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Abstract

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

Boceprevir (BOC) and telaprevir (TPV), when added to pegylated interferon and ribavirin for the treatment of chronic hepatitis C virus (HCV) infection, increase the rates of sustained virologic response in treatment-naïve persons to approximately 70%. Though these agents represent an important advance in the treatment of chronic HCV, they present new treatment challenges to the hepatology community. BOC and TPV are both substrates and inhibitors of the hepatic enzyme, cytochrome P450 3A, and the drug transporter, P-glycoprotein, which predisposes these agents to many drug interactions. Identification and appropriate management of potential drug interactions with TPV and BOC is critical for optimizing therapeutic outcomes during hepatitis C treatment. This review highlights the pharmacologic characteristics and drug-interaction potential of BOC and TPV and provides guidance on the management of drug interactions with these agents. (HEPATOLOGY 2012;)

The hepatitis community has eagerly awaited regulatory approval of new agents with direct-acting antiviral activity against chronic hepatitis C virus (HCV) infection. In 2011, two inhibitors of nonstructural 3/4A viral protease, boceprevir (BOC) and telaprevir (TPV), reached the market, changing the standard of care for the treatment of chronic HCV to triple therapy with pegylated interferon-alpha (Peg-IFN-α), ribavirin (RBV), and an HCV protease inhibitor. These agents increase the rates of sustained virologic response (SVR) in treatment-naïve patients by 30% when added to Peg-IFN and RBV 1-3 and offer a new treatment option for patients who failed previous therapy. 4, 5 However, because of the clinical pharmacology of these agents, hepatology providers are faced with new challenges in treating persons with HCV. Owing to their short half-lives and insolubility, TPV and BOC require frequent dosing (every 8 hours) with a large number of pills (6 and 12 per day, respectively) in the fed state, which may adversely affect adherence. Additionally, their routes of metabolism and transport predispose them to drug-drug interactions. Herein, we review the pharmacologic characteristics and drug-interaction potential of BOC and TPV and provide guidance on the management of drug interactions with these agents.

BOC

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

When combined with Peg-IFN-α2b and RBV, BOC demonstrated superior efficacy to Peg-IFN-α2b and RBV alone in phase III clinical trials. 1, 4 In trials, the following adverse effects were reported more frequently in patients on BOC, Peg-IFN-α2b and RBV relative to those on Peg-IFN-α2b and RBV alone: fatigue, anemia, nausea, dysgeusia, chills, insomnia, alopecia, neutropenia, diarrhea, decreased appetite, irritability, vomiting, arthralgias, dizziness, dry skin, rash, asthenia, thrombocytopenia, and dyspnea on exertion. 6

BOC is dosed as 800 mg (four 200-mg capsules) every 8 hours. BOC area under the concentration-time curve (AUC) is increased up to 65% in the fed, relative to fasted, state so the drug should be taken with food, but bioavailability is similar whether taken with a high- or low-fat meal. 6 BOC is administered as an approximately equal mixture of two diastereomers, SCH534128 (pharmacologically active) and SCH534129 (inactive), but in plasma, the ratio of active to inactive form is 2:1. 7 BOC is metabolized by aldoketoreductase 1C2 and 1C3 and cytochrome P450 (CYP) 3A (CYP3A). 7 After a single 800-mg oral dose of 14C-BOC, a diastereomeric mixture of ketone-reduced metabolites predominate with a mean exposure approximately 4-fold greater than that of BOC. 6 BOC is a potent inhibitor of CYP3A. 6 BOC is also a substrate and inhibitor of the drug transporter, P-glycoprotein (P-gp). 7 In vitro, at concentrations up to 52,000 ng/mL, BOC did not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. 6 After incubation with 520-52,000 ng/mL of BOC in cultured human hepatocytes, there was little (<2-fold) or no induction of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5. 6 Seventy-nine percent and nine percent of the dose is excreted in the feces and urine, respectively, after a single oral 800-mg dose of 14C-BOC. 6 BOC is 75% protein bound in human plasma. 6 The pharmacokinetics of BOC is shown in Table 1. 6 After a single 400-mg BOC dose, SCH534128 AUC and maximum concentration (Cmax) were increased 32% and 28%, respectively, in those with moderate (Child-Pugh 7-9) and 45% and 62%, respectively, in those with severe hepatic impairment (Child-Pugh 10-12), relative to subjects with no impairment. 6 No dosage adjustment is necessary for patients with renal impairment. BOC AUC is 10% lower in patients with end-stage renal disease requiring hemodialysis. 6

