Darunavir/Ritonavir versus Simeprevir
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Study Design
Interactions between darunavir/ritonavir and simeprevir were evaluated in a phase I, randomized, open-label, threeperiod crossover study with a washout period of at least 7 days. Healthy subjects [n = 25 (13 male)] received simeprevir (150 mg once daily), darunavir/ritonavir (800/ 100 mg once daily) or simeprevir (50 mg once daily) plus darunavir/ritonavir (800/100 mg once daily) for 7 days [41]. A lower dose of simeprevir (50 mg once daily) was used in the simeprevir/darunavir/ritonavir coadministration group because of the increased simeprevir exposure seen with coadministration of simeprevir and ritonavir alone.
Study Results
There was increased exposure to simeprevir with coadministration in spite of the dose-reduction of simeprevir to 50 mg. The Cmax and AUC24h were 1.79- and 2.59-fold higher, respectively, in comparison with administration of 150 mg simeprevir alone. For darunavir, the Cmax and AUC24h were unaffected by coadministration (the Cmin was increased by 1.31-fold; however, the 90 % CIs for the darunavir Cmin and AUC24h did not include 1. For ritonavir, the Cmax and AUC24h were increased by 1.23- and 1.32-fold, respectively, with coadministration in comparison with ritonavir alone.
Drug Effect on PK PK Parameters
Cmax AUC Cmin
Simeprevir Increase 1.79 (1.55 – 2.06) 2.59 (2.15 – 3.11) 4.58 (3.54 – 5.92)
Darunavir/r Increase 1.04 (0.99 – 1.1) 1.18 (1.11 – 1.25) 1.31 (1.13 – 1.52)
Study Conclusions
Given the significant increase in simeprevir exposure, despite dose adjustment, coadministration of simeprevir and darunavir/ritonavir is not recommended.
References
Ouwerkerk-Mahadevan, S, Snoeys J, Peeters M, Beumont-Mauviel M, Simion A. Drug–drug interactions with the ns3/4a protease inhibitor simeprevir. Clinical Pharmacokinetics. 2016; 2: 197-208.
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