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GI II - EXAM 2 > 11-30 Treatment of Hepatitis DSA - Pharm > Flashcards

11-30 Treatment of Hepatitis DSA - Pharm Flashcards

1
Q

What are the drug classes for treatment of HBV?

A

Interferon alfa

Nucleoside/Nucleotide Analogs (NAs)

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2
Q

What are the advantages of interferon alfa versus NAs?

A

finite duration of treatment, resistance is not a problem, responses are more durable.

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3
Q

What are the disadvantages of interferon-alfa versus NAs?

A

side effects; cannot be used in patients with decompensated disease.

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4
Q

What is the MOA for Interferon alfa?

A

cytokine which exhibits complex antiviral, immunomodulatory, and anti-proliferative actions.

Inhibits viral penetration, translation, transcription, protein processing, maturation, and release.

Enhanced phagocytic activity of macrophages and augmentation of proliferation/survival of cytotoxic T-cells.

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5
Q

What is the Pk of interferon alfa?

A

Interferon alfa-2a, alfa-2b (SubQ or IM) – t1/2 2-5 hours; filtered by glomerulus, proteolytic degradation during tubular reabsorption.

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6
Q

What is pegylated interferon? Why is it used?

A

Pegylated interferon (peginterferon, Peg-IFN): polyethylene glycol complexed (non-toxic polymer excreted in the urine); always given subcutaneously;

slower clearance (30% renal – dose adjust in impairment),

longer t1/2 of 40 hours,

steadier concentration allows for less frequent dosing (once-weekly compared to daily or thrice-weekly dosing).

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7
Q

What is the clinical use of interferon alfa?

A

chronic HBV and chronic HCV (see clinical pharmacology section below).

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8
Q

What are the ADRs for interferon alfa?

A
  1. 30% of patients experience flu-like illness (headache, fever, chills, myalgias, malaise) within first week of therapy; occurs ~6 hours following dose (generally resolves with continued therapy).
    1. Transient increase in hepatic enzymes (first 8-12 weeks) à common in treatment responders.
    2. Chronic therapy – neurotoxicity (mood disorders, depression, somnolence, confusion, seizures), myelosuppression, profound fatigue, weight loss, rash, cough, myalgia, alopecia, tinnitus, reversible hearing loss, retinopathy, pneumonitis, possibly cardiotoxicity.
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9
Q

What are the contraindications for interferon alfa?

A
  1. CIs: hepatic decomposition, autoimmune disease (can cause induction of autoantibodies), history of cardiac arrhythmia, pregnancy.
    1. Cautions: psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia.
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10
Q

What are the DDIs for interferon alfa?

A
  1. DDIs: may increase levels of theophylline and methadone.
    1. Co-administration not recommended with didanosine (increased risk of hepatic failure) or zidovudine (exacerbates cytopenias).
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11
Q

What is the MOA for NAs?

A
  1. Nucleoside/Nucleotide Analogs (NAs)
    1. General MOA: interfere with viral replication.
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12
Q

What is the general Pk for NAs?

A

renal elimination and must be dose adjusted in renal impairment. Long t1/2 allowing once-daily dosing.

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13
Q

What are the advantages of NAs compared to interferon?

A
  1. Advantages vs. Interferon: PO administration (tablets or solution), better tolerated, higher response rate, can be used for chronic therapy or in patients with significant liver disease.
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14
Q

What are the disadvantages of NAs?

A
  1. Disadvantages: sustained response limited after therapy discontinuation, resistance can be problematic, some agents cause peripheral neuropathy, general warning for lactic acidosis and hepatic steatosis (mitochondrial dysfunction).
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15
Q

Name some NAs.

A

Adefovir dipivoxil

Entecavir

Lamivudine

Telbivudine

Tenofovir

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16
Q

What is the MOA for Adefovir dipivoxil?

A

adenine nucleotide analog; inhibits HBV DNA polymerase, chain termination after incorporation into viral DNA.

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17
Q

What is the therapeutic use for adefovir dipivoxil?

A
  1. Active against a wide range of DNA and RNA viruses, including HBV, HIV, and herpesviruses.
  2. Not recommended as first-line agent for HBV due to slow response and low likelihood of HBeAg seroconversion.
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18
Q

What are the ADRs for adefovir dipivoxil?

A
  1. headache, diarrhea, abdominal pain; potential nephrotoxicity (dose-dependent).
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19
Q

What is the resistance to adefovir dipivoxil?

A
  1. Resistance: early development low, but up to 30% after 4 years.

No cross-resistance with lamivudine or entecavir

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20
Q

What is the MOA for Entecavir?

