Physiologically Based Modeling of Pravastatin Transporter-Mediated Hepatobiliary Disposition and Drug-Drug Interactions
To develop physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and drug-drug interactions (DDI) of pravastatin, using the in vitro transport parameters.
In vitro hepatic sinusoidal active uptake, passive diffusion and canalicular efflux intrinsic clearance values were determined using sandwich-culture human hepatocytes (SCHH) model. PBPK modeling and simulations were implemented in Simcyp (Sheffield, UK). DDI with OATP1B1 inhibitors, cyclosporine, gemfibrozil and rifampin, was also simulated using inhibition constant (Ki) values.
SCHH studies suggested active uptake, passive diffusion and efflux intrinsic clearance values of 1.9, 0.5 and 1.2 μL/min/106cells, respectively, for pravastatin. PBPK model developed, using transport kinetics and scaling factors, adequately described pravastatin oral plasma concentration-time profiles at different doses (within 20% error). Model based prediction of DDIs with gemfibrozil and rifampin was similar to that observed. However, pravastatin-cyclosporine DDI was underpredicted (AUC ratio 4.4 Vs ~10). Static (R-value) model predicted higher magnitude of DDI compared to the AUC ratio predicted by the PBPK modeling.
PBPK model of pravastatin, based on in vitro transport parameters and scaling factors, was developed. The approach described can be used to predict the pharmacokinetics and DDIs associated with hepatic uptake transporters.
KEY WORDSdrug-drug interaction OATP1B1 physiologically based pharmacokinetic (PBPK) model pravastatin transporters
area under the plasma concentration-time curve
breast cancer resistance protein
maximum plasma concentration
fraction unbound in the incubations
maximum inhibitor concentration at the inlet to the liver
multidrug resistance-associated protein
organic anion transporting polypeptide
physiologically based pharmacokinetic
percentage prediction error
sandwich cultured human hepatocyte
ACKNOWLEDGMENTS & DISCLOSURES
The authors would like to thank Emi Kimoto and Yi-An Bi for conducting the SCHH studies, and Larry Tremaine and Dennis Scott for the valuable suggestions on the manuscript. All authors are full-time employees of Pfizer Inc.
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