Application of physiologically based pharmacokinetic modeling in predicting drug-drug interactions for sarpogrelate hydrochloride in humans

Abstract

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.

Conclusion: 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.

Keywords: CYP2D6 inhibition; M-1; PBPK modeling; sarpogrelate hydrochloride.

Figure 1

Comparison of simulated and observed plasma concentration of sarpogrelate (A) and M-1 (B) after single oral dosing of sarpogrelate hydrochloride 100 mg. Notes: Thin colored lines represent the mean plasma concentration-time curves of sarpogrelate (A) and M-1 (B) for one virtual trial (n=10), the thick black lines indicate the overall mean for ten virtual trials (n=100). The dashed gray lines represent the 5th and 95th percentiles of simulated plasma concentration–time curves for ten virtual trials (n=100). Closed colored circles (blue; black; green; gray; orange24) represent mean plasma concentration-time curves of sarpogrelate (A) and M-1 (B) observed clinical data from the references.– Copyright ©2015. Adapted from John Wiley and Sons. Park JB, Bae SK, Bae SH, Oh E. Simultaneous determination of sarpogrelate and its active metabolite in human plasma by liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study. J Sep Sci. 2015;38(1):42–49. Adapted from the package insert of Anplag^® with permission of Yuhan Corporation. Adapted with permission from The Korean Society for Laboratory Medicine. Yang JS, Kim JR, Cho E, Huh W, Ko JW, Lee SY. A novel simultaneous determination of sarpogrelate and its active metabolite (M–1) in human plasma, using liquid chromatography-tandem mass spectrometry: clinical application. Ann Lab Med. 2015;35(4):391–398. Adapted from Journal of Pharmaceutical and Biomedical Analysis, 53(3), Zhang C, Wang L, Yang Y, et al, Validated LC-MS/MS method for the determination of sarpogrelate in human plasma: application to a pharmacokinetic and bioequivalence study in Chinese volunteers, 546–551, Copyright ©2010, with permission from Elsevier. Adapted with permission of Blackwell Publishing Ltd., from Takada Y, Takada A, Urano T. MCI-9042, the new selective antagonist of serotonergic (5-HT2A) receptors. Cardiovasc Drug Rev. 1997;15(2):101–121; permission conveyed through Copyright Clearance Center, Inc.

Figure 2

Sensitivity index plots of log P, B/P, fu_p, and fu_mic for sarpogrelate hydrochloride on the AUC (A, D, G, and J) and C_max (B, E, H, and K) of sarpogrelate, and the CYP2D6 inhibition (AUC fold ratio of metoprolol [C, F, I, and L]). Abbreviations: Log P, log-transformed partition coefficient; pKa, acid dissociation constant; B/P, blood-to-plasma partition coefficient; fu_p, fraction unbound in plasma; K_a, first-order absorption rate constant; fu_mic, fraction unbound in human liver microsomes; K_i, reversible inhibition constant; AUC, area under the curve; CYP, cytochrome P450; C_max, maximum plasma concentration.

Figure 3

Simulated and observed plasma concentration–time profiles of metoprolol after a single oral dose of 100 mg (A) in the absence of sarpogrelate; (B) after single oral dose of 100 mg sarpogrelate hydrochloride; (C) after multiple oral doses of 100 mg sarpogrelate hydrochloride (tid, for 3 days); (D) median AUC ratios of metoprolol with or without sarpogrelate simulated in ten different trial groups (n=10, closed diamonds). Notes: For figures (A–C), the thin lines indicate the simulated mean plasma concentration-time curve of metoprolol for each trials, the thick black lines represent the mean plasma concentration–time curve of metoprolol for ten trials and the closed circles are observed data. For figure (D), the solid green line represents the median of the virtual population and the dashed lines represent the 5th and 95th percentiles of the virtual population. (A–C) Copyright ©2015 Taylor & Francis. Cho DY, Bae SH, Lee JK, et al. Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers. Xenobiotica. 2015;45(3):256–263. Adapted by permission of Taylor & Francis Ltd, http://www.tandfonline.com. Abbreviations: AUC, area under the curve; tid, three times daily.