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TO THE EDITORS:

Recurrent hepatitis C is a major cause of graft loss and death after liver transplantation. Previous antiviral therapy has achieved viral clearance (a sustained virological response) in less than 30% of patients.[1] Hepatitis C virus–specific protease inhibitors increase the sustained virological response rate in nontransplant patients with genotype 1 from 40% to 70%.[2] However, these drugs are both substrates and inhibitors of cytochrome P450 3A4 and thus inhibit the metabolism of many drugs, including calcineurin and mammalian target of rapamycin inhibitors. Telaprevir increases the dose-normalized (DN) area under the curve (AUC) of cyclosporine 4.6-fold and the DN AUC of tacrolimus 70-fold.[3] Boceprevir increases the DN AUC of cyclosporine 2.7-fold and the DN AUC of tacrolimus 17-fold.[4] Mammalian target of rapamycin inhibitors such as sirolimus and everolimus are increasingly being used after liver transplantation to help preserve renal function.[5] We report here the pharmacokinetics of sirolimus during telaprevir administration. After institutional review board approval, ten liver transplant recipients were treated with telaprevir, pegylated interferon alpha-2a, and ribavirin for recurrent genotype 1 hepatitis C virus infections. Their immunosuppression consisted of sirolimus without a calcineurin inhibitor or steroids; 7 were also on mycophenolate. Nine of the 10 patients received pegylated interferon alpha-2a and ribavirin as part of a lead-in period of at least 4 weeks for the assessment of drug tolerance. Telaprevir was given at a dose of 1125 mg every 12 hours.[6] After an initial dose of 0.5 mg, sirolimus levels were monitored closely over the first 24 hours and then daily until a stable dosing regimen was achieved.

Pharmacokinetic parameters were determined via standard noncompartmental methods with PK Solutions 2.0 (Summit Research Services, Montrose, CO). The maximum concentration and AUC of sirolimus were also DN to 1 mg to account for the different doses administered with telaprevir. The mean ratio indicates the fold change in a pharmacokinetic parameter when telaprevir was coadministered versus the pharmacokinetic parameter reported for sirolimus alone.

Exposure to sirolimus increased dramatically when it was administered with telaprevir (Table 1). The mean drug clearance decreased from 139 to 0.51 L/hour, and this resulted in a 3.1-fold increase in the DN maximum concentration, a 26.1-fold increase in the DN AUC, an 8.3-fold increase in the time to reach the maximum concentration, and a 1.5-fold increase in the mean terminal elimination half-life.

Table 1. Mean Pharmacokinetic Parameters for Post–Liver Transplant Patients on Stable Doses of Sirolimus With the Addition of Telaprevir During Therapy With Pegylated Interferon Alpha-2a and Ribavirin
ParameterSirolimus AloneaSirolimus With TelaprevirFold Change
  1. NOTE: The mean parameters were calculated on the basis of 5 patients with serial pharmacokinetic values and 5 patients with daily levels.

  2. a

    The pharmacokinetic parameters came from the package insert.

AUC (ng·hour/mL)230 ± 671502.1 ± 594.96.5
DN AUC0-∞ (ng·hour/mL/mg)115 ± 343004.2 ± 1189.826.1
Maximum concentration (ng/mL)15.0 ± 4.911.6 ± 3.60.8
DN maximum concentration (ng/mL)7.5 ± 2.523.2 ± 7.23.1
Terminal elimination half-life (hours)62 ± 1692.8 ± 37.41.5
Time to reach maximum concentration (hours)3.5 ± 2.429.1 ± 15.28.3
Clearance (L/hour)139 ± 630.51 ± 0.30.004

Table 2 shows the sirolimus dosing during the lead-in period, the first 4 weeks of triple therapy, and weeks 5 to 12 of triple therapy. Concurrently with the change in drug exposure, the dosing of sirolimus was considerably reduced to an average of 7.6% of the pretelaprevir dose during the first 4 weeks and to an average of 11.3% during the subsequent treatment period.

Table 2. Dosing of Sirolimus Before and After Telaprevir Initiation
Patient NumberPretreatmentTelaprevir: Weeks 1 to 4Telaprevir: Weeks 5 to 12
Sirolimus DoseIntervalMean Minimum (Trough) Serum Concentration (ng/mL)MycophenolateDose (mg)Interval% ofInitial DoseDose (mg)Interval% ofInitial Dose
11Daily3.8Yes0.5Every week6.7%0.5Twice per week13.3%
22Daily22.4No0.5Every 9 days2.8%0.5Every 6 days4.2%
31.5Daily6.8No0.5Every week4.4%0.5Every 11 days3.0%
40.5Daily2.9Yes0.5Every 20 days5.0%0.5Every 17 days5.8%
51Daily5.1Yes0.5Every week6.7%0.5Every week6.7%
60.5Daily3.4Yes0.5Every 8 days12.5%0.5Every week13.3%
70.5Every other day1.1No0.5Every 14 days13.0%0.5Every 6 days33.3%
82Daily10.5Yes1Every week7.1%1Every 5 days10.0%
91Every other day5.3Yes0.5Every 8 days12.5%0.5Every 8 days12.5%
101Daily4.9Yes0.5Every 10 days5.0%Not availableNot availableNot available
Mean      7.6%  11.3%

The potential benefits of triple antiviral therapy in eradicating virus and controlling progressive liver disease can be significant in the posttransplant setting. However, this treatment is not without risks, which include drug interactions, severe anemia, rejection, and death.[7] In an ideal world, one would wait for safer interferon-free antiviral regimens without drug interactions. Sadly, however, many patients with recurrent hepatitis C do not have the luxury of waiting, so it is important to understand that telaprevir results in a 26.1-fold increase in drug exposure, and the degree of interaction can change over time.

  • Jacqueline G. O'Leary, M.D., M.P.H.

  • Greg J. McKenna, M.D.

  • Göran B. Klintmalm, M.D., Ph.D.

  • Gary L. Davis, M.D.

  • Annette C. and Harold C. Simmons Transplant Institute Baylor University Medical Center Dallas TX

REFERENCES

  1. Top of page
  2. REFERENCES
  • 1
    Terrault NA, Berenguer M. Treating hepatitis C infection in liver transplant recipients. Liver Transpl 2006;12:1192-1204.
  • 2
    Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; for American Association for Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:1433-1444.
  • 3
    Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011;54:20-27.
  • 4
    Hulskotte E, Gupta S, Xuan F, van Zutven M, O'Mara E, Feng HP, et al. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012;56:1622-1630.
  • 5
    McKenna GJ, Ruiz R, Onaca N, Campsen J, Klintmalm E, Levy MF, et al. The impact of timing in sirolimus conversion for renal insufficiency in liver transplant recipients [abstract]. Liver Transpl 2011;17(suppl 1):A84.
  • 6
    Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or −2b to patients with chronic hepatitis C. Gastroenterology 2011;140:459-468.e1.
  • 7
    Coilly A, Roche B, Dumortier J, Botta-Fridlund D, Leroy V, Pageaux PG, et al. Efficacy and safety of protease inhibitors for hepatitis C recurrence after liver transplantation: a first multicentric experience [abstract]. Hepatology 2012;56(suppl 1):194A.