Table 1. Pharmacokinetics of TPV and BOC
 BOC (800 mg Q8H)TPV (750 mg Q8H)
  1. Abbreviations: Q8H, administered every 8 hours; Ctrough, trough concentration; Tmax, time to maximum plasma concentration; CL/F, apparent oral clearance; V/F, volume of distribution; PB, protein binding.

AUC0-8 (ng*hour/mL)5,40822,300
Cmax (ng/mL)1,7233,510
Ctrough (ng/mL)882,030
Tmax (hours)24-5
Half-life (hours)3.49-11
CL/F (L/hour)16132.4
V/F (L)772252
PB (%)7559-76

The BOC half-maximal inhibitory concentration (IC50) in vitro is 100 ng/mL. 7 Early studies (BOC monotherapy or combined with Peg-IFN alone) found BOC pharmacokinetics to be associated with HCV decline. 8 However, a U.S. Food and Drug Administration exposure-response analysis of limited phase III data found no exposure-response relationship between BOC trough or AUC with antiviral activity, but an upward trend of increasing anemia with increasing BOC AUC. The predicted incidence of anemia at the lowest and highest BOC exposure quartiles (3.2 and 6.3 μg·hour/mL) was 43% and 58%, respectively. 7 However, RBV demonstrated a steeper exposure-response relationship with incidence of anemia, compared to BOC. 7

TPV

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

When combined with Peg-IFN-α2a and RBV, TPV demonstrated superior efficacy to Peg-IFN-α2a and RBV alone in phase III clinical trials. 2, 3, 5 In trials, the following adverse effects were reported more frequently in patients on TPV, Peg-IFN-α2a and RBV, relative to those on Peg-IFN-α2a and RBV alone: hyperuricemia, rash, fatigue, thrombocytopenia, pruritus, hyperbilirubinemia, nausea, anemia, diarrhea, lymphopenia, vomiting, hemorrhoids, anorectal discomfort, dysgeusia, and anal pruritus. 9

TPV is dosed as 750 mg (two 375-mg tablets) every 8 hours. TPV (1125 mg twice-daily) dosing demonstrated similar rates of SVR (82.3% versus 82.9%) to thrice-daily dosing in a trial of 161 patients. 10 TPV should be taken with a high-fat (≥20 g) meal or snack for optimal absorption. 11 Examples of foods with at least 20 g of fat are shown in Table 2. 11, 12 TPV interconverts to an R-diastereomer, VRT-127394, which is the major metabolite in plasma and is approximately 30-fold less potent than TPV. 9 TPV's primary route of metabolism is CYP3A, but non-CYP-mediated metabolism may play a role after multiple doses. 9 After a single 14C-TPV 750-mg dose, 82% was recovered in feces, 9% in exhaled air, and 1% in urine. 9 TPV is a substrate and inhibitor of P-gp. 9 TPV is 59%-76% protein, bound primarily to α-1 acid glycoprotein and albumin. 13 The pharmacokinetics of TPV is shown in Table 1. 9 In vitro, TPV did not inhibit CYP1A2, 2C9, 2C19, or 2D6, and the drug has a low potential to induce CYP2C, 3A, or 1A. 9 Relative to participants with no hepatic impairment, TPV AUC and Cmax were reduced 46% and 49%, respectively, in those with moderate (Child-Pugh B) hepatic impairment subsequent to multiple doses of TPV. 14 This is counterintuitive, but has also been observed with the HIV protease inhibitor, ritonavir, and attributed to reduced absorption. 15 Thus, the appropriate dose of TPV in those with moderate or severe hepatic impairment has not been determined. The reduction in TPV AUC and Cmax was less for those with Child-Pugh A hepatic impairment (15% and 10%, respectively), so no dose adjustment is necessary in those with mild hepatic impairment. A single-dose study of TPV in subjects with creatinine clearances less than 30 mL/min found a 10% higher Cmax and 21% higher AUC, compared to those without renal impairment, thus no dosage adjustment is necessary for those with mild, moderate, or severe renal impairment, but TPV has not been studied in persons with end-stage renal disease or those requiring hemodialysis. 9

