Simeprevir + Cyclosporine = Precautionary

Effect on Concentration

Simeprevir
Increase
Applies within class?
No
Cyclosporine
No change
Applies within class?
No

Pharmacologic Effects

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

Interaction History

N/A

Last Updated 18-Jul-2018

Summary

Sources

Simeprevir versus Cyclosporine ^

Study Design

In a two-panel, randomized, open-label, two-period crossover study, 14 healthy subjects (eight male) received cyclosporine (100 mg single dose) or simeprevir (150 mg once daily on days 1–10) plus cyclosporine (100 mg single dose on day 7). Simeprevir alone was administered under fed conditions; all other treatments were administered under fasting conditions. In an ongoing phase of this open-label, multicentre study in subjects with recurrent HCV genotype 1b infection following orthotopic liver transplantation with METAVIR fibrosis scores of F1–F2, nine patients who were on stable immunosuppressive therapy with cyclosporine [n = 9 (five male)] and received simeprevir (150 mg once daily), daclatasvir (60 mg once daily) or body weight–based RBV (range 1000–1200 mg daily) were analyzed.

Study Results

In the first study arm, the mean cyclosporine Cmax was increased by 1.16-fold and the cyclosporine AUClast was increased by 1.19-fold with simeprevir coadministration in comparison with cyclosporine alone. In the second study arm, a planned review of interim pharmacokinetic data (from the day 14 pharmacokinetic analysis) showed increases of 4.7- and 5.8-fold in the Cmax and AUC24h, respectively, for simeprevir [Cmax 15,321 ng/mL (n = 9); Drug AUC LSMR (90% CI) Cmax LSMR (90% CI) Simeprevir 5.81 (3.56-9.48) 4.74 (3.12-7.18) Cyclosporine 1.19 (1.13-1.26) 1.16 (1.07-1.26) Of the 9 participants in the second study, 7 of them required dose reductions to every other day dosing of simeprevir. There were no significant safety findings.

Study Conclusions

Concomitant use of simeprevir and cyclosporine is not recommended due to significantly increased plasma concentrations of simeprevir from inhibition of CYP3A, OATP1B1 and P-gp by cyclosporine. Coadministration did not result in significant pharmacokinetic changes in cyclosporine.

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.