Application of physiologically based pharmacokinetic modeling in predicting drug-drug interactions for sarpogrelate hydrochloride in humans.
BACKGROUND
Evaluating the potential risk of metabolic drug-drug interactions (DDIs) is clinically important.


OBJECTIVE
To develop a physiologically based pharmacokinetic (PBPK) model for sarpogrelate hydrochloride and its active metabolite, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine.


METHODS
The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol.


RESULTS
The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol, desipramine, imipramine, dextromethorphan, and tolterodine following single and multiple sarpogrelate hydrochloride oral doses were within the range of ≥1.25, but <2-fold, indicating that sarpogrelate hydrochloride is a weak inhibitor of CYP2D6 in vivo. Collectively, the predicted low DDIs suggest that sarpogrelate hydrochloride has limited potential for causing significant DDIs associated with CYP2D6 inhibition.


CONCLUSIONS
This study demonstrated the feasibility of applying the PBPK approach to predicting the DDI potential between sarpogrelate hydrochloride and drugs metabolized by CYP2D6. Therefore, it would be beneficial in designing and optimizing clinical DDI studies using sarpogrelate as an in vivo CYP2D6 inhibitor.
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon.
Jee Sun
JS
Min
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon.
Doyun
D
Kim
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon.
Jung Bae
JB
Park
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon.
Hyunjin
H
Heo
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea.
Soo Hyeon
SH
Bae
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon.
Jae Hong
JH
Seo
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon.
Euichaul
E
Oh
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon.
Soo Kyung
SK
Bae
D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000378:metabolism; D004123:Dimethylamines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D020005:Propanols / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D013386:Succinates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
C000616751:(R,S)-1-(2-(2-(3-methoxyphenyl)ethyl)-phenoxy)-3-(dimethylamino)-2-propanol; D004123:Dimethylamines; D020005:Propanols; D013386:Succinates; C064294:sarpogrelate; D019389:Cytochrome P-450 CYP2D6
CYP2D6 inhibition; M-1; PBPK modeling; sarpogrelate hydrochloride
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