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To Use Them Together or Not Understanding Drug Interactions With HCV Medications

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Title: To Use Them Together or Not Understanding Drug Interactions With HCV Medications


1
To Use Them Together or Not Understanding Drug
Interactions With HCV Medications
  • Rajwant Minhas, FH Resident
  • HIV/AIDS Rotation
  • May 2012

2
Objectives
  • Understand principles of drug interactions
  • Become aware of drug interactions of HCV
    medications with
  • Antiretrovirals
  • Antidepressants
  • Statins
  • Antihypertensives
  • Contraceptives and hormonal replacement
  • Methadone
  • Steroids

3
Drug-Time Concentration Curve
Source http//www.skepticnorth.com/2012/01/generi
c-drugs-should-we-be-skeptical/
4
How Are Drugs Eliminated From Body?
  • Renal Excreted unchanged in the urine.
  • Clearance directly proportional to renal function
  • Probenecid Drug that blocks renal excretion of
    other drugs

Patrick D. Drug Metabolism. University of Texas
Pharm 143M Class Notes. Fall 2008
5
Drug Metabolism
  • Liver Primary site for drug metabolism
  • Mediated by Cytochrome P-450 system present in
    liver and enterocytes of small intestine

Patrick D. Drug Metabolism. University of Texas
Pharm 143M Class Notes. Fall 2008
Image Source http//www.nature.com/nrd/journal/v1
/n1/fig_tab/nrd705_F1.html
6
Drug Metabolism
  • Drug metabolism Chemical transformation of drug
    by enzymatic systems
  • Goal
  • To de-toxify drugs, and
  • Make them either more water soluble (for
    excretion in urine) or more fat soluble (for
    excretion in the bile, and then into the feces).
  • Hydrosoluble molecules Low toxicity risk ? ?
    renal excretion
  • Lipophilic drugs ? Hydrophilic Metabolites

Patrick D. Drug Metabolism. University of Texas
Pharm 143M Class Notes. Fall 2008
7
CYP450
  • The P450 cytochromes chemically oxidize or reduce
    drugs
  • gt than 25 human cytochrome P450s
  • They are named by number and letter
  • 4 major families ?indicated by number
  • 6 major sub-families ? indicated by letter
  • Individual enzymes within a subfamily ? indicated
    by number
  • For example 3A4, 2D6, 2C19

Badea G. Drug Metabolism. Feb 2007
8
CYP450 System
Badea G. Drug Metabolism. Feb 2007
9
P-glycoprotein
  • Transports drugs out of the cell
  • Tissue expression is varied
  • Found in the major absorption, distribution and
    elimination organs
  • P-gp inducers and inhibitors\

Source http//www.nature.com/nrc/journal/v2/n6/im
ages/nrc823-f3.gif
10
Drug Interactions
  • Pharmacokinetic Interactions
  • Inhibition of metabolism
  • Induction of metabolism
  • Altered drug absorption
  • Inhibition of renal excretion
  • Displacement from plasma protein binding sites
  • Pharmacodynamic Interactions
  • Synergism or antagonism of drug effects, without
    alterations in concentrations of either drug

Badea G. Drug Metabolism. Feb 2007
11
Examples of Drug Interactions
  • Drug interactions involving oral medications can
    take place in at least 2 sites the liver and the
    intestine.
  • Drug Inhibition
  • Saquinavir ritonavir Inhibition of CYP 3A4
  • 20 fold ? in plasma concentration
  • Drug Induction
  • Phenytoin Lopinavir/Ritonavir Multi-agent
    interaction, mechanism unclear. Both phenytoin
    and ritonavir are drug inducers, ritonavir is a
    drug inhibitor too
  • 30 lower lopinavir AUC
  • 35 lower ritonavir AUC
  • 23 lower phenytoin AUC
  • Pharmacodynamic Interaction
  • Enhanced bone marrow suppression in patients
    given concurrent zidovudine and ganciclovir

Lexicomp. Kiser JJ et al. Hepatology
2012551620-1628.
12
But How Do I Find All This Information?
13
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14
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15
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16
hep-druginteractions.org/
17
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18
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19
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20
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21
BOC and TVR Pharmacokinetics
  • BOC Metabolized by CYP3A4, CYP3A5 and
    aldoketoreductases
  • Strong reversible inhibitor of CYP3A4 and
    p-glycoprotein
  • Protein binding 75
  • TPV Substrate and strong inhibitor of CYP3A4 and
    p-glycoprotein
  • Protein binding 59-76

