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
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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:
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Case #1
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 2 of 15
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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
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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
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AudienceQuestion #1
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 3 of 15
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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?
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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
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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
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 4 of 15
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Sofosbuvir metabolism
GS-007
Sofosbuvir
007-MP
First-pass metabolism
Portal vein
Nucleoside
Systemic circulation
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Sofosbuvir metabolism
GS-007
Sofosbuvir
007-MP
007-DP
007-TP
First-pass metabolism
Portal vein
Nucleoside
Systemic circulation
Active metabolite
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What is the drug interaction potential of sofosbuvir?
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 5 of 15
Slide 14 of 46
AudienceQuestion #2
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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.
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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
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 6 of 15
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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
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sofosbuvir
sofosbuvir
sofosbuvir
sofosbuvir
sofosbuvir
sofosbuvir
Sofosbuvir
Sofosbuvir
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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
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 7 of 15
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Other HCV polymerase inhibitors
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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
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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
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 8 of 15
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Why isn’t mericitabine as potent as sofosbuvir???
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Mericitabine
aka GS007
Ma et al., J Biol Chem 2007; 282: 29812
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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
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 9 of 15
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What about other DAAs?
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Case #1 revisited
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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
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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
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Drug interaction potential of newer HCV protease inhibitors
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AudienceQuestion #3
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 11 of 15
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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.
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Effect of simeprevir on the PK of ARVs
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(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
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 12 of 15
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 13 of 15
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Drug interaction potential of other new HCV DAAs
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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
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Drug interactions of DAAs with ARVs
Kiser et al., Nature Rev Gastro Hep 2013
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 14 of 15
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Drug interactions of DAAs with ARVs
Kiser et al., Nature Rev Gastro Hep 2013
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Drug interactions of DAAs with ARVs
Kiser et al., Nature Rev Gastro Hep 2013
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Drug interactions of DAAs with ARVs
Kiser et al., Nature Rev Gastro Hep 2013
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C. W. Flexner, MD
Boston, MA: October 14, 2014, IAS–USA Page 15 of 15
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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
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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.
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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?
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