tacrolimus and telaprevir

Studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C genotype 1 infection have demonstrated dramatic increases in tacrolimus, cyclosporine, and mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldaprevir will likely have improved efficacy and safety profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based antiviral therapy are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.

Topics: Administration, Oral; Anti-Bacterial Agents; Antiviral Agents; Calcineurin Inhibitors; Chemical and Drug Induced Liver Injury; Drug Interactions; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Oligopeptides; Proline; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, 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 every 8 hours [q8h]). In Part B, 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(0-∞)) by approximately 4.6-fold and increased tacrolimus DN_AUC(0-∞) by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t(½)) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(½) of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours.. In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.

Topics: Adolescent; Adult; Antiviral Agents; Area Under Curve; Cyclosporine; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Oligopeptides; Tacrolimus; Young Adult

Recurrence of hepatitis C virus (HCV) infection after orthotopical liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virological response rates in patients after OLT in combination with pegylated interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug-drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT patients with IS are unknown. Aim of the present study was to analyse telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS.. Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1-infected patients patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily and pegylated interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analysed by liquid chromatography-electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase chain-reaction.. Median (range) telaprevir plasma concentrations of TW 4, 8 and 12 were 3970 (1980-4430) ng/ml and 2520 (1870-8730) ng/ml in patients after OLT and ciclosporin- or tacrolimus-based IS, respectively, as compared to 2790 (1870-3140) in non-OLT patients (P = 0.3). In one patient with tacrolimus-based IS, telaprevir dose had to be adjusted to achieve virological response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8 and 12 in patients with and without IS.. Telaprevir drug monitoring may be necessary in patients with tacrolimus-based IS in patients with HCV graft infection after OLT.

Topics: Antiviral Agents; Chromatography, Liquid; Drug Monitoring; Drug Therapy, Combination; Hepatitis C; Humans; Immunosuppression Therapy; Interferon-alpha; Liver Transplantation; Oligopeptides; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Recurrence; Ribavirin; Statistics, Nonparametric; Tacrolimus; Tandem Mass Spectrometry

Graft loss because of hepatitis C virus recurrence is a serious problem after liver transplantation (LT), and the response to pegylated interferon (PEG-IFN) and ribavirin (RBV) is poor. The significantly better response rates achieved with telaprevir (TVR)-based triple therapy have led to better graft and patient survival rates, but severe drug interactions may limit the usefulness of this therapy for LT patients. We report our single-center experience with a specially developed protocol that involved administering a low daily dose of tacrolimus (TAC) to a cohort of 17 patients with a recurrence of hepatitis C virus genotype 1 after LT.. Patients were treated with TVR, PEG-IFN, and RBV for 12 weeks, followed by 12 or 36 weeks of dual therapy with PEG-IFN and RBV. After TVR administration was initiated, the TAC dosage was skipped until trough levels began to decline; it was then administered at a dose of 0.1 mg once or twice daily. Tacrolimus trough levels and laboratory values were closely monitored during the TVR phase.. Deviations in trough levels were avoided, thus preventing any clinically evident renal toxicity related to TAC. In addition, histologic studies performed at the end of therapy showed that no rejection episodes had occurred. All patients tolerated the medication. Sustained virologic response was documented for 10 of 17 patients (58%) 24 weeks after end of treatment.. In conclusion, substantial dose reduction and daily administration of low doses of TAC compose a safe and efficient immunosuppressive regimen during TVR-based triple therapy.

Topics: Adult; Aged; Antiviral Agents; Drug Monitoring; Drug Therapy, Combination; Feasibility Studies; Female; Genotype; Germany; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferons; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Oligopeptides; Recurrence; Retrospective Studies; Ribavirin; Tacrolimus; Time Factors; Treatment Outcome; Virus Activation

Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation.. All patients had severe HCV recurrence [fibrosis stage ≥F2 or acute hepatitis ≥A2 (n = 5) or fibrosing cholestatic hepatitis (n = 2)] associated with genotype 1a (n = 4) or 1b (n = 3). Patients were treated with Peg-interferon/ribavirin and boceprevir (n = 2) or telaprevir (n = 5) immediately (n = 3) or after a 4-week lead-in phase (n = 4). Immunosuppression included either cyclosporine (n = 5) or tacrolimus (n = 2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug-drug interactions.. At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (n = 2), infection (n = 2), acute rejection (n = 1) and myocardial infarction (n = 1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients.Average cyclosporine doses were reduced by 50-84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir.. Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug-drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy.

Topics: Adult; Antiviral Agents; Coinfection; Cyclosporine; Drug Therapy, Combination; Female; Hepatitis C, Chronic; HIV Infections; Humans; Immunosuppression Therapy; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Proline; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Viral Load

Telaprevir inhibits CYP3A resulting in drug-drug interactions (DDI) of unprecedented magnitude. We investigated the mechanisms by which telaprevir inhibits the oxidation of midazolam and tacrolimus in human liver microsomes (HLM).. We performed a static mechanistic DDI prediction to evaluate whether previously reported competitive inhibition of CYP3A by telaprevir and its diastereomeric metabolite - VRT-127394 is sufficient to explain the remarkable reduction in oral clearance observed with oral midazolam and tacrolimus. To further explore the inhibitory mechanisms of telaprevir, we assessed whether telaprevir-mediated inhibition of the oxidation of midazolam and tacrolimus is time-dependent in human liver microsomes, and whether any observed time-dependency was irreversible or reversible in nature.. The competitive inhibition model failed to account for the magnitude of telaprevir interactions in human subjects. In comparing HLM incubations with and without a prior 30-min exposure to telaprevir, a respective 4- and 11-fold reduction in IC50 was observed with midazolam and tacrolimus as substrates. This time-dependent inhibition was shown to be NADPH-dependent. Upon dilution of microsomes following pre-incubation with telaprevir, time-dependent inhibition of midazolam metabolism was completely reversed, whereas partial reversal occurred with tacrolimus.. The interaction between telaprevir and midazolam or tacrolimus involves both competitive and time-dependent inhibition. The time-dependent component is not explained by irreversible inactivation of CYP3A. Formation of potent inhibitory metabolites may contribute to the remarkable in vivo inhibitory potency of telaprevir.

