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Physiologically Based Pharmacokinetic Modeling of Fimasartan, Amlodipine, and Hydrochlorothiazide for the Investigation of Drug–Drug Interaction Potentials

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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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Correspondence to Kyung-Sang Yu.

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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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