Table 2. Examples of Foods With at Least 20 g of Fat
Bagel with cream cheese
½ cup of nuts
3 tablespoons of peanut butter
1 cup of ice cream
2 ounces of American or cheddar cheese
2 ounces of potato chips
½ cup of trail mix
1 cup of granola (33 g)
3 slices of homemade French toast
2 cups 3.3% whole milk
2-oz. chocolate candy bar with almonds or peanuts
2 2-oz. plain doughnuts
1 slice pecan pie
1 medium avocado
3.5-oz. lean hamburger in bun
3.5-oz. salami
4 slices of bologna
One 3.5-oz broiled pork chop
Three 3.5-oz. sausage patties
2 cups chow mein noodles
1 7-oz. fried chicken breast
2 small roasted chicken legs

The TPV IC50 value against wild-type HCV is 190 and 241 ng/mL in HCV subtype 1a and 1b replicon assays, respectively. 9 TPV trough concentrations were associated with HCV viral decline in an early study of TPV monotherapy, 16 but higher TPV exposure was only weakly associated with increased SVR in the pivotal trials. TPV exposures were not significantly associated with the development of rash, but were significantly associated with an increased risk of anemia and hemoglobin (Hg) toxicity, defined as Hg less than 10 g/dL or any decrease from baseline of more than 3.5 g/dL. As with BOC, the association between RBV exposures and Hg toxicity was stronger than the association with TPV. 17

Drug Interactions

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

Drug interactions have the potential to increase drug toxicity and/or decrease drug efficacy. For drugs with a narrow therapeutic index (i.e., the range between the minimally efficacious concentration and the maximum tolerable concentration is small), drug interactions can have important clinical implications. There are also patient populations or clinical scenarios where maintenance of adequate drug concentrations is critical to treatment success not only for the HCV drugs a patient may be taking, but also other concomitant medications. For example, in the treatment of persons with human immunodeficiency virus (HIV) coinfection or post-transplantation, maintenance of appropriate antiretroviral and immunosuppressant concentrations, respectively, is a necessity.

Sixty percent of marketed medications are metabolized by CYP3A, 18 so there are many interactions to consider with BOC and TPV, which are both substrates and inhibitors of CYP3A. Studies with CYP3A probes support that many drug interactions with TPV and BOC are mediated by CYP3A. Rifampin, a potent CYP3A inducer, when dosed to steady state, reduced the single-dose TPV AUC and Cmax by 92% and 86%, respectively. 19 Thus, rifampin should not be used with TPV or BOC. Rifabutin at 150 mg daily or every other day is used with ritonavir-boosted HIV protease inhibitors, but requires study with BOC and TPV. Ketoconazole, a potent CYP3A inhibitor, increased single-dose TPV AUC and Cmax by 62% and 24%, respectively, after a single dose of ketoconazole. 19 Single-dose BOC AUC and Cmax were increased 131% and 41%, respectively, when administered after 6 days of ketoconazole at 400 mg twice-daily. 20 Midazolam is a selective CYP3A substrate. BOC increases the AUC0-12 of oral midazolam by 430%. 20 Oral midazolam is increased to a greater extent by TPV than intravenous (IV) midazolam. Oral midazolam AUC and Cmax were increased 8.96- and 2.86-fold, respectively, when combined with TPV. IV midazolam AUC was increased 3.4-fold, but Cmax was unchanged. 21 Oral midazolam should not be used with TPV or BOC, but halving the dose of IV midazolam could be considered with monitoring for therapeutic and toxic effects.

