E. Tsakalozou,1 M. Sampson,1 M. Z. Wang,2 K. L. Brouwer1; 1University of North Carolina, Chapel Hill, NC, 2University of Kansas, Lawrence, KS
BACKGROUND: Lovastatin induced CYP4F2 in vitro and may increase vitamin K metabolism. However, lovastatin and warfarin coadministration at therapeutic doses in healthy subjects did not affect INR. To evaluate lovastatin hepatic exposure, a WB-PBPK model for lovastatin lactone and active acid metabolite was developed.
METHODS: GastroPlusTM was used to integrate lovastatin physicochemical properties and published estimates for lactone CYP3A4 metabolism and hydrolysis, OATP1B1-mediated acid uptake, and lactone MDR1- and acid MRP2-mediated biliary clearance. Vmax values for lactone-acid interconversion were fit to describe the impact of pH. Sensitivity analysis was performed.
RESULTS: Simulations agreed with reported plasma lovastatin concentration-time data (Figure). Predicted total lovastatin hepatic Cmax was 1.5ng/mL (3.75 nM), which was lower than concentrations reported to induce CYP4F2 in vitro (1000 nM). Systemic lactone and acid exposure were dependent on metabolism/hydrolysis and OATP1B1 expression.
CONCLUSION: This novel mechanistic WB-PBPK model incorporated factors influencing lactone and acid disposition. Results suggested low warfarin-lovastatin interaction potential. Limitations to be addressed in future modeling efforts include the pH-dependent lactone-acid interconversion.