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Pharmaceutical Research

, Volume 29, Issue 10, pp 2860–2873 | Cite as

Physiologically Based Modeling of Pravastatin Transporter-Mediated Hepatobiliary Disposition and Drug-Drug Interactions

  • Manthena V. S. Varma
  • Yurong Lai
  • Bo Feng
  • John Litchfield
  • Theunis C. Goosen
  • Arthur Bergman
Research Paper

ABSTRACT

Purpose

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/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.

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.

KEY WORDS

drug-drug interaction OATP1B1 physiologically based pharmacokinetic (PBPK) model pravastatin transporters 

ABBREVIATIONS

AUC

area under the plasma concentration-time curve

BCRP

breast cancer resistance protein

Cmax

maximum plasma concentration

DDI

drug-drug interaction

Fa

fraction absorbed

fu

fraction unbound

fuinc

fraction unbound in the incubations

Iin,max

maximum inhibitor concentration at the inlet to the liver

Ki

inhibition constant

MRP

multidrug resistance-associated protein

OATP

organic anion transporting polypeptide

PBPK

physiologically based pharmacokinetic

PPE

percentage prediction error

SCHH

sandwich cultured human hepatocyte

SF

scaling factor

Notes

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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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Manthena V. S. Varma
    • 1
  • Yurong Lai
    • 1
  • Bo Feng
    • 1
  • John Litchfield
    • 1
  • Theunis C. Goosen
    • 1
  • Arthur Bergman
    • 2
  1. 1.Pharmacokinetcis, Dynamics and MetabolismPfizer Inc.GrotonUSA
  2. 2.Clincial PharmacologyPfizer Inc.GrotonUSA

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