In addition to interactions mediated by CYP3A, TPV and BOC are susceptible to membrane transporter-mediated interactions. Both agents are substrates and inhibitors of P-gp. Digoxin is not metabolized, but is a selective substrate of P-gp. TPV increased digoxin Cmax and AUC by 1.5- and 1.85-fold, respectively, so lower doses of digoxin may be needed in patients on TPV, and digoxin concentrations should be monitored during TPV treatment. 21 In vitro, BOC is an inhibitor of the hepatic uptake transporter, organic anion transporting polypeptide (OATP) 1B1 (IC50 = 18 μM) and the efflux transporter, breast cancer resistance protein (IC50 = 81 μM). 7

Below are summaries of the available interaction data with TPV and BOC and other classes of medications that may be used in persons with HCV. When possible, recommendations on therapeutic alternatives are provided. This is not an exhaustive list of potential interactions, and new information accrues continuously. Additional information may be available in the product information for both agents or through the University of Liverpool website (available at: www.hep-druginteractions.org).

Immunosuppressants

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

HCV recurs in nearly 100% of patients who undergo liver transplantation. Thus, it is imperative to determine the safest, most effective doses of TPV and BOC to use in this setting. Multidose BOC and TPV have been studied with single-dose cyclosporine and tacrolimus in healthy volunteers. The pharmacokinetic data from these studies are shown in Table 3. BOC and TPV slow the clearance of cyclosporine and tacrolimus. The AUC of cyclosporine is increased 4.64- and 2.7-fold by TPV and BOC, respectively. 22, 23 The AUC of tacrolimus is increased 70.3- and 17.1-fold by TPV and BOC, respectively. 22, 23 BOC and TPV pharmacokinetics are not affected by cyclosporine or tacrolimus. Sirolimus is expected to behave similarly to tacrolimus, but has not been studied. These preliminary data suggest that 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. When initiating TPV or BOC-based HCV therapy in patients on cyclosporine, one may consider empirically reducing the cyclosporine dose by 75%, then using therapeutic drug monitoring to further refine the cyclosporine dose and frequency. Another option may be to hold the doses of cyclosporine and tacrolimus after TPV or BOC have been introduced and redose these medications when the immunosuppressant concentrations are in the desired range. This has been done with ritonavir-boosted HIV protease inhibitors. 24-27

Table 3. Cyclosporine and Tacrolimus Pharmacokinetics With and Without Concomitant BOC and TPV Administration
  Mean (SD) CL/F (L/Hour)Mean (SD) t1/2 (Hours)Mean (SD) AUC0-∞ (ng*Hour/mL)Mean (SD) Cmax (ng/mL)
  1. Abbreviations: CL/F, apparent oral clearance; CSA, cyclosporine; DN GLS, dose-normalized geometric least square; CI, confidence interval; GMR, geometric mean ratio; TAC, tacrolimus.

Cyclosporine 
 TPV studyCSA 100 mg (n = 10)56.3 (14)12 (1.67)1,880 (489)489 (142)
CSA 10 mg + TVR (n = 9)12.5 (3.33)42.1 (11.3)853 (218)62.2 (18.9)
DN GLS mean ratio (90% CI)  4.64 (3.9, 5.51)1.32 (1.08, 1.6)
 BOC studyCSA 100 mg (n = 10)58.8 (15.3)11.3 (4.1)1,800 (468)388 (186)
CSA 100 mg + BOC (n = 10)21 (3.36)15.7 (3.6)4,870 (779)737 (199)
GMR (90% CI)  2.7 (2.39, 3.05)2.01 (1.69, 2.4)
Tacrolimus 
 TPV studyTAC 2 mg (n = 10)32 (10.2)40.7 (5.85)67.3 (17.3)3.97 (1.82)
TAC 0.5 mg + TVR (n = 9)0.48 (0.19)196 (159)1,310 (866)8.7 (3.23)
DN GLS mean ratio (90% CI)  70.3 (52.9, 93.4)9.35 (6.73, 13)
 BOC studyTAC 0.5 mg (n = 12)29.6 (16.9)36.7 (8.1)21.8 (11.6)0.81 (0.29)
TAC 0.5 mg + TVR (n = 12)1.6 (0.5)61.3 (11)345 (110)7.8 (1.95)
GMR (90% CI)  17.1 (14, 20.9)9.9 (7.96, 12.3)

