1. Protease Inhibitors in Chronic Hepatitis C: An Update
Chapter 2 – Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection
Edited by
Morris Sherman MD BCh PhD FRCP(C)
Associate Professor of Medicine
University of Toronto
November 2012

2. Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection
Alice Tseng, Pharm.D., FCSHP, AAHIVP
Toronto General Hospital
University of Toronto

3. Outline Review principles of drug interactions
Understand how the pharmacology of DAAs contribute to drug interactions
Highlight important HCV drug interactions
Outline a strategy for identifying and managing drug interactions
Identify pertinent HCV drug interaction resources

4. Drug Interactions Pharmacodynamic
Change in pharmacological effect of a drug
Additive, synergistic, or antagonistic activity or toxicity
e.g., ribavirin + AZT =  anemia
Pharmacokinetic
Change in the amount of drug(s) in body
Absorption, distribution, metabolism, elimination may be affected
Often involves CYP450 system or transporters
Drug interactions may be classified as being either pharmacokinetic or pharmacodynamic in nature.
With pharmacodynamic interactions, additive, synergistic, or antagonistic drug combinations may affect parameters of pharmacological response, including efficacy and toxicity.
Pharmacodynamic drug–drug interactions may be beneficial, when agents with complementary mechanisms of action (eg, reverse transcriptase inhibitors plus PIs or NNRTIs) are administered to enhance clinical efficacy. In contrast, certain combinations may be undesirable if antagonism or additive toxicity occurs. For example, lamivudine and zalcitabine have been shown to negatively interact in vitro, likely via competition for intracellular phosphorylation, and thus should not be coadministered. Similar concern exists regarding the combination of zidovudine and stavudine.
With pharmacokinetic interactions, absorption, distribution, metabolism, or elimination may be affected, resulting in an alteration of the amount and/or concentration of one or both agents in the body. Sometimes this is desirable if the pharmacokinetic profile of a drug is improved. On the other hand, certain interactions may be undesirable when the disposition of an agent with a narrow therapeutic index is affected. 4

5. Interactions Affecting Drug Metabolism
Majority of drugs transformed to inactive forms prior to elimination through Phase I (oxidation) or Phase II (conjugation) reactions
Phase I primarily involves cytochrome P450 system
Superfamily of microsomal heme-containing enzymes
Primarily located in liver, small bowel; also kidney, lung, brain
CYP3A is the most abundantly expressed isoenzyme, is involved in the metabolism of ~50% of clinically used drugs
others: CYP2D6, 2C9, 2B6, 1A2, etc.
P-glycoprotein
Efflux membrane transporter which prevents drug accumulation in cells; has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure
Many drugs that are administered orally are fat-soluble. This is a desirable characteristic for oral absorption because lipophilic agents can passively diffuse through membranes of the gut, whereas drugs that are not lipophilic pass unaltered through body in the stool.
However, once lipophilic drugs are absorbed, they circulate in blood bound to plasma proteins, or are sequestered in fat; thus, they are not readily excreted by the kidney into the urine. Therefore, to eliminate these agents, they are converted in the body to more water-soluble metabolites which can then be excreted by the kidney. The majority of these conversions occur in the liver, via phase I and phase II reactions.
Phase I reactions are the most common, and involve the cytochrome P450 system.
The cytochrome P450 system is a superfamily of microsomal heme-containing enzymes which chemically oxidize or reduce drugs and endogenous substances such as steroid hormones, fatty acids, and prostaglandins. CYP450 enzymes are present in high concentrations in the liver; they are also present in lower concentrations in other areas of the body, including the gastrointestinal tract, kidneys, lungs, and brain. The presence and amount of certain CYP isozymes may also vary between individuals (ie, genetic polymorphism).
Classified into families, subfamilies, and individual enzymes
– families: all members have >40% identity in amino acid sequences (indicated by a number)
– subfamilies: amino acid sequences are >55% identical (indicated by letter)
– individual enzymes within a subfamily (indicated by number).
To date, at least 14 families, 22 subfamilies, and 36 CYP enzymes have been identified in human beings.
Of these, only 3 families (CYP1, CYP2, CYP3) are currently thought to be responsible for the majority of hepatic drug metabolism.
CYP3A is the most abundantly expressed isoenzyme and is involved in the metabolism of about 50% of clinically used drugs
P-glycoprotein (P-gp) is an ATP-dependent, efflux membrane transporter. Originally detected in numerous tumour cell types, and implicated in the role of multidrug resistance (MDR). P-gp expels drug from cells, resulting in decreased intracellular drug concentrations, and consequently decreased antitumour activity. In addition, P-glycoprotein is present in tissues:
– epithelial cells of the gastrointestinal tract, liver, and kidney
– expressed at level of the blood-brain barrier
– also noted in subsets of CD4+ T lymphocytes.
P-gp has broad substrate specificity, and appears to play a role in the transport of many natural substances and xenobiotics, resulting in:
– decreased drug absorption (gastrointestinal tract)
– enhanced elimination into bile (liver) and urine (kidney)
– prevention of drug entry into the central nervous system (blood-brain-barrier).
P-Glycoprotein has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure.
– oral absorption: oral bioavailability may be limited by the presence of CYP3A4 in the GI tract and liver (first-pass effect), as well as P-gp, which may transport absorbed drug back into the intestinal lumen.
– CNS exposure: in addition to other factors such as lipophilicity, plasma protein binding, molecular weight, and concentration, P-gp may play a significant role in limiting drug penetration into the brain.
Examples of P-gp inducers: phenobarbital, phenytoin, rifampin, St John’s wort
Examples of P-gp inhibitors: erythromycin, clarithromycin, diltiazem, felodipine, intraconazole, ketoconazole, nicardipine, grapefruit, HIV protease inhibitors, HCV protease inhibitors
References:
Kashuba ADM, Bertino JS Jr. Mechanisms of drug interactions I. In: Piscitelli S, Rodvold K, eds. Drug Interactions in Infectious Diseases, 2nd edition. New Jersey: Humana Press.  2005, pp
Metheny CJ, Lamb MW, Brouwer KLR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001;21: 5