A

guanosine nucleoside analog; inhibits DNA polymerase (base priming, reverse transcription of negative strand, and viral DNA synthesis).

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21
Q

What is the therapeutic use for Entecavir?

A
  1. recommended first-line therapy for HBV; exhibits good viral suppression and normalization of liver enzymes with slowing of liver damage.
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22
Q

What are the ADRs for Entecavir?

A

well-tolerated; side effects include headache, fatigue, dizziness, nausea, rash, fever

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23
Q

What is the resistance for entecavir?

A

rare (< 1% at 4 years).

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24
Q

What is the MOA for lamivudine (3TC)?

A

cytosine analog; inhibits DNA polymerase, competes for incorporation into viral DNA, causes chain termination.

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25
Q

What is the therapeutic use for Lamivudine?

A
  1. HIV treatment regimens.
  2. Rapidly suppresses HBV, but not recommended as first-line therapy due to high rate of resistance (15-30% at 1 year and 70% at 5 years) and progressive liver disease.
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26
Q

What are the ADRs for lamivudine?

A

excellent safety profile, including use during pregnancy;

side effects are rare, but include

headache, nausea, diarrhea, myalgia, and dizziness;

co-infection with HIV may increase risk of pancreatitis.

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27
Q

What is the resistance to lamivudine like?

A

cross-resistance with entecavir may occur; often used in combination with adefovir to combat resistance

28
Q

What is the MOA for Telbivudine?

A

: thymidine nucleoside analog; inhibits DNA polymerase (competitive inhibition), incorporates into viral DNA, causes chain termination

29
Q

What is the therapeutic use of telbivudine?

A
  1. Rapidly suppresses HBV and causes HBeAg seroconversion with reduced liver damage, but not recommended as first-line therapy due to high rate of resistance (22%), which increases after one year of therapy.
30
Q

What are the ADRs for Telbivudine?

A

well-tolerated; side effects are generally mild and may include fatigue, headache, cough, abdominal pain, diarrhea, increased creatine kinase levels, nausea, and vomiting

31
Q

What are the CIs for Telbivudine?

A
  1. avoid concurrent use with interferon alfa due to increased risk of peripheral neuropathy.
32
Q

What is the resistance for telbivudine like?

A

cross-resistance with lamivudine

33
Q

What is the MOA for tenofovir?

A

nucleotide analog of adenosine; competitively inhibits DNA polymerase, incorporates into viral DNA, causes chain termination

34
Q

What is the therapeutic use of tenofovir?

A
  1. Recommended first-line therapy for HBV; treats lamivudine- and entecavir-resistant isolates, but exhibits reduced activity against adefovir-resistant strains.
  2. HIV treatment regimens.
35
Q

What are the ARDs associated with Tenofovir?

A

nausea, diarrhea, vomiting, decreased bone mineral density (consider calcium and vitamin D supplementation and monitor bone density in long-term use).

36
Q

What is the resistance like for tenofovir?

A
  1. Resistance: rare, less frequent than with adefovir.
37
Q

What are the drug classes for Tx of HCV?

A

Direct-Acting Antivirals

Interferon alfa

Ribavirin

Protease inhibitors

38
Q

What are the drugs in the diract-acting antivirals (DAA) class?

A

Daclatasvir

Lepidasvir-sofosbuvir

Ombitasvir-paritaprevir-ritonir + dasabuvir

Sofosbuvir

Simeprevir

39
Q

What is the MOA for daclatasvir?

A

binds N-terminus of HCV nonstructural protein 5A (NS5A), inhibits viral RNA replication and virion assembly

40
Q

What is the Pk for Daclatasvir?

A

metabolized via CYP3A (caution DDIs; concurrent use of strong CYP3A inducers is CI

41
Q

What is the therapeutic use for Daclatasvir?

A

HCV

42
Q

What are the ADRs for Daclatasvir?

A

fatigue, headache, nausea, diarrhea, increased serum lipase (all ADRs are from combination trials with sofosbuvir).

43
Q

What is the cost for daclatasvir?

A

Cost: $147,000 for 12-weeks of treatment with daclatasvir and sofosbuvir

44
Q

What is the MOA for ledipasvir?

A
  1. Ledipasvir-sofosbuvir (Harvoni) FDA approved October 10, 2014 in a combined formulation; the following information is for ledipasvir.

MOA: inhibits HCV NS5A protein necessary for viral replication; also acts as a chain terminator

45
Q

What is the Pk for ledipasvir?

A

oxidative metabolism – mechanism unknown

46
Q

What is the therapeutic use for ledipasvir?

A

HCV

47
Q

What are the ADRs for ledipasvir?

A

fatigue, headache, insomnia, nausea, diarrhea, increased serum lipase.

