Purpose:
Act-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug-drug interaction study with atorvastatin and simvastatin to explore complex cyp3a4 inductive and inhibitory properties.
Methods:
Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. on days 6 to 33, 500 mg act-178882 was administered once daily. plasma concentrations of act-178882, simvastatin, and atorvastatin were measured by lc-ms/ms. routine safety assessments were performed throughout the study.
Results:
Exposure (as based on area under the curve) to simvastatin and 6ฮฒ-hydroxyacid simvastatin increased (90 % confidence interval) 4.63-fold (3.90, 5.50) and 3.71-fold (3.19, 4.32), respectively, when comparing day 9 and day 1. on day 9, exposure to atorvastatin was similar but cmax decreased, while both variables decreased for ortho-hydroxy atorvastatin when compared to day 1. on day 31, after prolonged administration of act-178882, exposure to atorvastatin, ortho-hydroxy atorvastatin, simvastatin, and 6ฮฒ-hydroxyacid simvastatin decreased by 14, 19, 21, and 27 %, respectively, when compared to day 9. however, on this day, exposure to simvastatin and its metabolite was still markedly higher when compared to day 1. effects of act-178882 had largely dissipated on day 41.
Conclusions:
This design enabled the study of complex time-dependent effects on cyp3a4 activity with clinically relevant substrates.