Antiretroviral Drugs

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

Thirty percent of persons with HIV are coinfected with HCV. 28 HIV/HCV-coinfected patients have higher baseline HCV viral loads, more rapid progression of liver disease and fibrosis, and are at increased risk for cirrhosis, end-stage liver disease, and hepatocellular carcinoma. 29 Preferred agents for the treatment of HIV include the following two nucleos(t)ide reverse transcriptase inhibitors, tenofovir disoproxil fumarate (TDF) and emtricitabine; the non-nucleoside reverse-transcriptase inhibitor (NNRTI), efavirenz; two ritonavir-boosted protease inhibitors, darunavir and atazanavir; and the integrase inhibitor, raltegravir. 30 Results from healthy volunteer drug-interaction studies performed with BOC or TPV and antiretroviral drugs are shown in Table 4. TDF does not affect the pharmacokinetics of BOC or TPV, but the Cmax of tenofovir is increased approximately 30% with both HCV protease inhibitors. 31, 32 This effect has also been observed with some HIV protease inhibitors. 33-35 Data suggest that those on HIV protease inhibitors with TDF may have greater declines in renal function from TDF than those on non–protease inhibitor containing antiretroviral regimens, 36 though renal adverse events from TDF are uncommon. 37 Concentrations of both TPV and BOC are reduced by efavirenz. 20 A higher dose of TPV (1,125 mg thrice-daily) is being used in combination with efavrienz in clinical trials of HIV/HCV-coinfected patients with promising initial results. 38 In the treatment of HIV, ritonavir is used at a low dose (100 mg once- or twice-daily) to inhibit CYP3A metabolism of other HIV protease inhibitors and pharmacokinetically enhance their levels. This strategy was investigated for both BOC and TPV. Unfortunately, ritonavir boosting does not appear to decrease TPV or BOC pill burden or dosing frequency. 20, 39 TPV has some deleterious bidirectional interactions with ritonavir-boosted protease inhibitors. 31 Ritonavir-boosted darunavir, fosamprenavir, and lopinavir all significantly reduce TPV concentrations (AUCs decreased by 32%-54%). Atazanavir also reduces TPV levels, but the effect is smaller (AUC reduced by 20%). In addition to the TPV levels being reduced, TPV also reduces darunavir and fosamprenavir by 40% and 47%, respectively, whereas lopinavir is essentially unchanged and atazanavir AUC is slightly increased (17%) and trough is increased (85%). Ritonavir-boosted atazanavir is being studied in HIV/HCV-coinfected patients on TPV without dose adjustment of either agent, 38 but whether TPV can be safely combined with darunavir, fosamprenavir, and lopinavir requires additional study. Darunavir, fosamprenavir, and lopinavir have CYP-induction properties, so they may induce TPV metabolism, but the shapes of the TPV pharmacokinetic profiles suggest a possible interaction at the level of protein-binding displacement or at the level of bioavailability. In vitro data do not show TPV to be a CYP inducer, so the mechanism for the reduction in darunavir and fosamprenavir is unclear. Raltegravir is an attractive agent for use in the treatment of HCV in the HIV/HCV-coinfected patient because it does not inhibit or induce CYP enzymes and its primary route of metabolism is glucuronidation. In combination with TPV, raltegravir AUC was increased 31%, presumably the result of TPV's inhibition of P-gp. TPV levels were unchanged. Raltegravir has a wide therapeutic index, and a 31% increase in AUC is not expected to have clinical relevance. Studies of the interaction potential of BOC with ritonavir-boosted protease inhibitors and raltegravir are ongoing. A phase II trial of BOC in 98 HIV/HCV-coinfected participants allowed the use of NRTIs, ritonavir-boosted HIV protease inhibitors, raltegravir, and the chemokine coreceptor 5 antagonist, maraviroc, but excluded those on NNRTI. SVR data are not yet available, but at 24 weeks of treatment, 70.5% of those on BOC, Peg-IFN-α2b, and RBV had undetectable HCV RNAs. 40