Topics: Antiviral Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Immunosuppressive Agents; Inhibitory Concentration 50; Microsomes, Liver; Midazolam; NADP; Oligopeptides; Tacrolimus; Time Factors

Recurrent hepatitis C infection leads to accelerated graft loss in liver transplant recipients. Telaprevir offers a higher chance of cure in these patients. We sought to assess the effectiveness of telaprevir in treatment of hepatitis C in liver transplant recipients.. We report a series of 17 patients who received telaprevir for recurrent hepatitis C virus infection. These patients were previous treatment failures including 10 null responders. All patients received pegylated interferon alpha 2a (180 μg/wk) and ribavirin (800 mg/d) for 1 year and telaprevir 750 mg every 8 hours for 12 weeks. The immunosuppressive regimen was not changed during therapy, but the dosages were modified based on serum levels of the drugs.. In an intention-to-treat analysis, the overall sustained virologic response 12 was 58%, with a relapse rate of 24%. Nine patients (52%) achieved extended rapid virologic response. Seven patients (77%) with extended rapid virologic response achieved sustained virologic response 12. Four patients (40%), who were previous null responders to interferon and ribavirin also achieved sustained virologic response 12. Anemia and ribavirin dosage reduction were common. Severe thrombocytopenia was seen in 2 patients resulting in discontinuation of therapy. A tacrolimus-based immunosuppressive regimen could be continued with close monitoring. During the initial 4 weeks of therapy, there were wide fluctuations in tacrolimus levels. However, after 4 weeks, tacrolimus could be dosed weekly maintaining a trough level of 3 to 10 ng/mL.. Telaprevir can be used effectively in liver transplant recipients receiving tacrolimus-based immunosuppression. Sustained virologic response 12 can be achieved in a significant number of these "difficult-to-treat" patients.

Topics: Aged; Antiviral Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Time Factors; Treatment Outcome; Viral Load

Telaprevir, a chronic hepatitis C virus (HCV) protease inhibitor, is known to be a cytochrome P450 (CYP) 3A4/5 substrate and inhibitor. In the present study, the in vitro inhibitory effect of telaprevir on the metabolism of tacrolimus in human liver microsomes was investigated using 13-O-demethyltacrolimus (M-I) as a monitor metabolite. Telaprevir inhibited M-I formation in a time-dependent fashion with rate of enzyme inactivation (kinact ) and concentration to reach 50% of kinact (KI ) values of 0.113 min(-1) and 0.511 µm, respectively. Using the inhibition parameters generated, in vitro-in vivo extrapolations were performed to evaluate the clinical relevance of the effect of telaprevir on the area under the curve versus time (AUC) of tacrolimus. When 750 mg of telaprevir was administered orally, the intestinal wall availability (Fg ) of tacrolimus was estimated to be increased 3.7- to 7.0-fold. The hepatic intrinsic clearance (CLint ) of tacrolimus was also estimated to be decreased 4.4- to 19-fold. These results suggest that the increased AUC of tacrolimus in the presence of telaprevir was caused by intestinal and hepatic metabolism inhibition. In addition, the inhibitory effect of telaprevir on the hepatic uptake of tacrolimus was also examined using human cryopreserved hepatocytes. However, no significant inhibitory effect was noted, suggesting that the effect of telaprevir on hepatic transporters did not contribute to the increase in tacrolimus exposure.

Topics: Administration, Oral; Area Under Curve; Biotransformation; Cells, Cultured; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Hepacivirus; Hepatocytes; Humans; Intestinal Absorption; Intestinal Mucosa; Liver; Male; Microsomes, Liver; Models, Biological; Oligopeptides; Predictive Value of Tests; Protease Inhibitors; Tacrolimus; Time Factors; Tissue Distribution

The management of hepatitis C virus (HCV) recurrence after liver transplantation (LTx) is a major challenge in patient care. For patients with HCV GT1, treatment standard with pegylated interferon (PEG-IFN) and ribavirin (RBV) has been augmented in 2011 by first generation protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC). We report our first experiences with TVR-based triple therapy in patients with GT1-reinfection of the graft.. 13 patients with histologically proven HCV GT1-reinfection of the graft received 12 weeks of PEG-IFN/RBV/TVR followed by 12 weeks of PEG-IFN/ RBV only. During the triple therapy phase immune suppression was tightly monitored, and the patients were also closely monitored for side effects.. The dosage of immunosuppressants had to be reduced significantly (TAC: 30-fold; CSA 3,5-fold). Stable levels were achieved by daily or over-daily dosing of a special size application of 0,1 mg tacrolimus (Tac) bid or a minimal dose of 10 mg cyclosporine (CSA) bid or qd, respectively. In all patients hematological side effects were observed, 65 % of which required RBV dose reduction, administration of erythropoietin or blood transfusions. Increase of kidney retention values requiring infusions occurred in 50 %. All side effects were reversible. There were no early discontinuations of therapy. An early viral response (EVR) with viral decline below limit of detection was noted at week 12 in 9/13 patients and at week 12 in further 3 patients.. Our preliminary results show high EVR response rates of TVR-based triple therapy in LTx patients with HCV-GT1 re-infection.

Topics: Adult; Antiviral Agents; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Postoperative Complications; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Viral Load

Topics: Antiviral Agents; Cyclosporine; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Oligopeptides; Proline; Tacrolimus