clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Slideset on: 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: Telaprevir Markedly Increases Cyclosporine and Tacrolimus Exposure in Healthy Volunteers This program is supported by an educational grant from

clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Background and Rationale  Cirrhosis due to chronic hepatitis C leading cause of liver transplantation –HCV infection of graft in 100% of patients if virus not eradicated prior to transplant  Telaprevir, potent, oral HCV NS3 protease inhibitor –Antiviral efficacy in combination with pegIFN/RBV in genotype 1 patients demonstrated in 3 pivotal phase III studies –Substrate and inhibitor of CYP3A –Can saturate or inhibit P-glycoprotein in gut  Cyclosporine and tacrolimus immunosuppressive therapies used posttransplantation –Both drugs substrates of CYP3A and P-glycoprotein –Coadministration with telaprevir may increase systemic exposure Garg V, et al. Hepatology. 2011;54:20-27.

clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Study Design Garg V, et al. Hepatology. 2011;54:  Healthy volunteers enrolled in either of 2 parallel study parts  Part A: effect of telaprevir on cyclosporine (n = 10) –Period 1, Day 1: single 100-mg oral dose of cyclosporine administered 2.5 hrs after standard, medium-fat breakfast –Minimum 8-day washout period between periods 1 and 2 –Period 2, Days 1-11: 750-mg oral dose of telaprevir administered every 8 hrs –Meal or snack administered 30 mins before telaprevir dose –Period 2, Days 1 and 8: single 10-mg oral dose of cyclosporine administered 2.5 hrs after standard, medium-fat breakfast

clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Study Design Garg V, et al. Hepatology. 2011;54:  Part B: effect of telaprevir on tacrolimus (n = 10) –Period 1, Day 1: single 2-mg oral dose of tacrolimus administered 2.5 hrs after standard, medium-fat breakfast –Minimum 14-day washout period between periods 1 and 2 –Period 2, Days 1-13: 750-mg oral dose of telaprevir administered every 8 hrs –Meal or snack administered 30 mins before telaprevir dose –Period 2, Day 8: single 0.5-mg oral dose of tacrolimus administered 2.5 hrs after standard, medium-fat breakfast  Blood samples collected routinely during each part to determine whole blood concentrations of cyclosporine, tacrolimus, and plasma concentration of telaprevir  PK parameters determined using standard noncompartmental methods

clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Main Findings Garg V, et al. Hepatology. 2011;54:  Dose-normalized cyclosporine concentrations increased with coadministration of telaprevir vs cyclosporine administered alone  Both single-dose and steady-state telaprevir exerted marked effects on cyclosporine PK PK Parameter Cyclosporine 100 mg (n = 10) Cyclosporine 10 mg + Telaprevir Day 1 (n = 9) Cyclosporine 10 mg + Telaprevir Day 8 (n = 9) Mean GLS Mean RatioMean GLS Mean Ratio DN AUC 0-INF, ng*hr/mL/mg DN C max, ng/mL/mg t 1/2, hr t max, hr* V 2 /F, L CL/F, L/hr *Median.

clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Main Findings Garg V, et al. Hepatology. 2011;54:  Dose-normalized tacrolimus concentrations dramatically increased with coadministration of steady-state telaprevir vs tacrolimus administered alone  Steady-state telaprevir exerted very marked effects on tacrolimus PK –Most notably, dose-normalized C max increased 9.4-fold, dose-normalized AUC increased 70-fold, and t 1/2 increased ~ 5-fold PK Parameter Tacrolimus 2 mg (n = 10) Tacrolimus 0.5 mg + Telaprevir Day 8 (n = 9) Mean GLS Mean Ratio DN AUC 0-INF, ng*hr/mL/mg DN C max, ng/mL/mg t 1/2, hr t max, hr* V 2 /F, L CL/F, L/hr *Median.

clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Other Outcomes Garg V, et al. Hepatology. 2011;54:  Steady-state telaprevir exposure consistent with historical data whether coadministered with cyclosporine or tacrolimus –Findings suggest that neither single-dose cyclosporine nor single-dose tacrolimus had relevant effect on telaprevir exposure  Coadministration of telaprevir with either cyclosporine or tacrolimus generally well tolerated PK ParameterTelaprevir Day 8 + Cyclosporine (n = 9) Telaprevir Day 8 + Tacrolimus (n = 9) Mean AUC 0-8hr, ng*hr/mL21,90016,600 Mean C max, ng/mL Mean C min, ng/mL Median t max, hr

clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Summary of Key Conclusions  Coadministration of telaprevir with either cyclosporine or tacrolimus in healthy volunteers markedly increased exposure of both immunosuppressants compared with administration of either immunosuppressant without telaprevir –Cyclosporine AUC increased up to 4.6-fold –Tacrolimus AUC increased ~ 70-fold  Telaprevir has not been studied in transplantation patients  Study findings suggest that changes in cyclosporine and tacrolimus PK during coadministration with telaprevir could lead to serious or life-threatening adverse events, particularly in HCV-infected patients with compromised hepatic function Garg V, et al. Hepatology. 2011;54:20-27.