6. Terms Definition Interaction Impact Common Examples Substrate
Agent which is primarily cleared via a certain enzymatic pathway
Rate of drug breakdown is affected by presence of enzyme inhibitors or enzyme inducers
antidepressants, azoles, benzodiazepines, statins, corticosteroids, calcium channel blockers, macrolides, rifamycins, HIV PIs & NNRTIs
Inhibitor
Agent which competes with another drug for binding at enzymatic site
Decreased clearance of substrate drug; quick onset & resolution of interaction effect
macrolides, azoles, HIV protease inhibitors
Inducer
Drug that stimulates the production of additional metabolic enzymes
Increased clearance of substrate drug; slower onset and resolution of interaction effect
anticonvulsants, rifamycins, HIV NNRTIs, St. John’s wort
A substrate is any drug that is metabolized by one or more of the P450 enzymes or other transporter systems.
The majority of metabolized drugs are substrates for the CYP3A4 enzyme.
Examples of CYP3A4 substrates include: anti-infectives (macrolides, azoles, rifamycins, many antiretrovirals), benzodiazepines, antidepressants, anticonvulsants, statins, calcium channel blockers, corticosteroids, etc.
A P450 enzyme inhibitor is any drug that inhibits the metabolism of a P450 substrate.
This inhibition process is generally competitive in nature (ie, the inhibitor competes with a substrate for binding at the enzyme’s binding site), and is reversible. Competitive inhibition depends upon:
– the affinity of the substrate for the enzyme being inhibited
– the concentration of substrate required for inhibition
– the half-life of the inhibitor drug
This competitive mechanism results in accumulation of the target drug (substrate).
Inhibition interactions usually occur rapidly, ie, within a few doses, once sufficient concentrations of the inhibiting agent are present in the liver.
These interactions also tend to resolve quickly once the offending agent (inhibitor) is removed.
NB: a drug does not necessarily need to be a P450 substrate to be an enzyme inhibitor (eg, fluconazole is primarily excreted renally, but is a moderate to weak P450 inhibitor).
Common classes of inhibitors include macrolide antibiotics, azole antifungals, HIV protease inhibitors.
Another, less common mechanism of inhibition is noncompetitive; this can occur as a result of inactivation of the enzyme. The duration of this type of inhibition may be longer if new enzymes need to be synthesized after removal of the inhibitor drug.
An enzyme inducer stimulates the production of more P450 enzymes. It does this by binding directly to promoter elements in the DNA region, resulting in an increase in P450 transcription (ie, increasing messenger RNA), and subsequently increasing the amount of enzymes present. The presence of these additional enzymes results in a net increase in metabolic activity; the body is able to eliminate substrates more quickly, which results in a net reduction in substrate concentrations. Unlike inhibition, induction persists for several days, even after the inducing drug is gone. This is because the enzymes persist for several days following induction. Enzyme induction is also influenced by age and liver disease. For instance, elderly patients, or those with cirrhosis or hepatitis may be less susceptible to enzyme induction.
Inducers may also vary by specificity and potency:
– Some inducers are able to influence several types of enzymes.
– Inducers also affect enzyme activity to varying degrees. For example, rifampin is a more potent inducer than rifabutin and, as such, substrate levels are more likely to be reduced to a greater extent in the presence of rifampin vs. rifabutin.
Common classes of inducers include anticonvulsants, rifamycins, and HIV non-nucleoside reverse transcriptase inhibitors.
It should be noted that herbal/complementary agents can also be associated with pharmacokinetic interactions.
St. John’s Wort is a popular remedy for treatment of mild-to-moderate depression. However, St. John’s wort is a potent inducer of CYP3A4, and can cause significant drug interactions. It is contraindicated in patients taking either boceprevir or telaprevir.
In contrast to enzyme inhibition interactions, enzyme induction interactions generally have a slower onset and resolution of effect.
Enzyme induction interactions do not usually become apparent for a week or more, since the enzyme inducer must first reach steady state, and new drug metabolizing enzymes need to be synthesized. Usually, maximum induction effect is attained after approximately 2 weeks. Similarly, once the inducing agent is removed, the interaction may take a few weeks to resolve (time for the inhibitor to be cleared, and for enzymes to degrade).
References
1. Food and Drug Administration. Risk of drug interactions with St. John’s wort. JAMA 2000;283:1679. 6

7. Boceprevir and Telaprevir Pharmacology
Dosing
800 mg q8h with food
750 mg q8h with food (20 g fat)
Substrate
CYP3A4, P-gp, AKR
CYP3A4, Pgp
Inhibitor
3A4, P-gp
3A4, P-gp, renal transporters (?)
Inducer
No inducing effects in vitro (in vivo?)
Boceprevir and telaprevir are substrates and inhibitors of CYP3A4. Boceprevir is also metabolized via aldoketoreductases, but this appears to be a minor pathway.
Both agents also inhibit p-glycoprotein and telaprevir may inhibit renal transporters. Boceprevir and telaprevir have not demonstrated enzyme inducing activity in vitro.
Maintaining adequate plasma concentrations is important for directly acting antiviral agents. These drugs have short half-lives, and thus must be taken at regular (every 8 hours) dosing, with the proper amount of food for in order to be adequately absorbed. Use of other agents which inhibit or induce CYP3A4 and/or p-glycoprotein can result in altered plasma concentrations of DAAs.
Many phase 3 HCV agents are also substrates of CYP450, P-gp, and/or other transporters, and may also possess inhibiting or inducing properties.
Therefore, there is a high potential for interactions between current and future directly acting antiviral agents and other drug classes.
These interactions may be clinically significant, complex, and sometimes unpredictable.
= +++ potential for interactions with other drugs
can be clinically significant
sometimes unpredictable 7

8. Potential Consequences of DAA Drug Interactions
Interactions may occur in a two-way manner:
Concentrations of DAA may be altered by other drug(s)
Concentrations of concomitant drug(s) may be altered by DAA
Potential consequences include:
Increased risk of toxicity
Decreased efficacy
Maintenance of adequate drug concentrations is necessary to achieve optimal virological benefit. The use of interacting drugs which inhibit or induce CYP3A4 and/or p-glycoprotein can result in altered plasma concentrations of DAAs. Potential consequences of drug interactions include:
Increased risk of toxicity. Increased drug concentrations may increase the risk of dose-related side effects. This in turn may lead to decreased quality of life, risk of non-adherence, or dose reduction or even premature drug discontinuation.
Decreased antiviral efficacy. Decreased drug concentrations may lead to suboptimal disease/symptom control, inadequate viral suppression, development of drug resistance, incomplete treatment response or disease progression. Given the fact that there may be cross-resistance between not only current but also future DAAs in development, current as well as future HCV treatment options may be compromised.
It is important to note that interactions may occur in a two-way manner with DAAs, since they are both substrates and inhibitors of CYP3A4 and p-glycoprotein.
In other words, DAAs can increase concentrations of other drugs, which may lead to increased risk of toxicity.
In turn, other drugs can either increase or decrease concentrations of DAAs, which may lead to either increased risk of toxicity or decreased antiviral efficacy.
The clinical significance of an interaction will depend upon several factors, including:
– the magnitude of change in pharmacokinetic parameters
– the efficacy and toxicity of the affected agent(s).
the nature/severity of the disease(s) being treated 8