Table 4. Interactions With BOC and TPV and Antiretroviral Drugs
 BOCAntiretroviralTPVAntiretroviral
 CmaxAUCCminCmaxAUCCminCmaxAUCCminCmaxAUCCmin
  1. Data are presented as the geometric mean ratios of BOC, TPV, and the antiretroviral drugs when given in combination relative to when given alone.

  2. Abbreviation: NR, not reported.

Tenofovir1.051.081.081.321.05NR1.011.001.031.31.31.41
Efavirenz0.920.810.561.111.2NR0.910.740.530.840.930.98
Atazanavir/ritonavir0.790.80.850.851.171.85
Darunavir/ritonavir0.640.650.680.60.60.58
Fosamprenavir/ritonavir0.670.680.70.650.530.44
Lopinavir/ritonavir0.470.460.480.961.061.14
Raltegravir1.071.071.141.261.311.78

3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

Simvastatin and lovastatin are highly dependent on CYP3A for metabolism. There are multiple reports in the literature of myopathy and rhabdomyolysis in patients whose simvastatin concentrations were raised by a drug interaction with a potent CYP3A inhibitor. 41 Thus, simvastatin and lovastatin use should be avoided in patients on BOC or TPV. Administered as 20 mg daily, atorvastatin Cmax and AUC are increased 10.6- and 7.88-fold by TPV. 42 Atorvastatin AUC and Cmax, when administered as a single 40-mg dose, were increased 2.3- and 2.7-fold, respectively, by multidose BOC. 43 Atorvastatin use should be avoided with TPV and the lowest dose used then titrated to effect with BOC. Pravastatin is metabolized by multiple pathways. In combination with BOC, pravastatin AUC and Cmax are increased 1.6- and 1.5-fold, respectively. 43 The mechanism for the interaction with pravastatin is unclear, but may relate to BOC's inhibition of OATP1B1. Rosuvastatin, which is not extensively metabolized by CYP3A, could be considered for use in combination with TPV and BOC, but has not been studied to date. Unexpected increases in rosuvastatin concentrations were noted when used in combination with several HIV protease inhibitors, 44-46 so increased monitoring for symptoms of myopathy may be necessary.

Oral Contraceptives

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

Ribavirin is highly teratogenic, 47 so prevention of pregnancy during antiviral treatment of HCV is critical. BOC and TPV lower ethinyl estradiol AUC by approximately 25%. 32, 48 With TPV, the reduction in ethinyl estradiol levels increases follicle-stimulating hormone and luteinizing hormone and decreases endogenous progesterone levels, suggesting that this pharmacokinetic alteration could result in loss of contraceptive efficacy. 48 BOC and TPV have different effects on the progestin component of oral contraceptives. TPV reduces norethindrone slightly (∼11%), whereas BOC increases drosperinone AUC and Cmax by 99% and 57%, respectively. 32 Progestin-only contraception is effective, 49 but it is difficult to know with certainty whether BOC would increase the levels of all progestins or if it is unique to drosperinone. There may also be more progestin-associated adverse effects with increased progestin concentrations. Furthermore, because drosperinone inhibits potassium excretion in the kidneys, the increase in drosperinone concentrations could theoretically cause hyperkalemia. Thus, considering the potential for increased adverse effects (with BOC) and loss of contraceptive efficacy (with TPV), the use of ethinyl estradiol and progestin-based hormonal contraception should not be relied upon during triple therapy for HCV and for 2 weeks after the discontinuation of BOC or TPV.

