Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents - A potentially lethal cocktail
Authors: Michael Charlton
Journal: Hepatology (2011)

Hepatitis C virus (HCV) associated liver disease continues to be the most common indication for liver transplantation. Although the impact of HCV infection varies substantially between recipients, allograft failure secondary to recurrence of HCV infection is the most frequent cause of death and graft failure in HCV-infected recipients, accounting for two thirds of long term graft loss.1 Histological features of hepatitis develop in approximately 75% of recipients in the first 6 months following liver transplantation,2 with up to 30% progressing to cirrhosis by the fifth postoperative year.2 Mortality and graft loss related to recurrence of HCV has led to long-term graft survival for recipients with HCV infection that is lower than that of recipients undergoing liver transplantation for most other indications.3 Patients who achieve sustained virological response (SVR) to treatment of posttransplant HCV infection experience less severe recurrence and lower mortality and graft loss rates than nonresponders.4-6 Although the likelihood of response to antiviral therapy varies substantially with donor and recipient IL28B genotype,7 the overall safety and efficacy of peginterferon and ribavirin in the treatment of posttransplant HCV infection are both lower than we would wish.8, 9 A recent prospective randomized controlled trial found that less than 60% of liver transplant recipients are able to complete peginterferon and ribavirin antiviral therapy and, on an intention to treat basis, the SVR rate was just over 20%.10 Results of meta-analyses and single center studies are only slightly more encouraging.11, 12 Developing safe and effective treatment of posttransplant HCV infection is one of the most important clinical challenges in our field. It has been with great anticipation that we have observed the steady progress of the lead candidate direct-acting antiviral agents, telaprevir and boceprevir, move through their respective clinical trial development, culminating in the Food and Drug Administration's (FDA) approval in May of 2011. These agents offer compelling and meaningful improvements in the efficacy of treatment of genotype 1 chronic HCV infection. In the preliminary summary of the presentations for telaprevir and boceprevir the FDA Antiviral Products Advisory Committee concluded (www.FDA.gov downloads posted May 5th 2011) that for Caucasian patients who are treatment-naïve and have genotype 1 chronic HCV infection SVR rates were 75% (telaprevir) and 69% (boceprevir). For African American patients who are treatment-naïve with genotype 1 chronic HCV infection SVR rates were 65% (telaprevir) and 53% (boceprevir). Proportional increases in efficacy of these agents over peginterferon and ribavirin are even greater among treatment experienced patients. It is expected that many patients who have taken to the sidelines awaiting the routine availability of a more efficacious anti-HCV therapy will now step forward to consider treatment or re-treatment. It is likely, and with good cause, that the expectations among patients and providers are even greater among liver transplant recipients and their physicians. In this issue of HEPATOLOGY, Garg et al.,13 report findings of a drug–drug interaction study that suggests that for transplant recipients the protease inhibitors may add peril and promise in equal measure. HCV, hepatitis C virus : SVR, sustained virological response. Telaprevir, is an inhibitor of the enzyme cytochrome P450 3A, which is responsible for the metabolism of both cyclosporine and tacrolimus. Garg et al., conducted a Phase I, open-label, nonrandomized, single sequence study to assess the effect of telaprevir coadministration on the pharmacokinetics of a single dose of cyclosporine and tacrolimus in two separate panels of 10 healthy volunteers each. The study design is somewhat unusual and merits detailed consideration. In Part A of this study, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg q8h). In Part B of the study by Garg et al., tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC) by approximately 4.6-fold and increased tacrolimus DN_AUC by approximately 70-fold. Similar effects were observed for elimination half-life (t1/2) of cyclosporine and tacrolimus. The authors conclude that "telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly." The authors go on to point out that telaprevir has not been studied in organ transplant patients and its use in these patients is not recommended until the required studies have been completed and regulatory approval has been obtained. I couldn't agree more. The risk to transplant recipients of drug toxicities from inappropriate use of telaprevir cannot be overstated. Although drug–drug interaction studies with immunosuppressive agents have not been completed, as boceprevir is also known to be an inhibitor of cytochrome P450 3A4, the only safe course is to presume similar effects of boceprevir and telaprevir on calcineurin inhibitor pharmacokinetics. It is highly responsible of Vertex to have conducted these drug–drug interaction studies and to have released the results to HEPATOLOGY so soon. The preparedness to conduct and publish these studies will, without question, save many patients from avoidable calcineurin inhibitor toxicities that would have inevitably resulted from a rush to administer telaprevir (or boceprevir) to liver transplant recipients. Sadly, the rush to treat is unlikely to be completely avoided. We would do well to consider some of the limitations (distinct from criticisms) of the study by Garg et al., the results of which only hint at the potential for pharmacological misadventure. The first important limitation of the study is that the studies were conducted in healthy volunteers, not liver transplant recipients with recurrence of HCV. Both telaprevir and boceprevir are primarily cleared through hepatic metabolism, with only small amounts appearing in urine. As HCV infection has biologically meaningful effects on hepatic function, including inhibition of mitochondrial cytochromes,14 the effects of standard doses of telaprevir and boceprevir on CNI clearance are likely to be magnified in liver transplant recipients with HCV infection through reduced clearance and greater exposure to telaprevir and boceprevir. The effect of HCV on posttransplant cytochrome function is apparent clinically in the metabolism of tacrolimus and cyclosporine, which increases by approximately 30% following clearance of HCV in liver transplant recipients.15, 16 The effect of telaprevir/boceprevir administration on tacrolimus and cyclosporine levels and exposure is thus likely to be highly variable during the course of antiviral therapy. In addition, the effects of multiple co-administered doses of telaprevir (or boceprevir) cannot be accurately predicted from the study by Garg et al., as drug dosing only minimally overlapped in this study, probably before the maximal effect on tacrolimus and cyclosporine pharmacokinetics was achieved. The reported magnitude of the effects of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus are greater than those reported for ritonavir and lopinavir, highly potent cytochrome P450 inhibitors.17 This has important implications. A tacrolimus dose of less than 1 mg/wk can be sufficient to maintain adequate blood tacrolimus concentrations in patients on ritonavir/lopinavir, with further dosing not required for 3 to 5 weeks, depending on liver function.18 It should also be noted that cyclosporine and tacrolimus are only two of the many agents that transplant recipients receive that are metabolized by cytochrome P450. Others include sirolimus, mycophenolate, macrolides, HIV antivirals, Ca2+ channel blockers, statins, analgesics and many more. The potential for medically significant drug interactions in liver transplant recipients who might receive telaprevir/boceprevir is almost limitless. Should any liver transplant recipients receive these HCV protease inhibitors? I would counsel that three criteria should be met by any recipient who for whom telaprevir or boceprevir is prescribed: 1. There should be evidence of aggressive histological recurrence of HCV (e.g. ≤ stage 3 fibrosis) in the absence of hepatic decompensation; 2. The patient should be treated by physicians experienced in managing complex drug-drug interactions; and 3. Treatment should be in the context of informed consent by the recipient to participate in a protocol reviewed and approved by the appropriate Insititutional Review Board/Ethics Committee. In Samuel Beckett's play Waiting for Godot, the protagonists Vladimir and Estragon wait endlessly in vain for Godot. The tragedy is that despite both claiming Godot as an acquaintance, they hardly know him and he never arrives. Physicians treating and patients with posttransplant recurrence of HCV have similarly waited for safer and more efficacious treatments. For Vladimir and Estragon the combination of impatience and ignorance was nearly lethal. Thanks to the study by Garg et al., we know enough about telaprevir and, by inference, boceprevir to avoid turning frustration into tragedy.