5-mg dose; day 8, period 2) are presented in Fig. 2. Tacrolimus concentrations were considerably higher when coadministered with telaprevir than for tacrolimus administered alone. The mean (SD) PK and statistical parameters for tacrolimus administered either alone (2-mg dose; day 1, period 1) or with telaprevir Opaganib supplier (0.5-mg dose; day 8, period 2) are summarized in Table 2. In Part B, a comparison of PK parameters when tacrolimus was administered alone versus coadministered with telaprevir indicated that median tmax of tacrolimus increased from 2.25 hours on day 1, period 1 to 3.03 hours on day 8, period 2; mean Vz/F decreased from 1,910 L on day 1, period 1 to 106 L on day 8, period 2; mean CL/F decreased from 32.0

L/h on day 1, period 1 to 0.48 L/h on day 8, period 2; and mean t½ increased from 40.7 hours on day 1, period 1 to 196 hours on day 8, period 2. The DN_Cmax GLS mean ratio (90% CI) for tacrolimus coadministered with telaprevir was 9.35 (6.73, 13.0) on day 8, period 2 compared to tacrolimus administered alone (day 1, period 1). Similarly, the DN_AUC0-∞ GLS mean ratio (90% CI) for tacrolimus

coadministered with telaprevir was 70.3 (52.9, 93.4) on day 8, period 2 compared to tacrolimus administered alone (day 1, period 1), indicating a significant effect of telaprevir on the PK of tacrolimus. Mean (SD) PK parameters for telaprevir when coadministered with either cyclosporine or tacrolimus are shown in Table 3. Steady-state concentrations of telaprevir on day 8, period 2 were similar

when telaprevir was coadministered Gamma-secretase inhibitor with either cyclosporine or tacrolimus. Steady-state exposure of telaprevir reported in this study was comparable with historical data.22 In Part A, adverse events of mild vessel puncture site pain (n = 1), mild pharyngitis (n = 1), mild accidental needle stick (n = 1), and moderate neutropenia (n = 1) occurred when cyclosporine was administered alone. Moderate neutropenia led to premature discontinuation of the volunteer from the study. Adverse events of mild dyspepsia (n = 1); mild rash (n = 2); mild herpes simplex eltoprazine (n = 1); mild contusion (n = 1); mild blood creatine phosphokinase increase (n = 1); mild somnolence (n = 1); and mild vaginal discharge (n = 1) occurred when cyclosporine was coadministered with telaprevir. Dyspepsia and rash were considered by the study investigator to be possibly related to the study drugs. In Part B, an adverse event of mild constipation (n = 1) occurred when tacrolimus was administered alone. Adverse events of mild pruritus (n = 1) and mild excoriation (n = 1) occurred when tacrolimus was coadministered with telaprevir. No serious, life-threatening, or severe adverse events occurred in any group. There were no notable clinically significant trends for any of the chemistry parameters, hematology parameters, vital signs, 12-lead electrocardiograms, or physical examination findings.