Antidepressants

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

The selective serotonin reuptake inhibitors (SSRIs) are generally chosen as first-line treatment for depression because of their safety in overdose and improved tolerability. 50 BOC and TPV have been studied with escitalopram. Escitalopram is metabolized by CYP2C19, with a minor contribution by CYP3A4 and CYP2D6. The single-dose AUC of escitalopram was reduced by 21% (with a reduction in half-life from 31 to 22 hours) after multiple doses of BOC. 51 Multiple-dose escitalopram exposures were reduced an average of 35% by multiple doses of telaprevir. 52 The mechanism for this interaction is unclear. With HIV protease inhibitors, paroxetine and sertraline exposures are reduced. 53, 54 There are no obvious concentration-effect data for the SSRIs, so it is unknown whether reductions in exposures translate into reduced ability to control depressive symptoms, but providers should be aware of the potential for reductions in SSRI exposures with TPV and BOC and increase the antidepressant doses as needed.

Antipsychotics

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

There are no formal drug-interaction studies between TPV or BOC and antipsychotics, thus predictions must be made based on knowledge of the clinical pharmacology of each agent. Quetiapine relies solely on CYP3A for metabolism, and the potent CYP3A inhibitor, ketoconazole, increases quetiapine exposures by 335%. 55 There are case reports of quetiapine toxicity when combined with HIV protease inhibitors. 56 Aripiprazole concentrations are increased 63% by ketoconazole, 57 and there is a case of presumed aripiprazole toxicity in a patient taking the ritonavir-boosted HIV protease inhibitor, darunavir. 58 Ketoconazole increases the iloperidone AUC by 57%. 59 If possible, quetiapine use should be avoided in patients undergoing BOC- and TPV-based HCV treatment, and the dosage of aripiprazole and iloperidone should be empirically reduced by half when TPV or BOC are initiated and the antipsychotic dose then titrated to effect. When available and when therapeutic concentrations have been established (e.g., clozapine plasma concentration >350 ng/mL), therapeutic drug monitoring of the antipsychotic may have clinical utility.

Anxiolytics and Sleep Aids

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

Benzodiazepines are commonly used as anxiolytics and sleep aids. Flurazepam, quazepam, and triazolam are highly dependent on CYP3A for metabolism and their use should be avoided with BOC and TPV. Alprazolam AUC is increased 35% with TPV. 60 Zolpidem, zaleplon, and eszopiclone are non-benzodiazepine hypnotics that induce sleepiness. Zolpidem AUC is reduced 42% by TPV and zolpidem half-life is shortened from 4.32 to 3.37 hours, so a higher dose of zolpidem may be required with TPV. 60 The antidepressant, trazodone, is also used as a sleep aid. With the HIV protease inhibitor, ritonavir, trazodone exposures are increased with nausea, dizziness, hypotension, and syncope. 61

Opioid Replacements

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

Methadone and buprenorphine do not inhibit or induce CYP enzymes, but their pharmacokinetics and pharmacodynamics can be affected by drugs that do affect CYP enzymes. Methadone, administered as a combination of the R- and S-isomers, is 85% plasma protein bound and is metabolized by CYP2B6, 2C19, and 3A. 62 Buprenorphine is 96% plasma protein bound and is metabolized by CYP3A, 2C8, and glucuronidation. 63 TPV has been studied with methadone and buprenorphine. Total R-methadone (the isomer responsible for opioid effect) AUC and minimum concentration (Cmin) in plasma were reduced by approximately 30%, but unbound (i.e., free) methadone concentrations were unchanged with TPV. There were no symptoms of withdrawal in the 18 study participants. Thus, TPV displaced methadone from its plasma protein-binding sites, but because free concentrations were unchanged, a methadone dose adjustment is likely unnecessary with the addition of TPV. 64 TPV has no effect on buprenorphine pharmacokinetics. 65

