Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions.
OBJECTIVE
To develop physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and drug-drug interactions (DDI) of pravastatin, using the in vitro transport parameters.


METHODS
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.


RESULTS
SCHH studies suggested active uptake, passive diffusion and efflux intrinsic clearance values of 1.9, 0.5 and 1.2 μL/min/10(6)cells, 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.


CONCLUSIONS
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.
Pharmacokinetcis, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut, USA. manthena.v.varma@pfizer.com
Manthena V S
MV
Varma
Yurong
Y
Lai
Bo
B
Feng
John
J
Litchfield
Theunis C
TC
Goosen
Arthur
A
Bergman
D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001692:Biological Transport; D002478:Cells, Cultured; D003198:Computer Simulation; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D015248:Gemfibrozil / Q000008:administration & dosage / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D017035:Pravastatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
D004791:Enzyme Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D016572:Cyclosporine; D017035:Pravastatin; D015248:Gemfibrozil; D012293:Rifampin