderate

Faldaprevir Substrate for CYP 3A4, PgP, OATP1B1 & MRP2

Inhibitor of CYP 3A4, 2C9, UGT1A1,Probably inhibits OATP1B1/3, MRP2 Moderate

Simeprevir Substrate for CYP 3A4, PgP Inhibits OATP1B1, MRP2Mild inhibitor gut CYP 3A4, PgP

Moderate

MK-8742 Substrate for CYP 3A4, PgP, ?OATP1B1 weak inhibitor of UGT1A1 Moderate

Sofosbuvir cathepsin A, esterases, kinasesPgP & BCRP substrate (parent)

Weak inhibitor of gut PgP & BCRP Low

Daclatasvir Substrate for CYP 3A4, PgP Inhibits OATP1B1/3 & PgP Moderate

VICTIM of DDI PERPETRATOR of DDI DDI potential

Asunaprevir Substrate for OATP1B1/2B1CYP 3A4

Inhibits CYP2D6 (mod) & OATP1B1/3 (weak), ?BCRP, Weak CYP3A4 inducer

?

Dasabuvir(ABT-333)

Substrate of CYP 2C8 > 3A4 > 2D6, Substrate of PgP, BCRP

Weak inhibitor of UGT1A1

Ombitasvir(ABT-267)

Substrate for PgP, BCRP(CYP 3A4 )

Weak inhibitor of UGT1A1Moderate to Significant (RTV)

Ledipasvir Primarily excreted unchanged (>98% faeces), PgP / BCRP substrate

Weak inhibitor of PgP/BCRP, ?OATP1B1/3 ?

TLPTelaprevir Substrate for CYP 3A4, PgPInhibits CYP 3A4, PgP, OATP1B1/2? Protein binding

Significant

Boceprevir Substrate for aldoketoreductase, CYP 3A4, PgP, BCRP

Inhibits CYP 3A4, PgP, OCT 1&2Significant

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 45 of 46

Conclusions

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.

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

Slide 46 of 46

Which statement best describes the PK of sofosbuvir?

1. Higher plasma sofosbuvir concentrations are associated with more-rapid clearance of HCV.

2. Sofosbuvir plasma concentrations are of no value in predicting clinical outcomes.

3. Sofosbuvir increases intracellular ribavirin-triphosphate and subsequent risk of anemia.

4. Ritonavir increases plasma sofosbuvir concentrations (AUC) by an average of 34%.

5. What the heck is sofosbuvir?

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________

___________________________________