Oliver Hatley (1), Rachel H. Rose (1), Masoud Jamei (1)
(1) Simcyp Ltd (a Certara Company), Sheffield, UK
Objectives: The fractional contribution of an enzyme to systemic elimination (fm) is an important determinant of the drug-drug interaction (DDI) potential of a victim drug. In static DDI predictions, fm is assumed to be constant. However, this assumption is not valid for victim drugs that show for example metabolism saturation or time-dependent inhibition (autoinhibition) of one or more of their own metabolic pathways. Time variation in the fm of CYP2D6 and CYP3A4 was investigated for paroxetine, which is both a substrate and a potent mechanism-based inhibitor (MBI) of CYP2D6.
Methods: Multiple daily dosing of 30 mg paroxetine for 21 days was simulated in the Simcyp Simulator V15.1 for CYP2D6 extensive metabolisers (EMs) and poor metabolisers (PMs) using the built-in Sim-Healthy Volunteer population library and SV-Paroxetine compound file. The paroxetine model includes MBI for both CYP2D6 and CYP3A4. DDI with ketoconazole (400mg QD for 8 days) was simulated for paroxetine on day 1 and day 21. Dynamic variation in fm for CYP2D6 and CYP3A4 was considered for paroxetine, assuming a well-stirred liver model and accounting for the minor contribution of renal elimination.
Results: For CYP2D6 EMs, the fm CYP2D6 was 0.97-0.98 for the first dose paroxetine, and decreased to 0.54-0.71 on day 21 as a result of MBI. The reported range of fm values for EMs reflect concentration sensitivity of MBI, as well as a progressive change in fm over time. The fm CYP3A4 was 0.016-0.021 for the first dose and increased to 0.22-0.35 on day 21, which corresponded to an increase in the predicted AUC ratio in the presence of ketoconazole from 1.13 (day 1) to 1.97 (day 21). For CYP2D6 PMs, the fm CYP3A4 was 0.77 (day 1) and 0.75 (day 21) and AUC ratio with ketoconazole was 1.21 (day 1) to 1.68 (day 21).
Conclusions: For paroxetine, autoinhibition of CYP2D6 in EMs results in a decrease in fm CYP2D6 and corresponding increase in CYP3A4 fm following multiple dosing. This observation explains an increased susceptibility to DDI with the CYP3A4 inhibitor ketoconazole following multiple dosing. The absence of CYP2D6 in PMs results in little change in CYP3A4 fm following multiple dosing and a smaller increase in ketoconazole DDI. Dynamic models that incorporate the time variation in fm can predict and explain differences in DDI liability following single and multiple dosing of a victim with autoinhibition, autoinduction or metabolism saturation.
Reference: PAGE 25 () Abstr 5816 [www.page-meeting.org/?abstract=5816]
Poster: Drug/Disease modeling - Absorption & PBPK