Kiser JJ et al. Hepatology 2012551620-1628.
22
Drug Interactions With BOC TPV
  • Rifampin Potent CYP3A4 inducer
  • Reduced the single dose TPV AUC and Cmax by 92
    and 86
  • Ketoconazole A potent CYP3A inhibitor
  • Increased single dose TPV AUC and Cmax by 62
    and 24 after a single dose of ketoconazole
  • TPV increased digoxin Cmax and AUC by 1.5 and
    1.85 fold
  • Lower doses may be required, monitor digoxin
    levels

Kiser JJ et al. Hepatology 2012551620-1628.
23
Drugs to Avoid or Use With Caution in Patients on
BOC or TPV
  • Anxiolytics and Sleep Aids
  • Antidepressants
  • Antihypertensive Agents
  • Antipsychotics
  • Drug addiction support medications
  • Immunosuppressants
  • Opioid Replacements
  • Oral Contraceptives
  • Statins

Kiser JJ et al. Hepatology 2012551620-1628.
24
Protease Inhibitors With Statins
Statin Boceprevir Telaprevir
Atorvastatin
Lovastatin
Simvastatin
Rosuvastatin
Pravastatin
  • Contraindicated, potential for myopathy
    including rhabdomyolysis
  • A lower maintenance dose may be warranted, with
    additional clinical monitoring

Hep-druginteractions.org
Tseng A. Toronto General Hospital April 24, 2012
25
TPV Atorvastatin
Combination contraindicated
  • Mean plasma concentration-time profile of
    atorvastatin following oral administration with
    and without telaprevir. Error bars represent the
    standard error of the mean.

Lee JE et al. Antimicrob Agents Chemother. 2011
October 55(10) 45694574.
26
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27
Opioid Replacements
Methadone and buprenorphine Do not inhibit or
induce CYP enzymes
Methadone Buprenorphine
85 plasma protein bound Metabolized by CYP3A, 2C8 and glucuronidation TPV displaces methadone from its plasma protein binding sites But free concentrations were unchanged A methadone dose adjustment likely unnecessary with the addition of TPV BOC ? or ? methadone Limited data have been reported showing that BOC is safely tolerated with methadone, with no dose reductions required  96 plasma protein bound Metabolized by CYP3A, 2C8 and glucuronidation TPV No effect on buprenorphine pharmacokinetics BOC Monograph ? or ? buprenorphine Clinical monitoring recommended
Kiser JJ et al. Hepatology 2012551620-1628.
28
TPV Methadone
No dose adjustment required
Levin J. 46th Annual Meeting of the European
Association for the Study of the Liver (The
International Liver Congress 2011), Berlin,
Germany, 30 March-3 April 2011
29
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30
Antidepressants
hep-druginteractions.org/
31
Antidepressants
BOC TPV
Escitalopram CYP2C19 with a minor contribution by CYP3A4 and CYP2D6 ? BOC ? ? vs ? Escitalopram Conflicting reports ? TPV ? Escitalopram Wide therapeutic index but dose may need to be adjusted
Desipramine Trazodone ? Desipramine ? Trazodone May lead to SEs nausea, dizziness, hypotension, syncope Use with caution and consider a lower dose ? Desipramine ? Trazodone May lead to SEs nausea, dizziness, hypotension, syncope Use with caution and consider a lower dose
Be aware of potential for reductions in SSRI
exposures with TPV and BOC, increase the
antidepressant doses as needed
Levin J. 46th Annual Meeting of the European
Association for the Study of the Liver (The
International Liver Congress 2011), Berlin,
Germany, 30 March-3 April 2011
Kiser JJ et al. Hepatology 2012551620-1628.
32
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33
Anxiolytics and Sleep Aids
  • Flurazepam, triazolam highly dependent on CYP3A
    for metabolism
  • Avoid use with BOC and TPV
  • Consider dose reduction with diazepam
  • Zopiclone Co administration has not been studied
    but may increase zopiclone concentrations through
    CYP3A inhibition.
  • A clinically significant effect on BOC exposure
    is unlikely
  • Zolpidem AUC ? 42 by TPV and t1/2 ? from 4.32
    to 3.37 hrs. Higher dose may be required with TPV

Alprazolam (IV) Midazolam (IV) Triazolam (IV) ? alprazolam ? midazolam ? triazolam No interaction studies with IV benzodiazepines Closely monitor for respiratory depression and/or prolonged sedation Avoid use and if necessary consider dose adjustment of benzodiazepines
Victrelis Triple monograph. 2011 Merck Canada.
Kiser JJ et al. Hepatology 2012551620-1628.
34
Antipsychotics
  • No formal drug interaction studies
  • Predictions must be made based on knowledge of
    clinical pharmacology of each agent
  • Quetiapine ? metabolized solely by CYP3A4
  • Avoid with BOC and TPV when possible
  • Aripiprazole ?
  • Reduce by half when TPV or BOC are initiated and
    titrate antipsychotic dose to effect
  • Risperidone ? Co administration has not been
    studied but may ? risperidone concentrations. 

