Abstract
Purpose
To build a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide, and to investigate the drug–drug interaction (DDI) potentials.
Methods
The PBPK model of each drug was developed using Simcyp software (Version 15.0), based on the information obtained from literature sources and in vitro studies. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data collected from healthy subjects after multiple oral doses of fimasartan, amlodipine, and hydrochlorothiazide. The DDI potentials after co-administration of three drugs were simulated using the final model.
Results
The predicted-to-observed ratios of all the pharmacokinetic parameters met the acceptance criterion. The PBPK model predicted no significant DDI when fimasartan was co-administered with amlodipine or hydrochlorothiazide, which is consistent with the observed clinical data. In the simulation of DDI at steady-state after co-administration of three drugs, the model predicted that fimasartan exposure would be increased by ~24.5%, while no changes were expected for the exposures of amlodipine and hydrochlorothiazide.
Conclusions
The developed PBPK model adequately predicted the pharmacokinetics of fimasartan, amlodipine, and hydrochlorothiazide, suggesting that the model can be used to further investigate the DDI potential of each drug.
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Abbreviations
- ADAM:
-
Advanced dissolution absorption metabolism
- AUC:
-
Area under the concentration–time curve
- AUCτ,ss :
-
Area under the concentration–time curve within a dosing interval
- BCRP:
-
Breast cancer resistance protein
- CLpo,ss :
-
Apparent clearance at steady state
- Cmax,ss :
-
Maximum concentration at steady state
- CYP:
-
Cytochrome P450
- DBP:
-
Diastolic blood pressure
- DDI:
-
Drug-drug interaction
- GMR:
-
Geometric mean ratio
- HEK293:
-
Human embryonic kidney 293 cell
- HLM:
-
Human liver microsome
- Kp :
-
Tissue-to-plasma partitioning coefficients
- LLC-PK1:
-
Porcine kidney epithelial cell
- MDCK:
-
Madin Darby canine kidney
- Mech KiM:
-
Mechanistic kidney model
- OAT:
-
Organic anion transporter
- OATP:
-
Organic anion transporting polypeptide
- OCT:
-
Organic cation transporter
- PBPK:
-
Physiologically based pharmacokinetic
- Peff,man :
-
Effective permeability in human
- PerL:
-
Permeability-limited liver model
- RAF/REF:
-
Relative activity factor or relative expression factor
- SBP:
-
Systolic blood pressure
- Tmax,ss :
-
Time to Cmax,ss
- UGT:
-
UDP-glucuronosyltransferase
- Vss :
-
Steady state volume of distribution
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Rhee, Sj., Lee, H.A., Lee, S. et al. Physiologically Based Pharmacokinetic Modeling of Fimasartan, Amlodipine, and Hydrochlorothiazide for the Investigation of Drug–Drug Interaction Potentials. Pharm Res 35, 236 (2018). https://doi.org/10.1007/s11095-018-2511-5
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DOI: https://doi.org/10.1007/s11095-018-2511-5