9. Statin Interactions Most statins are P450 substrates
DAAs can significantly increase statin levels:
Atorvastatin: 130%  with boceprevir, 7.88-fold  with telaprevir
Pravastatin: 60%  with boceprevir
 risk of toxicity, including myopathy and rhabdomyolysis
Boceprevir
Telaprevir
Lovastatin, Simvastatin
CONTRAINDICATED
Atorvastatin
May need to  atorvastatin dose; do not exceed >20 mg/d
CONTRA- INDICATED
Pravastatin
Start with recommended dose and monitor for toxicity.
Possible  in statin; use with caution.
Rosuvastatin, Fluvastatin
Possible  in statin; use with caution.
Atorvastatin – Lipitor; lovastatin – Mevacor; simvastatin – Zocor; rosuvastatin – Crestor; pravastatin – Pravachol; fluvastatin – Lescol
pitavastatin – Livalo (N/A in Canada) – via UGT
Most statins are substrates of the P450 system, primarily CYP3A4. However, there are some within-class differences:
atorvastatin, lovastatin, simvastatin: CYP3A4
rosuvastatin: <10% metabolized; 2C9, 2C19, Pgp?
pravastatin: % Clrenal; CYP3A(?), OATP1B1, OATP2B1
fluvastatin: CYP2C9 >>3A4 (minor)
Boceprevir and telaprevir can significantly increase concentrations of statins, which can lead to increased risk of toxicity including myopathy and rhabdomyolysis.
Atorvastatin 40 mg + boceprevir:
atorvastatin AUC  130% and Cmax  170% vs atorvastatin alone
Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin
Pravastatin 40 mg + boceprevir:
pravastatin AUC  60% and Cmax  50% vs. pravastatin alone
Can initiate pravastatin at the recommended dose when co-administered with BOC, with close clinical monitoring
Atorvastatin 20 mg+ telaprevir:
In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, atorvastatin Cmax  10.6-fold and AUC  7.88-fold.
Atorvastatin, lovastatin and simvastatin are contraindicated with telaprevir.
In March 2012, the FDA issued a Drug Safety Communication regarding the risk of increased toxicity with statins when combined with either HIV or HCV protease inhibitors. The product monographs were subsequently updated to reflect these dosing recommendations.
References:
Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother 2011;55(10):
Hulskotte EGJ, Gupta S, Xuan F, et al. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin [abstract 122]. HEP DART, December 4-8, 2011, Koloa, Hawaii.
U.S. Food and Drug Administration. HIV/AIDS Update - Important info about interactions between certain HIV drugs and cholesterol-lowering statin drugs. March 1, 2012.
[Victrelis & Incivek Product Monographs, FDA HIV/AIDS Drug Safety Communication, March 1, 2012] 9

10. Atorvastatin Interactions with Boceprevir and Telaprevir
Atorvastatin 40 mg + boceprevir:
Atorvastatin AUC  130% and Cmax  170% vs. atorvastatin alone
Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin
Atorvastatin 20 mg + telaprevir:
Atorvastatin AUC  7.88-fold
Combination is contraindicated
30,000
100
25,000
Atorvastatin alone
Atorvastatin + Boceprevir
10.0
20,000
With telaprevir
Atorvastatin concentration (pg/mL)
15,000
Concentration (ng/mL)
1.00
10,000
Without telaprevir
0.10
5,000
0.01
Boceprevir and telaprevir can significantly increase concentrations of statins, which can lead to increased risk of toxicity including myopathy and rhabdomyolysis.
Atorvastatin 40 mg + boceprevir:
atorvastatin AUC  130% and Cmax  170% vs. atorvastatin alone
Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin
Pravastatin 40 mg + boceprevir:
pravastatin AUC  60% and Cmax  50% vs. pravastatin alone
Can initiate pravastatin at the recommended dose when co-administered with BOC, with close clinical monitoring
Atorvastatin 20 mg+ telaprevir:
In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, atorvastatin Cmax  10.6-fold and AUC  7.88-fold.
Atorvastatin, lovastatin and simvastatin are contraindicated with telaprevir.
In March 2012, the FDA issued a Drug Safety Communication regarding the risk of increased toxicity with statins when combined with either HIV or HCV protease inhibitors. The product monographs were subsequently updated to reflect these dosing recommendations.
References:
Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother 2011;55(10):
Hulskotte EGJ, Gupta S, Xuan F, et al. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin [abstract 122]. HEP DART, December 4-8, 2011, Koloa, Hawaii.
U.S. Food and Drug Administration. HIV/AIDS Update - Important info about interactions between certain HIV drugs and cholesterol-lowering statin drugs. March 1, 2012. 8 16 24 32 40 48 10 20 30 40 50
Time (hrs)
Nominal time (hrs)
Hulskotte EGJ et al. HEP DART 2011,
Koloa, Hawaii, poster 122
Lee JE et al. Antimicrob Agents Chemother 2011, 55(10): 10

11. Concentration (ng/mL)
Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg
5.00
Calcium channel blockers (CCBs)
Amlodipine, diltiazem, felodipine, nifedipine, nicardapine, verapamil are CYP3A4 substrates
Concentrations may be  by boceprevir or telaprevir
Use with caution, clinical monitoring
Consider dose reduction
With telaprevir
0.50
Concentration (ng/mL)
Without telaprevir
0.05
In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, amlodipine Cmax  27% and AUC  179%. Monitor for dose-related amlodipine toxicity when coadministering with telaprevir.
Calcium channel blockers are CYP3A4 substrates, and drug concentrations may be increased in the presence of boceprevir or telaprevir. Caution is warranted and clinical monitoring of patients is recommended if concomitant therapy is required.
References:
Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother 2011;55(10):
Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.
Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011.
0.01 50
100
150
200
250
Nominal time (hrs)
Amlodipine AUC  179%
Monitor for dose-related toxicity
Lee JE et al. Antimicrob Agents Chemother 2011, 55(10): 11