Kiser JJ et al. Hepatology 2012551620-1628.
35
PIs and Steroids
BOC TPV
BOC inhaled budesonide and fluticasone ?
budesonide ? fluticasone resulting in
significantly reduced serum cortisol
concentrations Dexamethasone BOC ? BOC,
dexamethasone CYP3A4/5 inducer May result in
loss of therapeutic effect, avoid this
combination if possible and use with caution if
necessary
Victrelis Triple monograph. 2011 Merck Canada.
hep-druginteractions.org/
36
Antimigraine Agents
Ergots Potential for acute ergot toxicity
characterized by peripheral vasospasm and
ischemia of the extremities and other
tissues. Rizatriptan Co administration has not
been studied but, based on metabolism and
clearance, a clinically significant interaction
is unlikely. Eletriptan CONTRAINDICATED with
TPV due to potential for coronary artery
vasospasm, transient MI, MI, ventricular
tachycardia, and ventricular fibrillation
Victrelis Prescribing Information, Merck Co
Inc, May 2011.
hep-druginteractions.org
37
Oral Contraceptives
BOC TPV
Ethinyl estradiol ? AUC by 25 ? AUC by 25 TPV ? ethinyl estradiol levels ? ? FSH, LH ? ? endogenous progesterone levels ?loss of contraception efficacy
Progesterone component ? drosperinone AUC and Cmax by 99 and 57 resp. Progestin only contraception is effective, but it is difficult to know with certainty whether BOC would increase the levels of all progestins or if it is unique to drosperinone May lead to ? adverse effects with increased progestin concs. E.g. hyperkalemia ? norethindrone slightly (11)
BOC Drospirenone contraindicated BOC
Alternative methods of non-hormonal contraception
are recommended.
TPV Alternative methods of contraception should
be used when estrogen-based contraceptives are
coadministered with TPV.
Do not rely on the use of ethinyl estradiol and
progestin-based hormonal contraception during
triple therapy for HCV and for 2 weeks after the
discontinuation of BOC or TPV
Kiser JJ et al. Hepatology 2012551620-1628.
Tseng A. Toronto General Hospital April 24, 2012
38
Antihypertensive Agents
  • ACEI or Diuretics CYP enzymes are not involved
    in the metabolism
  • Drug interactions unlikely
  • B-Blockers Only carvedilol metabolized to some
    extent by CYP3A4
  • ARBS Irbesartan and losartan metabolized by
    CYP3A4
  • Dose reductions could be considered
  • Calcium Channel Blockers Highly reliant on CYP3A
  • Susceptible to increases in exposure from BOC and
    TPV
  • Consider reducing the dose

Kiser JJ et al. Hepatology 2012551620-1628.
39
TPV Amlodipine
Options Decrease amlodipine dose Use
ACE-inhibitor Diuretics
Mean plasma concentration-time profile of
amlodipine following oral administration with and
without telaprevir. Error bars represent the
standard error of the mean.
Lee JF et al. Antimicrob Agents Chemother. 2011
October 55(10) 45694574
40
Source Toronto General Hospital.
http//www.hivclinic.ca/main/drugs_interact_files/
DAA-ARV20int20table_summary.pdf
41
Contraindications to BOC and TPV
Antifungals Use ketoconazole, itraconazole,
posaconazole and voriconazole with caution
42
Thank You!
43
Concomitant Drug Effect on Concentration of BOC or Concomitant Drug Clinical Comment
Efavirenz ? BOC ? efavirenz ? plasma conc. of BOC (Cmin 44 ?) Clinical outcome has not been directly assessed
Tenofovir ? BOC ? Tenofovir ? plasma conc. of BOC (Cmax 32 ?) Changes were not considered clinically significant and no dose adjustment required
Ritonavir ? BOC ? or ? HIV PIs (Cmax 27 ?) Changes were not considered clinically significant and no dose adjustment required. Effect of ritonavir-boosted HIV PI on BOC unknown. Effect of BOC on HIV PI concs. is unknown.
44
Immunosuppresants
  • BOC and TPV slow the clearance of cyclosporine
    and tacrolimus
  • Sirolimus expected to behave similarly to
    tacrolimus, but has not been studied
  • Cyclosporine may be preferred to tacrolimus in
    the setting of TPV or BOC based HCV treatment,
    but it may still be possible to use tacrolimus in
    a very controlled manner
  • If patient is on cyclosporine, consider
    empirically reducing cyclosporine dose by 75
    empirically
  • Then use TDM to further refine the cyclosporine
    dose and frequency
  • Another option Hold doses of cyclosporine and
    tacrolimus after TPV or BOC have been introduced
    and redose when concentrations are in desired
    range
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