Antihypertensive Agents

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

CYP enzymes are not involved in the metabolism of ace inhibitors or diuretics, thus CYP-mediated drug interactions with these classes of antihypertensives and BOC and TPV are unlikely. Among the beta blockers, only carvedilol and nabivolol are metabolized, to some extent, by CYP3A4. 66 There is a contribution of CYP3A4 to the metabolism of the angiotensin II receptor blockers, irbesartan and losartan. 66 Thus, dose reductions could be considered for carvedilol, nabivolol, irbesartan, and losartan in patients initiating TPV and BOC. The calcium-channel blockers are highly reliant on CYP3A for metabolism 66 and are therefore susceptible to increases in exposure from BOC and TPV. Amlodipine Cmax and AUC are increased 1.27- and 2.79-fold by TPV, so a reduced dose of amlodipine should be considered in patients on TPV. 42

Conclusion

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References

TPV and BOC represent important advances in the treatment of chronic HCV, but their optimal use requires a significant appreciation for their clinical pharmacology and drug-interaction potential. Table 5 provides a summary of drugs to avoid and drugs to use with caution with BOC and TPV. Though several drug-interaction studies have been conducted, there is a relative paucity of information on the management of the interactions identified and still much to learn about concentration-effect relationships for these agents. This knowledge is essential for increasing the probability of virologic response while minimizing toxicities from HCV treatment.

Table 5. Summary of Drugs to Avoid and Drugs to Use With Caution in Combination With BOC and TPV
  Use With Caution
 Avoid[UPWARDS ARROW] Concentration of Concomitant Med or HCV PI[DOWNWARDS ARROW] Concentration of Concomitant Med or HCV PI
  • Interactions unique to one of the HCV protease inhibitors are indicated in parentheses (e.g., TPV or BOC).

  • Abbreviations: Med, medication; PI, protease inhibitor; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A.

  • *

    A higher dose of TPV (1,125 mg every 8 hours) has been studied with efavirenz with promising preliminary rates of SVR.

Alpha-1 adrenoreceptor antagonistAlfuzosinDoxazosin, terazosin, tamsulosin, silodosin 
AnticonvulsantsCarbamazepime, phenobarbital, phenytoin  
Antifungals Ketoconazole, itraconazole, posaconazole, voriconazole 
Antimicrobials Clarithromycin, erythromycin 
AntimycobacterialsRifampin, rifapentineRifabutin 
Antiretroviral drugsLopinavir (TPV), darunavir (TPV), fosamprenavir (TPV), efavirez (BOC) Efavirenz (TPV)*
Benzodiazepines and sleep aidsFlurazepam, quazepam, triazolam, oral midazolamAlprazolam, trazodone 
CardiovascularAmiodarone, bosentan, dofetilide, flecainide, lidocaine, propafenone, quinidine, sildenafil, and tadalafil for pulmonary arterial hypertensionCalcium-channel blockers, digoxin, carvedilol, nabivolol, irbesartan, losartan 
Ergot derivativesDihydroergotamine, ergonovine, ergotamine, methylergonovine  
Herbal productsSt. John's wort  
HMG-CoA reductase inhibitorsLovastatin, simvastatin, atorvastatin (TPV)Atorvastatin (BOC), pravastatin, rosuvastatin 
ImmunosuppressantsTacrolimus, sirolimusCyclosporine 
Oral contraceptives Drosperinone (BOC)Ethinyl estradiol
Respiratory Fluticasone, salmeterol 
Second-generation antipsychoticsQuetiapineIloperidone, aripiprazole 

References

  1. Top of page
  2. Abstract
  3. BOC
  4. TPV
  5. Drug Interactions
  6. Immunosuppressants
  7. Antiretroviral Drugs
  8. 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase Inhibitors
  9. Oral Contraceptives
  10. Antidepressants
  11. Antipsychotics
  12. Anxiolytics and Sleep Aids
  13. Opioid Replacements
  14. Antihypertensive Agents
  15. Conclusion
  16. References
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