12. Antihypertensive Medications
Class
Examples
Potential DAA Interactions
ACEI
Enalapril, lisinopril, ramipril (renal)
Not expected
ARBs
Losartan (2C9>>3A4 to active metabolite)
Candesartan, irbesartan (2C9)
Eprosartan, olmesartan, telmisartan, valsartan (biliary)
Possible  effect
Low
Beta- blockers
Propranolol (2D6, 3A4, 2C19), carvedilol (2D6, 2C9> 1A2, 2E1, 3A4)
Acebutolol, labetalol, metoprolol, pindolol (2D6)
Atenolol, nadolol (renal)
Possible 
Calcium channel blockers
Amlodipine, diltiazem, felodipine, nifedipine, verapamil (3A4)
Risk of  CCB exposures; use with caution
Diuretics
Hydrochlorothiazide, furosemide, spironolactone (renal)
Indapamide (2C9, 2D6, 3A4)
Calcium channel blockers are CYP3A4 substrates, and drug concentrations may be increased in the presence of boceprevir or telaprevir. Caution is warranted and clinical monitoring of patients is recommended if concomitant therapy is required. Calcium channel blocker dose reduction may be necessary.
Pharmacokinetic interactions are not expected with ACE inhibitors, most diuretics, and most beta-blockers which are excreted by the kidneys. Exceptions include the diuretic indapamide, and the beta-blockers propranolol and carvedilol, which are metabolized through a variety of CYP450 pathways including 3A4. These particular agents have not been studied with boceprevir or telaprevir, and the clinical significance of coadministration is unknown, since CYP3A4 is one of many isozymes involved in drug metabolism. Nevertheless, caution is warranted with these combinations. Clinicians may wish to consider initiating therapy with lower doses of these agents if patients are receiving DAAs.
Most angiotensin II receptor blockers (ARBs) are not metabolized by CYP450 enzymes and undergo biliary excretion, and hence are not predicted to interact with DAAs. In contrast, losartan is primarily converted to its active metabolite, E-3174 by 2C9 and to a lesser extent by 3A4; as such, there is a potential risk of interaction with DAAs, where reduction in formation of the metabolite and hence decreased effect may occur. Candesartan and irbesartan are substrates of 2C9, and the potential for pharmacokinetic interactions with DAAs is low.
References:
Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012;55:
Peyriere H, Eiden C, Macia J-C, Reynes J. Antihypertensive drugs in patients treated with antiretrovirals. Ann Pharmacother 2012;46:703-9. 12

13. Treatment of Depression in HCV
Place in Therapy
Examples (route of metabolism)
Potential DAA Interactions
First Line
Escitalopram, citalopram (2C19, 3A4>>2D6)
35%  with TVR, no interaction with BOC
Second Line
Paroxetine, fluoxetine (2D6), bupropion (2B6)
Sertraline (2B6>2C9/19, 3A4, 2D6), venlafaxine (2D6>3A4), desvenlafaxine (UGT>>3A4), mirtazapine (2D6, 1A3, 3A4)
Low
Possible 
Third Line
Nortriptyline (2D6)
Imipramine (2D6, 1A2, 2C19, 3A>UGT)
No Evidence
Modafinil (3A4; induces 3A4)
Amantadine (not metabolized)
Possible ;  DAA
Not expected
Avoid
Duloxetine (1A2, 2D6) - CONTRAINDICATED
Additive risk of hepatotoxicity
Patients with HCV may require antidepressant therapy. Escitalopram has been studied with both boceprevir and telaprevir.
In healthy volunteers, the kinetics of single dose escitalopram 10 mg were not altered to a clinically significant manner in the presence of multiple dose boceprevir 800 mg TID. The pharmacokinetics of boceprevir were similar with and without coadministration of escitalopram. No dosage adjustment is expected to be required with coadministration of this combination.[Hulskotte et al. 2011]
In healthy volunteers, coadministration of escitalopram 10 mg daily with telaprevir 750 mg q8h for 7 days resulted in 35%  escitalopram AUC, while telaprevir exposures were not affected. The dose of escitalopram may need to be titrated according to clinical response. [Van Heeswijk et al. 2010]
Antidepressants that are primarily metabolized by CYP pathways such as 2D6 or 2B6 (e.g., bupropion, paroxetine, fluoxetine, nortriptyline) are considered to be at low risk for pharmacokinetic interactions with boceprevir or telaprevir. Drugs which are metabolized through a variety of CYP isozymes including 3A4 (e.g., desvenlafaxine, sertraline, venlafaxine, mirtazapine, imipramine) may theoretically be at risk of pharmacokinetic interactions with boceprevir or telaprevir, but the clinical significance is not known since these particular combinations have not been studied, and CYP3A4 may play a relatively minor role in metabolism of these agents. Close monitoring of patients who require concomitant therapy with antidepressants and HCV treatment is recommended.
Duloxetine is contraindicated in patients with any liver disease resulting in hepatic impairment because of the risk of hepatotoxicity.
References:
de Knegt RJ, Bezemer G, Van Gool AR, et al. Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C. Aliment Pharmacol Ther 2011;34:
Eli Lilly Canada Inc. Cymbalta (duloxetine) Product Monograph, Toronto, ON, November 6, 2011.
Hulskotte EGJ, Gupta S, Xuan F, et al. Coadministration of the HCV protease inhibitor boceprevir has no clinically meaningful effect on the pharmacokinetics of the selective serotonin reuptake inhibitor escitalopram in healthy volunteers [abstract]. HEP DART, December 4-8, 2011, Koloa, Hawaii.
McNutt MD, Liu S, Manatunga A, et al. Neurobehavioral effects of interferon-α in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology 2012;37:
Ramasubbu R, Taylor VH, Samaan Z, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and select comorbid medical conditions. Annal Clin Psychiatry 2012;24:
Van Heeswijk RPG, Boogaerts G, De Paepe E, et al. The pharmacokinetic interaction between escitalopram and the investigational HCV protease inhibitor telaprevir [abstract 12]. 5th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 23-24, 2010, Boston, MA. 13

