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Telaprevir therapy required tacrolimus dose reduction in liver transplant recipients with HCV
  October 26, 2012

LAS VEGAS - Telaprevir affected the metabolism of tacrolimus in liver transplant recipients with HCV, but may be an effective treatment for this population, according to data presented at the 2012 American College of Gastroenterology Annual Scientific Meeting.

Researchers assigned telaprevir-based triple therapy to four patients who experienced HCV genotype 1 recurrence following a liver transplant. The dosage included 750 mg telaprevir three times daily, 600 mg ribavirin daily, and 180 mcg pegylated interferon alfa-2a once a week, for a mean duration of 10.75 weeks (range 8-16 weeks).

All four patients had been on tacrolimus for 6 months or longer, with a dosage ranging from 1 mg to 3 mg twice daily, prior to treatment initiation. Upon initiating triple therapy, half the pre-treatment tacrolimus dose was administered each day, with levels checked twice daily for two weeks and additional tacrolimus administered when levels reached 4 ng/mL to 6 ng/mL. Upon establishing a maintenance dose, investigators subsequently monitored tacrolimus levels weekly.

Tacrolimus levels peaked at 16.2 ng/mL, at 12 hours after initiation of telaprevir. The necessary dosage dropped to between one-fourth and one-half the initial daily dose after initiating triple therapy. AUC analysis indicated a value of 1,353.46 ng.hr/mL for tacrolimus during telaprevir treatment (range 685.25-2,040.05), which researchers compared with an expected AUC of 67 ng.hr/mL without telaprevir.

No incidence of acute rejection, infection or neurologic toxicity was observed. Anemia (Hb levels below 10 g/dL) occurred in two patients and required a 200-mg ribavirin dose reduction, as well as treatment with epoietin. Researchers also noted that mean creatinine levels increased from 1.12 mg/dL to 1.35 mg/dL during the study.

"There isn't FDA approval yet for telaprevir in post liver-transplant patients, so it's an off-label use, but when you do use it, you have to be very careful of the tacrolimus levels because they will skyrocket due to the inhibition of the CYP3A4 cytochrome system," researcher Gurshawn Singh, MD, resident at Cleveland Clinic told Healio.com, adding that six additional patients have been added to the study since the preliminary results. "Because of that drug interaction ... you want to dose-reduce tacrolimus and monitor tacrolimus levels when you initiate treatment." The researchers also wrote that additional study should be performed to assess the treatment's efficacy and impact on renal function.

For more information:

Alkhouri N. P1329: Effect of Telaprevir on the Pharmacokinetics of Tacrolimus in the Treatment of Hepatitis C After Liver Transplantation. Presented at: the 2012 American College of Gastroenterology Annual Scientific Meeting; Oct. 19-24, Las Vegas.

Effect of Telaprevir on the Pharmacokinetics of Tacrolimus in the Treatment of Hepatitis C After Liver Transplantation

Naim Alkhouri1, Jessica Bollinger1, Gurshawn Singh1, William D. Carey1, John Fung1, Nizar Zein1, Bijan Eghtesad1

1. Cleveland Clinic, Digestive Disease Institute , Cleveland, OH, United States.

Purpose: Limited data are available on using telaprevir (TVR)-based triple therapy to treat HCV recurrence post-liver transplantation (LTx). A study in healthy volunteers shows that TVR leads to major increase in tacrolimus (TAC) blood concentration. We report our preliminary experience on the effects of TVR on TAC pharmacokinetics (PK ) and the safety of TVR-based therapy in the post-LTx setting.

Methods: Patients with HCV genotype 1 recurrence post-LTx on stable dose of TAC for at least 6 months prior to starting the antiviral regimen were included in this study. TVR-based triple therapy was started with TVR 750 mg TID, ribavirin 600 mg daily, and peg-interferon a2a 180 mcg weekly. On day 1 of treatment, TAC at half the pre-treatment daily dose was given and levels were checked at 12 and 24 hours and every other day thereafter for 2 weeks to assess TAC PK. No additional TAC was given until the level was around 4-6 ng/mL. Once the maintenance dose of TAC was established, levels were assessed weekly.

Results: Four patients (1F, 3M), mean age 56.3 years, mean time from LTx 3.25 years, and mean fibrosis stage of 2.5 were treated. Two were HCV treatment naive and two were prior null-responders post-LTx. The mean duration of treatment was 10.75 weeks (range 8-16 weeks). The pre-treatment TAC dose ranged from 1-3 mg twice daily. The TAC dose required to maintain therapeutic levels was found to be approximately 3/4- 1/2 the pre-treatment daily dose at a frequency of once weekly. The mean area under the concentration time curve (AUC) for TAC while on TVR was 1353.46 ng.hr/mL (range 685.25-2040.05) compared to an expected AUC of 67 ng.hr/mL without TVR. The highest TAC level that we encountered in our study was 16.2 ng/mL (at 12-hour level after the initial dose). Clinically significant anemia (Hb <10 g/dL) developed in 2, requiring a decrease of the ribavirin dose to 400 mg daily and starting epoietin. No significant neurologic toxicity was encountered. The mean creatinine increased from 1.12 to 1.35 mg/dL. We did not encounter any infections or episodes of acute rejection.

Conclusion: 1. TVR had a profound effect on TAC metabolism; 2. Dose reduction of TAC based on blood levels is associated with normal TAC blood levels; 3. TVR therapy for HCV recurrence post-OLT in patients on TAC-based immunosuppression appears feasible; 4. The effect on renal function requires additional study. Longer follow-up is needed to demonstrate efficacy in achieving control of HCV.

Disclosures: Naim Alkhouri, MD: Speaker's Bureau and Advisory Board Member of Vertex (makers of telaprevir). Nizar N Zein: Speaker's Bureau and Advisory Board Member of Vertex (makers of telaprevir).

Citation: . EFFECT OF TELAPREVIR ON THE PHARMACOKINETICS OF TACROLIMUS IN THE TREATMENT OF HEPATITIS C AFTER LIVER TRANSPLANTATION. Program No. P1329. ACG 2012 Annual Scientific Meeting Abstracts. Las Vegas, NV: Amerxican College of Gastroenterology.

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