Simeprevir + Tacrolimus = Precautionary

Effect on Concentration

Simeprevir
Increase
Applies within class?
No
Tacrolimus
Decrease
Applies within class?
No

Pharmacologic Effects

Simeprevir
Effect
N/A
Applies within class?
No
Tacrolimus
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 18-Jul-2018

Summary

Sources

Simeprevir versus Tacrolimus ^

Study Design

In a twopanel, randomized, open-label, two-period crossover study, 14 healthy subjects (seven male) received tacrolimus (2 mg single dose) or simeprevir (150 mg once daily on days 1–12) plus tacrolimus (2 mg single dose on day 7). An ongoing phase II open-label study investigated the combination of simeprevir, daclatasvir, and ribavirin in patients with recurrent chronic HCV genotype 1b infection after liver transplantation. Patients received simeprevir (150mg) and daclatasvir (60mg) daily with ribavirin (1-1.2g/day) along with immunosuppresive agents cyclosporine A or tacrolimus. PK sampling was performed on day 14. 20 participants were included in the study. 11 participants were treated with tacrolimus.

Study Results

In the initial phase of this study, For tacrolimus, the mean Cmax was decreased by 24 % and the mean AUClast was decreased by 17 % with simeprevir coadministration in comparison with tacrolimus alone. In the second phase of this study, the interim analysis demonstrated 79 and 85 % increases in the Cmax and AUC24h, respectively, of simeprevir in subjects receiving simeprevir plus tacrolimus, in comparison with historical data on simeprevir alone (data on ?le). \ Drug AUC (LSMR 90% CI) Cmax (LSMR 90% CI) Simeprevir 150mg 1.85 (1.18-2.91) 1.79 (1.22-2.62) PK studies resulted in an increase in AUC and Cmax of simeprevir when co-administered with individualized tacrolimus doses .However, a decrease in AUC and Cmax of tacrolimus was noted when coadministered with simeprevir (150mg) daily for 7 days (n=14). Drug AUC LSMR (90% CI) Cmax LSMR (90% CI) Tacrolimus 2mg 0.83 (0.59-1.16) 0.76 (0.65-0.90)

Study Conclusions

The increased plasma concentrations of simeprevir when co-administered with tacrolimus were attributed to inhibition of OATP1B1 by tacrolimus. The authors concluded that co-administration of simeprevir and tacrolimus is possible without dose adjustment of either drug. Due to the very wide 90% confidence intervals, caution is recommended when utilizing this combination due to the uncertainty of the response. Further, due to a narrow therapeutic index, therapeutic drug monitoring of tacrolimus is always recommended.

References

Ouwerkerk Mahadevan S, Snoeys J, Peeters M, Beaumont Mauviel M, Simion A. Drug–drug interactions with the ns3/4a protease inhibitor simeprevir. Clinical Pharmacokinetics. 2016; 2: 197-208.