14. Methadone Interactions
Methadone is metabolized by CYP2B6, CYP2C19 & CYP3A, 85% protein bound; R-isomer is biologically active enantiomer
Boceprevir interaction:
In the presence of steady-state boceprevir, R-methadone AUC  16%, Cmax  10%; no clinical effects noted including opioid withdrawal
Boceprevir exposures not affected by methadone
Telaprevir interaction:
In the presence of steady-state telaprevir, R-methadone Cmin  31%, Cmax  21% and AUC  21%, but median unbound Cmin of R-methadone was similar before and during telaprevir coadministration and no withdrawal symptoms were noted
A priori methadone dose adjustments are not required when initiating DAA therapy, but close monitoring is recommended, with methadone dose adjustments if necessary
Methadone does not induce or inhibit CYP450 isoenzymes, so would not be expected to affect the pharmacokinetics of other agents including boceprevir and telaprevir.
Methadone is available as a combination of R- and S-isomers, and undergoes N-demethylation primarily via CYP3A4, CYP2B6, and CYP2C19 to inactive metabolites.[1] As such, the pharmacokinetics of methadone may be affected by other drugs which are CYP inducers or inhibitors.
Interaction Study with Boceprevir:
In HCV-negative volunteers on stable, maintenance doses ( mg QD) of methadone, boceprevir 800 mg q8h was coadministered for 6 days. In the presence of boceprevir, exposures of R-methadone were decreased (AUC  16%, Cmax  10%) and S-methadone were decreased (AUC  22%, Cmax  17%). These changes did not result in clinically significant effects including withdrawal. Boceprevir exposures in the presence of methadone were similar to historical controls.  Dose adjustment is likely not necessary when boceprevir is co-administered with methadone.[2]
Clinical monitoring is recommended, with dose adjustments of methadone if necessary during concomitant treatment with boceprevir.
Interaction Study with Telaprevir:
In HCV-negative volunteers on stable methadone maintenance therapy (median methadone dose 85 mg, range mg/day), telaprevir 750 mg q8h was co-administered for 7 days. In the presence of telaprevir, R-methadone Cmin  31%, Cmax  21% and AUC  21%. The AUC ratio of S-/R-methadone was comparable before and during coadministration of telaprevir. The median unbound fraction of R-methadone  from 7.92% to 9.98% during coadministration with telaprevir, but the median unbound Cmin of R-methadone was similar before and during telaprevir coadministration. A priori methadone dose adjustments are not required when initiating telaprevir, but close monitoring is recommended, with dose adjustments if necessary.[3]
References:
1. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 2004;16:36-44.
2. Hulskotte EGJ, Feng H-P, Bruce RD, et al. Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy [abstract PK_09]. 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 27-28, 2012, Cambridge, MA.
3. Van Heeswijk RPG, Vandevoorde A, Verboven P, et al. The pharmacokinetic interaction between methadone and the investigational HCV protease inhibitor telaprevir [abstract PK_18]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA.
Hulskotte et al , Van Heeswijk et al 14

15. Hormonal Contraceptives with DAAs
Hormonal contraceptives may not be as effective in women taking boceprevir or telaprevir
Boceprevir (Victrelis):
99%  AUC drospirenone, 24%  AUC EE
Use 2 alternate effective methods of contraception during treatment with BOC and Peg IFN/RBV
Drospirenone (Yaz®, Yasmin®, Angelique®) is contraindicated
Telaprevir (Incivek):
28%  AUC, 33%  Cmin of EE
Use 2 additional non-hormonal methods of effective birth control during TVR dosing and for 2 months after the last intake of TVR.
Hormonal contraceptives may not be a reliable form of contraception during boceprevir or telaprevir treatment.
Telaprevir:
In the presence of steady-state telaprevir, ethinyl estradiol AUC was reduced 28% and Cmin was reduced 33%.
Therefore, female patients of childbearing potential should use 2 additional non-hormonal methods of effective birth control during telaprevir dosing and for 2 months after the last intake of telaprevir.
Boceprevir:
The results of the drug interaction study between boceprevir 800 mg TID and oral drospirenone/ethinyl estradiol (3 mg/0.02 mg daily) at steady-state demonstrated an increased systemic exposure of drospirenone (AUC, 99 %; Cmax, 57 %) without notably affecting the exposures of ethinyl estradiol (AUC, 24 % ↓, no change in Cmax). Therefore, two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with boceprevir and concomitant PegIFNα/ribavirin.
Co-administration of boceprevir with drospirenone is contraindicated due to the potential for increased drospirenone concentrations and risk of hyperkalemia.
References:
Garg V, Van Heeswijk RPG, Yang Y, et al. The pharmacokinetic interaction between an oral contraceptive containing ethinyl estradiol and norethindrone and the HCV protease inhibitor telaprevir. J Clin Pharmacol 2011;Oct 30 [epub ahead of print].
Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.
Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.
Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011. 15

16. Benzodiazepine Interactions
Majority are substrates of CYP3A4
Risk for prolonged/excessive sedation
Oral midazolam & triazolam are contraindicated with boceprevir and telaprevir
IV midazolam: consider  dose, close monitoring for respiratory depression or prolonged sedation
Other benzodiazepines:  dose and monitor
Consider using benzodiazepines that are glucuronidated:
Lorazepam, oxazepam, temazepam
The majority of benzodiazepines are substrates of CYP3A4, and hence are susceptible to interactions with CYP3A4 inhibitors.
Significantly elevated benzodiazepine concentrations may result in prolonged or excessive sedative effects.
Midazolam is a CYP3A4 substrate. 5 to 9-fold  AUC with boceprevir or telaprevir using oral midazolam. Therefore, oral midazolam is contraindicated with HCV protease inhibitors.
IV midazolam: 3.4-fold  AUC with telaprevir; no data with boceprevir.
Co-administration with telaprevir should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Alternative options for short-term sedation: lorazepam (Ativan) or propofol (Diprivan)
Triazolam is also contraindicated with boceprevir & telaprevir.
For alprazolam, buspirone, diazepam, flurazepam, nitrazepam, zolpidem, zopiclone, eszopiclone: reduce benzodiazepine dose and titrate according to response.
An alternative is to use a benzodiazepine which undergoes a different route of metabolism. Oxazepam, lorazepam, and temazepam undergo glucuronidation, and may be less susceptible to inhibition interactions with DAAs.
References:
Garg V, Chandorkar G, Farmer HF, et al. Effect of telaprevir on the pharmacokinetics of midazolam and digoxin. J Clin Pharmacol 2012;Jan 26 [Epub ahead of print].
Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.
Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.
Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. 16

