29 Therefore, APO866 chemical structure the effect of telaprevir on these drugs may also vary based on CYP3A5 genotype. Although cyclosporine is a CYP3A and P-gp inhibitor,18 the effects of a single cyclosporine dose on systemic telaprevir exposure were considered negligible, because the cyclosporine dose (10 mg) was low and administered 2 hours after telaprevir administration. This study was not designed to test the effect of cyclosporine and tacrolimus on telaprevir exposure. However, telaprevir steady-state exposure in Parts A and B were similar to previous Phase I studies,22 so it is unlikely that coadministration of cyclosporine

or tacrolimus had a relevant effect on telaprevir exposure. Food decreases cyclosporine and tacrolimus exposure (Cmax by 33% and 65%; AUC by 13% and 28%, respectively),18, 19 whereas telaprevir exposure increases with food. Telaprevir was administered 30 minutes after the start

of a meal and cyclosporine or tacrolimus were administered 2 hours after telaprevir during coadministration. Volunteers refrained from further food or drink during the period see more between administration of telaprevir and cyclosporine or tacrolimus. This approach was used to minimize food effect on cyclosporine and tacrolimus exposure, while providing appropriate telaprevir dosing conditions. The extent to which simultaneous telaprevir administration with cyclosporine or tacrolimus in the fed state would impact these results is unknown. Another important consideration about concomitant tacrolimus or cyclosporine use with telaprevir in organ transplant patients is that after telaprevir treatment is completed or stopped, its inhibitory effect on CYP3A/P-gp would wear off and doses of immunosuppressant would need readjustments. Estimates of the recovery time of CYP3A activity vary widely30 and precise timing for CYP3A activity to resume to the levels before the start of telaprevir is unknown. Therefore, careful

blood concentration monitoring of immunosuppressants will be needed for approximately 2 weeks after telaprevir is stopped. Besides cyclosporine and tacrolimus, other immunosuppressants that are likely to have a significant interaction with telaprevir include those known 上海皓元 to have increased exposures when coadministered with strong CYP3A inhibitors, such as sirolimus and everolimus. Exposure of corticosteroids known to be metabolized by way of CYP3A may also increase in the presence of strong CYP3A inhibitors. However, studies with these drugs in combination with telaprevir have not been conducted. Finally, telaprevir has not been studied in pre-, post-, or peritransplant patients. The degree of the interaction with calcineurin inhibitors reported here suggests potential implications for patient safety.