48
Q

What is the cost for ledipasvir?

A

Cost: $94,500 for 12-weeks of treatment

49
Q

What is the MOA for ombitasvir-paritaprevir-ritonavir + dasubavir?

A
  1. MOA: distinct among the antiviral agents combined.
    1. Ombitasvir – inhibits HCV NS5A, interferes with viral RNA replication and virion assembly.
    2. Paritaprevir – inhibits HCV NS3/4A protease, interferes with HCV coded polyprotein cleavage necessary for viral replication.
    3. Dasabuvir – inhibits HCV RNA-dependent RNA polymerase necessary for viral replication.
    4. Ritonavir – no activity against HCV; used for its potent CYP3A inhibitory effects which increases plasma concentrations of paritaprevir and overall drug exposure.
50
Q

What is the Pk and therapeutic use for ombitasvir-paritaprevir-ritonavir + dasubuvir?

A
  1. PK: CYP metabolism; must use caution and consider DDIs.
    1. Ombitasvir – amide hydrolysis and oxidative metabolism; excreted in feces.
    2. Paritaprevir – CYP3A4 metabolism; excreted in feces.
    3. Dasabuvir – CYP2C8 & 3A4 metabolism; excreted in feces.
    4. Ritonavir – CYP3A4 & 2D6 metabolism; excreted in feces.
  2. Therapeutic Use: HCV
51
Q

What are the ADRs associated with ombitasvir-paritaprevir-ritonavir + dasabuvir? What is the cost?

A
  1. ADRs: fatigue, headache, nausea, pruritus, skin reactions, insomnia, and asthenia; elevations in serum alanine aminotransferase (ALT).
  2. Cost: $83,319 for 12-week supply.
52
Q

What is the MOA for sofosbuvir?

A
  1. Sofosbuvir (Sovaldi) FDA approved December 6, 2013.
    1. MOA: inhibits HCV NS5B RNA dependent RNA polymerase (essential for viral replication), acts as chain terminator
53
Q

What is the Pk for sofosbuvir?

A
  1. PK: 80% excreted in the urine, substrate of P-glycoprotein
54
Q

What is the therapeutic use for sofosbuvir? ADRs?

A
  1. Therapeutic Use: HCV
  2. ADRs: fatigue, headache, insomnia, pruritus, nausea, diarrhea, flu-like symptoms, anemia, neutropenia, weakness, myalgia
55
Q

What is the cost for sofosbuvir?

A

Cost: $84,000 for 12-week supply

56
Q

What is the MOA for simeprevir?

A
  1. Simeprevir (Olysio) FDA approved November 22, 2013.
    1. MOA: inhibits HCV NS3/4A protease (essential for viral replication)
57
Q

What is the Pk for simeprevir? Therapeutic use?

A
  1. PK: CYP3A4 oxidative metabolism, excreted in feces
  2. Therapeutic Use: HCV
58
Q

What are the ADRs with simeprevir?

A
  1. ADRs: skin rash, pruritus, nausea, increased serum bilirubin, myalgia
59
Q

What are the DDIs for simeprevir?

A
  1. DDIs: avoid with CYP inducers (rifampin) which will decrease simeprevir levels
    1. May increase concentration of other CYP3A4 substrates (i.e. statins)
60
Q

What is the cost for simeprevir?

A

Cost: $66,360 for 12-week supply

61
Q

What is the MOA for ribavirin?

A
  1. Ribavirin
    1. MOA: guanosine analog; interferes with guanosine triphosphate synthesis (inhibits capping of viral mRNA); inhibits initiation/elongation of RNA resulting in inhibition of viral protein synthesis.
62
Q

What is the therapeutic use for ribavirin?

A
  1. Chronic HCV, in combination with direct-acting antivirals.
  2. Influenza A and B, parainfluenza, respiratory syncytial virus (RSV), paramyxoviruses, and HIV-1
63
Q

What are the ADRs for ribavirin?

A
  1. ADRs:

Dose dependent hemolytic anemia (10-20%), depression, fatigue, nausea, rash, insomnia

64
Q

What are the contraindications/CIs for ribavirin?

A

anemia, end-stage renal failure, ischemic vascular disease, pregnancy (pregnant women and their partners);

pregnant women should not directly care for patients receiving aerosolized ribavirin.

Ribavirin is teratogenic, embryotoxic, oncogenic, and possibly gonadotoxic

65
Q

What are 2 protease inhibitors? Are they still recommended for HCV treatment?

A
  1. Protease Inhibitors (PIs)
    1. Telaprevir & Boceprevir (no longer recommended in guidelines – FYI only)
66
Q
A

GI II - EXAM 2 (11 decks)

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