17. Inhaled Corticosteroids
Corticosteroids are CYP3A4 substrates
Potential for  corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations
Inhaled/nasal fluticasone, budesonide:
Avoid co-administration with HCV PIs if possible, particularly for extended durations.
May wish to use corticosteroid associated with less adrenal suppression (e.g., beclomethasone, ciclesonide)
Use lowest possible dose, consider non-steroidal options
Corticosteroids are substrates of CYP3A4. Fluticasone has a longer receptor-binding half-life and a higher volume of distribution compared to other inhaled corticosteroids, and hence may be associated with higher rates of adrenal suppression, particularly at increased exposures.
Product Monograph information on inhaled/nasal fluticasone and budesonide:
Potential for  corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations. Avoid co-administration if possible, particularly for extended durations.1
Inhaled beclomethasone or ciclesonide, or intranasal beclomethasone or triamcinolone may be safer alternatives, but caution is still warranted. Use lowest possible corticosteroid dose and monitor closely for systemic corticosteroid side effects.23
Of note: Systemic dexamethasone is a CYP3A4 inducer, and may potentially decrease DAA concentrations. The product monographs recommend avoiding combination if possible, use with caution if necessary.
References:
Foisy MM, Yakiwchuk EMK, Chiu I, et al. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9(6):
Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.
Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011.
Victrelis & Incivek. Product Monographs, 2011 17

18. PDE5 Inhibitors (sildenafil, tadalafil, vardenafil)
PDE5 inhibitors are substrates of CYP3A4
Potential for DAAs to  concentrations
Dose-related side effects (headache, vasodilation, dyspepsia, visual disturbances)
Contraindicated with DAAs if using for PAH
For erectile dysfunction, use a lower dose with DAAs:
Sildenafil: 25 mg q48h, tadalafil: 10 mg q72h
Do not use vardenafil
Sildenafil, tadalafil and vardenafil are oral phosphodiesterase inhibitors approved for the treatment of erectile dysfunction.
Sildenafil and tadalafil are also approved for the treatment of pulmonary arterial hypertension.
PDE5 inhibitors are substrates of CYP3A4. DAAs may potentially increase PDE5 inhibitor concentrations, which may increase the risk of dose-related side effects including headaches, vasodilation, dyspepsia and visual disturbances.
Vardenafil should not be used with either boceprevir or telaprevir.
Sildenafil and tadalafil are contraindicated with DAAs if used for management of pulmonary arterial hypertension; for management of erectile dysfunction, dosing should be reduced:
sildenafil: 25 mg q48h (usual dose is mg daily)
tadalafil: 10 mg q72h (usual dose is mg daily)
References:
Victrelis Product Monograph, July 2011.
Incivek Product Monograph, August 2011. 18

19. Interactions Between HCV & HIV Medications
Challenges in treating HIV/HCV co-infected patients
Additive toxicities:
Anemia: ribavirin, zidovudine, DAAs
CNS: interferon, efavirenz
Potential for negative 2-way interactions
 concentrations of HIV agents
 concentrations of HCV DAAs
Boceprevir and telaprevir are substrates and inhibitors of CYP3A4. Both agents also inhibit p-glycoprotein and telaprevir may inhibit renal transporters. Similarly, HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors are substrates and inhibitors or inducers of numerous CYP450 hepatic enzymes and transporters. The CCR5 inhibitor maraviroc is a CYP3A4 substrate but does not exert inhibiting or inducing effects on the P450 system. Therefore, there is a high potential for drug interactions in the co-infected population, particularly if simultaneous treatment of HCV and HIV is required.
Both antiretrovirals and current HCV treatment have multiple adverse effects. For example, didanosine, stavudine, and zidovudine should be avoided with pegylated interferon and ribavirin because of increased risks of mitochondrial toxicity and anemia. Some controversy exists whether concomitant abacavir may be associated with a reduced response to pegylated interferon and ribavirin, but a recent in vitro study showed that the anti-HCV activity of ribavirin was not modified by abacavir. It is important to achieve adequate ribavirin trough levels via weight-based dosing, and there is insufficient evidence to recommend avoiding this combination. Ribavirin may cause a decrease in the total lymphocyte count, which can affect CD4 cell counts. Therefore, the CD4 percentage, rather than the absolute number, may be a more appropriate measure of immunologic efficacy during ribavirin treatment. Another example is the combination of pegylated interferon and efavirenz, where additive CNS effects including depression, mood changes, and suicidality, may occur.
Pharmacokinetic interactions between directly acting agents and antiretrovirals can result in negative impact on concentrations of DAAs and/or antiretrovirals. As such, these interactions between DAAs and antiretrovirals may limit cART treatment choices, which may be particularly challenging in HIV-treatment experienced patients. If dose modifications are required, such changes may be associated with significant increases in cost. There is also the potential for underdosing of antiretrovirals and/or DAAs, which may lead to treatment failure and development of resistance. Whenever possible, non-essential medications should be discontinued for the duration of HCV treatment.
References:
Tseng A, Foisy M. Important drug-drug interactions in HIV-infected persons on antiretroviral therapy: an update on new interactions between HIV and non-HIV drugs. Curr Infect Dis Report 2012; 14(1):67-82.
Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012;55: 19

20. Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir
Protease Inhibitors (PIs)
Avoid with ritonavir-boosted protease inhibitors
Avoid ritonavir-boosted darunavir, fosamprenavir and lopinavir
Atazanavir/ritonavir OK
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Avoid efavirenz
Dose  with efavirenz
Etravirine (?)
Etravirine OK
No data
Rilpivirine OK
Integrase Inhibitor
Raltegravir OK
Maraviroc
potential / maraviroc; potential benefit on fibrosis?
Nucleoside Reverse Transcriptase Inhibitors
Tenofovir OK
Avoid AZT (anemia)
This table summarizes potential and demonstrated pharmacokinetic interactions between ARVs and DAAs.
Negative two-way interactions have been observed between both boceprevir and telaprevir and ritonavir-boosted protease inhibitors, with significant reductions in exposures of HCV agents and HIV protease inhibitors. Therefore, telaprevir should not be coadministered with ritonavir-boosted darunavir, fosamprenavir, or lopinavir,15 and boceprevir is not recommended for use with boosted atazanavir, darunavir or lopinavir.16
With NNRTIs, telaprevir may be used at a higher dose with efavirenz,17 and without dosage adjustment with etravirine or rilpivirine.18 In contrast, boceprevir concentrations are significantly reduced in the presence of efavirenz, and this combination should be avoided.19 Recent data indicate etravirine concentrations are reduced in the presence of boceprevir; the clinical significance of this effect is unknown, and formal recommendations on coadministration are currently lacking.20
Raltegravir is not a P450 substrate, inducer or inhibitor, and may be used with both HCV agents without dosage adjustment.21, 22 Tenofovir is eliminated renally; in healthy volunteer studies, tenofovir Cmax was increased in the presence of boceprevir23 and tenofovir AUC was increased in the presence of telaprevir.24 These changes are not considered to be clinically relevant, and tenofovir may be coadministered with both boceprevir and telaprevir.
References:
15. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011.
16. Hulskotte EGJ, Feng H-P, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir [abstract 771LB] 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle, WA.
17. Van Heeswijk RPG, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers [abstract 119]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.
18. Kakuda TN, Leopold L, Nijs S, et al. Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir: a randomised, two-way crossover trial [abstract O_18]. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain.
19. Schering Corporation a subsidiary of Merck & Co. Victrelis (boceprevir) Product Monograph. Whitehouse Station, NJ May, 2011.
20. Hammond K, Wolfe P, Burton J, et al. Pharmacokinetic interaction between boceprevir and etravirine in HIV/HCV seronegative volunteers [abstract O_15]. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain.
21. de Kanter C, Blonk M, Colbers A, et al. The influence of the HCV protease inhibitor boceprevir on the pharmacokinetics of the HIV integrase Inhibitor raltegravir [abstract 772LB]. 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, WA.
22. Van Heeswijk RPG, Garg V, Boogaerts G, et al. The pharmacokinetic interaction between telaprevir and raltegravir in healthy volunteers [abstract A1-1738a]. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2011, Chicago, IL.
23. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.
24. Van Heeswijk R, Gysen V, Googaerts G, et al. The pharmacokinetic interaction between tenofovir disoproxil fumarate and the investigational HCV protease inhibitor telaprevir [abstract A-966]. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 25-28, 2008, Washington, DC. 20

21. Managing Drug Interactions: 1) Medication Reconciliation
Ensure medication records are up to date at each visit
Prescription, OTC, vitamins/herbals, recreational drugs, inhalers, topical, prn agents
Confirm doses, prn drugs
Include all agents that have been started or stopped
Patient education:
Encourage patients to ask before taking any new prescription/non-prescription drug or supplement
Communication with other HCP!
Given the rapid pace of HCV drug development, keeping abreast of potential interactions is an ongoing challenge. It is impossible to analyze all possible drug combinations prior to the licensing of a drug. Consequently, patients may receive combinations of drugs for which pharmacokinetic interaction data are not available. Even when drug interaction data are available for a particular combination, individual patient factors must also be taken into consideration when determining the clinical significance.
Therefore, it is critical to utilize a systematic approach to identifying and managing actual and potential drug interactions in clinical practice.
Steps include:
Medication Reconciliation. In addition to agents for HCV infection, many patients require treatment for concomitant conditions such as including HIV coinfection, psychiatric illness, illicit substance use, cardiovascular comorbidities, or solid-organ transplantation. Patients may also be taking vitamins, food supplements, complementary or alternative medicine (CAM) agents, or recreational agents, either regularly or occasionally. Obtaining an accurate (best possible) medication history through reviews of patient-related documents from GP care, specialist interventions, hospital reports, pharmacy refill records, and patient interview is essential. At each clinic visit, patients should be encouraged to inform staff of drugs that have been started or stopped, or dosages that have been altered. Patients should also be reminded that they should not be given any new drugs (except in an emergency) without checking for potential interactions with their hepatitis medications first. If the physician prescribing the new drug is unfamiliar with DAAs, they should be encouraged to check with the hepatology physician or team.
Patients should be encouraged to inform all health care providers of all the medications they are taking to minimize the risk of inadvertent drug interactions. Communication with all health care providers involved in the care of the patient is critical. Patients are also encouraged to utilize one pharmacy for all their prescriptions in order to facilitate thorough drug reviews by the pharmacist. 21

22. Managing Drug Interactions: 2) Identify Potential Interactions
Use a systematic approach to identify combinations of potential concern
Apply knowledge of known PK characteristics
Overlapping CYP pathways, substrate, inducer, inhibitor
High index of suspicion with key classes of drugs
Utilize current drug information resources:
Product monographs, CPS, literature
Conference abstracts, specialized HCV drug interaction websites
Step 2: Identifying interacting drug combinations.
Familiarity with the basic pharmacokinetic and pharmacodynamic characteristics of the involved agents may help practitioners predict the likelihood of interactions. Boceprevir and telaprevir are substrates of the cytochrome P450 system, and also possess enzyme inhibiting and possibly inducing properties. If concomitant medications are also metabolized by or affect the CYP450 system, then the potential for a pharmacokinetic interaction should be considered.
A high index of suspicion with key classes of drugs should be maintained; the following 2 slides summarize drug classes that are currently contraindicated with boceprevir or telaprevir.
The field of HCV-related drug interactions is growing rapidly, making many of the standard drug information resources such as product monographs and the Compendium of Pharmaceutical Sciences (CPS) out of date. It may also take months for pharmacokinetic studies to be published in the medical literature. Therefore, pharmacists must utilize current sources of information to make an accurate assessment, including conference abstracts and specialized drug interaction websites which are updated on a regular basis. Drug interaction websites with a focus on HCV drug interactions include by the University of Liverpool Pharmacology Group, and by the Toronto General Hospital. 22

23. Drugs Contraindicated with Boceprevir and Telaprevir (1)
1-adrenoreceptor antagonist
Alfuzosin
Hypotension, cardiac arrhythmia
Antiarrhythmics
Quinidine, propafenone, amiodarone.
Flecainide (TVR)
serious/life-threatening cardiac arrhythmia
Antimycobacterials
Rifampin
Loss of virologic response
Ergot derivatives
Acute ergot toxicity
Herbal product
St. John’s wort
Statins
Lovastatin, simvastatin.
Atorvastatin (TVR)
Myopathy including rhabdomyolysis
Neuroleptic
Pimozide
Serious/life-threatening cardiac arrhythmia
Many other drugs from several different classes are at risk of drug interactions with DAAs. The product monographs of boceprevir and telaprevir provide a list of drugs with known or potential CYP3A4 interactions. Examples of interacting drug classes include benzodiazepines (e.g., midazolam), HMG coenzyme A reductase inhibitors (statins), macrolides, antimycobacterials (e.g., rifampin), anticonvulsants, antiarrhythmics, psychotropics, antifungals, erectile dysfunction drugs, antipsychotics, inhaled corticosteroids, calcium channel blockers and more.
References:
Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.
Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011.
Victrelis & Incivek. Product Monographs, 2011 23

