To Use Them Together or Not
Understanding Drug Interactions With HCV Medications
Rajwant Minhas, FH Resident
HIV/AIDS Rotation
May 2012
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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
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Drug-Time Concentration Curve
Source: http://www.skepticnorth.com/2012/01/generic-drugs-should-we-be-skeptical/
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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
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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
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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
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CYP450
• The P450 cytochromes chemically
oxidize or reduce drugs
• > than 25 human cytochrome P450’s
• 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
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CYP450 System
Badea G. Drug Metabolism. Feb 2007
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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/images/nrc823-f3.gif
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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
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Badea G. Drug Metabolism. Feb 2007
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
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Lexicomp.
Kiser JJ et al. Hepatology 2012;55:1620-1628.
But How Do I Find All This
Information?
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hep-druginteractions.org/
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BOC and TVR Pharmacokinetics
• BOC: Metabolized by CYP3A4, CYP3A5
and aldoketoreductases
– Strong reversible inhibitor of CYP3A4 and pglycoprotein
– Protein binding 75%
• TPV: Substrate and strong inhibitor of
CYP3A4 and p-glycoprotein
– Protein binding 59-76%
Kiser JJ et al. Hepatology 2012;55:1620-1628.
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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 2012;55:1620-1628.
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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 2012;55:1620-1628.
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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
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Hep-druginteractions.org
Tseng A. Toronto General Hospital April 24, 2012
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.
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Lee JE et al. Antimicrob Agents Chemother. 2011 October; 55(10): 4569–4574.
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Opioid Replacements
Methadone and buprenorphine: Do not inhibit or induce CYP enzymes
Methadone
Buprenorphine
•85% plasma protein bound
96% plasma protein bound
•Metabolized by CYP3A, 2C8 and glucuronidation
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
TPV: No effect on buprenorphine
pharmacokinetics
BOC Monograph: ↑ or ↓ buprenorphine
Clinical monitoring recommended
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Kiser JJ et al. Hepatology 2012;55:1620-1628.
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
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Antidepressants
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hep-druginteractions.org/
Antidepressants
Escitalopram
CYP2C19 with a
minor contribution by
CYP3A4 and CYP2D6
BOC
TPV
↔ BOC
? ↓ vs ↔ Escitalopram
Conflicting reports
↔ TPV
↓ Escitalopram
Wide therapeutic index but
dose may need to be adjusted
Desipramine
↑ Desipramine
Trazodone
↑ 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 31
Kiser JJ et al. Hepatology 2012;55:1620-1628.
March-3 April 2011
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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)
↑ alprazolam
Midazolam (IV)
↑ midazolam
Triazolam (IV)
↑ triazolam
Kiser JJ et al. Hepatology 2012;55:1620-1628.
• 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.
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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 2012;55:1620-1628.
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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/
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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
hep-druginteractions.org
Victrelis Prescribing Information, Merck & Co Inc, May 2011.36
Oral Contraceptives
Ethinyl
estradiol
BOC
TPV
↓ AUC by ~25
↓ AUC by ~25%
TPV: ↓ ethinyl estradiol levels  ↑ FSH,
LH  ↓ endogenous progesterone levels
loss of contraception efficacy
BOC + Drospirenone = contraindicated
BOC: Alternative methods of nonhormonal contraception are
recommended.
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%)
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
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Tseng A. Toronto General Hospital April 24, 2012
Kiser JJ et al. Hepatology 2012;55:1620-1628.
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
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Kiser JJ et al. Hepatology 2012;55:1620-1628.
TPV + Amlodipine
Options:
Decrease
amlodipine dose
Use ACEinhibitor
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): 4569–4574
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Source: Toronto General Hospital. http://www.hivclinic.ca/main/drugs_interact_files/DAA-ARV%20int%20table_summary.pdf
Contraindications to BOC and TPV
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Antifungals: Use ketoconazole, itraconazole, posaconazole and voriconazole with caution
Thank You!
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