Pharmacokinetic Interactions Between Elbasvir/Grazoprevir and Immunosuppressant Drugs in Healthy Volunteers

Abstract

Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4-part, open-label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once-daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24-hour area under the concentration-time curve of GZR was increased by approximately 15-fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2-fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations.

Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir

“…Grazoprevir is a weak CYP3A inhibitor (14), while data suggest that elbasvir is not a CYP3A inhibitor (50% inhibitory concentration [IC 50 ] of Ͼ100 M) (14). In DDI trials of grazoprevir with midazolam and tacrolimus, both CYP3A substrates (14,25), grazoprevir increased the AUC of midazolam by approximately 30% (14), and coadministration with elbasvir-grazoprevir increased the AUC of tacrolimus by approximately 40% (26), which is comparable with the effect of grazoprevir on doravirine. Elbasvir inhibited P-gp in vitro but did not have a clinically meaningful effect on the PK of digoxin (14).…”

Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection

“…Importantly, complex interactions occur between DAAs and calcineurin inhibitors . Coadministration of elbasvir/grazoprevir and cyclosporine leads to a 15‐fold increase in grazoprevir and a 2‐fold increase in elbasvir area under the concentration–time curve; this DAA regimen and immunosuppressant combination should be avoided. A 40%‐50% increase in tacrolimus level is predicted with coadministration of elbasvir/grazoprevir; no dosing adjustments are anticipated, but tacrolimus levels should be monitored.…”

“…(383)(384)(385)(386)(387)(388) Coadministration of elbasvir/grazoprevir and cyclosporine leads to a 15-fold increase in grazoprevir and a 2-fold increase in elbasvir area under the concentration-time curve (389) ; this DAA regimen and immunosuppressant combination should be avoided. A 40%-50% increase in tacrolimus level is predicted with coadministration of elbasvir/grazoprevir (389) ; no dosing adjustments are anticipated, but tacrolimus levels should be monitored. Please see the online HCV guidance for additional information about drug-drug interactions between DAAs and immunosuppressants as well as other medications.…”

Process of selecting and educating HCV‐uninfected kidney waiting‐list candidates for HCV‐infected kidney transplantation

“…Side effects in the post‐KT setting may be more frequent or severe, although trials and retrospective series in KT recipients do not suggest a dramatic increase in side effects. However, pharmacokinetic interactions between elbasvir and grazoprevir and immunosuppression are important to recognize; both drugs can increase the tacrolimus area under the curve and cyclosporine can dramatically increase grazoprevir . Therefore, careful tacrolimus monitoring may be required after transplant.…”

“…However, pharmacokinetic interactions between elbasvir and grazoprevir and immunosuppression are important to recognize; both drugs can increase the tacrolimus area under the curve and cyclosporine can dramatically increase grazoprevir. 21 Therefore, careful tacrolimus monitoring may be required after transplant. There is no clinically relevant drug-drug interaction between grazoprevir and elbasvir with mycophenolate mofetil and prednisone.…”