24. Drugs Contraindicated with Boceprevir and Telaprevir (2)
PDE-5 inhibitor
Sildenafil.
tadalafil (BOC); vardenafil (TVR)
Visual abnormalities, hypotension, prolonged erection, syncope
Sedatives/ hypnotics
Oral midazolam, triazolam
Increased sedation or respiratory depression
Other
Cisapride, astemizole, terfenadine
Serious/life-threatening cardiac arrhythmia
Anticonvulsants
(BOC)
Carbamazepine, phenytoin, phenobarbital
Loss of virologic response
OC (BOC)
Drospirenone
Hyperkalemia
Aldosterone antagonist (TVR)
Eplerenone
Triptans (TVR)
Eletriptan
Coronary artery vasospasm, MI, vent. tachycardia, VF
The non-sedating antihistamines astemizole (Hismanal) and terfenadine (Seldane) are substrates of CYP3A4. In the presence of CYP3A4 inhibitors, concentrations of these agents are significantly increased, and the risk of dose-related adverse events (including cardiotoxicity) is increased. Similar concern exists for cisapride. Therefore, use of these agents should be avoided in people currently taking medications that inhibit CYP450.
The metabolism of many benzodiazepines may be signficantly reduced by the presence of CYP450 inhibitors. To minimize the risk of excessive sedation, practitioners may wish to consider reducing the benzodiazepine dose, or using an agent with a different metabolic pathway (eg, lorazepam, oxazepam, or temazepam).
Calcium channel blockers are primarily metabolized by CYP3A. Therefore, these agents should be used cautiously with inhibiting agents, to avoid excessive drops in blood pressure.
Many antidepressants are substrates of CYP3A4. They are at risk of interacting with agents that inhibit this isoenzyme; greatest precaution with ritonavir.
References:
Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.
Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA, May, 2011.
Victrelis & Incivek. Product Monographs, 2011 24

25. Managing Drug Interactions: Therapeutic Options
Determine clinical significance
Evaluate therapeutic options:
Alter drug dose/dosing frequency
Substitute with alternate agent
Can any drugs be permanently or temporarily discontinued while on DAA treatment?
Consider patient convenience and cost factors
Patient counselling & close monitoring is critical
Determining clinical significance. The clinical significance of an interaction will depend upon several factors, including:
– the magnitude of change in pharmacokinetic parameters
– the efficacy and toxicity of the affected agent(s)
- the nature and severity of the disease(s) being treated
Evaluating therapeutic options. Management options may vary depending upon a number of factors, including the mechanism and clinical consequences of the interaction, availability of therapeutic alternatives, patient convenience, and cost.
Space dosing times. e.g., to avoid absorption interactions. Can this be done in a practical and/or convenient way for the patient?
Change drug dose or dosing frequency. The potential impact of dosage manipulation on patient adherence should be carefully considered. This in turn may depend upon the drug formulations available, existing pill burden and dosing schedule, and cost. For instance, to adequately adjust for the interaction between telaprevir and efavirenz, telaprevir should be increased to 1125 mg every 8 hours. This results in an increased pill burden and increased drug cost. In such situations, therapeutic alternatives to either efavirenz may need to be considered.
On the other hand, the interaction between sildenafil and boceprevir or telaprevir is more straightforward to manage. The standard sildenafil dose is 50 mg taken as needed approximately minutes before sexual activity, maximum once per day. In the presence of boceprevir or telaprevir, sildenafil dose should be reduced to 25 mg once every 48 hours. A 25 mg tablet formulation of sildenafil is available.
Change agent (eg, change simvastatin to low-dose atorvastatin or rosuvastatin for lipid management). What are the comparative efficacy, side effects, cost, availability, compliance issues, and drug interactions associated with the new agent?
3) Monitor the patient. In all situations, the patient should be counselled and monitored for potential changes in drug efficacy or toxicity.
In certain situations (eg, low likelihood of an interaction occurring, minor or insignificant clinical impact of a potential interaction) the practitioner may wish to maintain the patient’s current regimen and monitor the patient’s condition. Remember the onset of interaction will depend upon the mechanism (inhibition = rapid; induction = gradual); understanding these time frames may be useful when counselling patients on when to expect potential effects. 25

26. Summary
High potential for pharmacokinetic interactions between directly acting antivirals and other drug classes
Consequences may include therapeutic failure and increased toxicity
Often, interactions can be managed, but heightened level of awareness is needed
Use a systematic approach to identify and manage individual drug regimens
Importance of a specialized, inter-disciplinary team including pharmacy 26

27. Additional Resources General Hansten PD. Science Med 1998;16-25.
Kashuba ADM, Bertino JS Jr. Drug Interactions in Infectious Diseases, 2nd edition, c. 2005, pp:13-39.
Metheny CJ et al. Pharmacotherapy 2001;21:
Interactions in HCV and HIV:
Kiser J et al. Hepatology 2012;55:
Tseng & Foisy. Curr Infect Dis Rep 2012;14:67-82.
Internet
Toronto General Hospital Immunodeficiency Clinic;
Liverpool Pharmacology Group;
General
Hansten PD. Understanding drug-drug interactions. Science Med 1998:16-25.
Kashuba ADM, Bertino JS Jr. Mechanisms of drug interactions I. In: Piscitelli S, Rodvold K, eds. Drug Interactions in Infectious Diseases, 2nd edition. New Jersey: Humana Press.  2005, pp
Metheny CJ, Lamb MW, Brouwer KLR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001;21:
Interactions in HCV
Tseng A, Foisy M. Important drug-drug interactions in HIV-infected persons on antiretroviral therapy: an update on new interactions between HIV and non-HIV drugs. Curr Infect Dis Report 2012; 14(1):67-82.
Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012; 55:
Internet
1. Toronto General Hospital Immunodeficiency Clinic; <
2. Liverpool HIVPharmacology Group; < 27

28. For more information visit www.liver.ca or call 1-800-563-5483.
The Canadian Liver Foundation gratefully acknowledges the participating health care professionals for their contributions to this project and for their commitment to the liver health of Canadians.
The Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease.
For more information visit or call
This project made possible through the financial support of Merck Canada Inc. The views, information and opinions contained herein are those of the authors and do not necessarily reflect the views and opinions of Merck Canada Inc.