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

Figures & data

Table 1 Observed and predicted pharmacokinetic parameters of sarpogrelate and M-1 after single (50 mg, 100 mg, or 400 mg) and multiple (100 mg, three times for 1 day) oral administration of sarpogrelate hydrochloride

Single	Ref	Sarpogrelate			M-1
		AUC (ng h/mL)	Cmax (ng/mL)	Tmax (hours)	AUC (ng h/mL)	Cmax (ng/mL)	Tmax (hours)
50 mg	^Citation21	265.9 (41.2)	269.3 (68.4)	0.66 (46.6)
Predicted		322.2 (41.3)	237.1 (43.8)	0.84 (12.4)	45.5 (54.6)	16.5 (45.3)	1.11 (14.3)
100 mg	^Citation21	535.2 (44.7)	602.8 (55.9)	0.78 (73.2)
100 mg	^Citation20	621.5 (47.3)	635.1 (26.1)	0.67 (0.3–1.5)a	86.2 (9.10)	47.6 (20.3)	1.0 (0.33–1.5)a
100 mg	^Citation22	567.5 (67.2)	429.8 (61.7)	1.00 (1.0–4.0)a
100 mg	^Citation23	417.8 (32.4)	592.2 (47.8)	0.39 (50)
100 mg	^Citation24	348.3 (27.8)	343.0 (33.3)	1.15 (41.7)
Predicted		645.4 (41.4)	494.2 (43.8)	0.84 (12.4)	91.0 (54.6)	38.9 (50.7)	1.11 (14.2)
400 mg	^Citation24	2,210 (17.9)	1,824.8 (30.5)	1.37 (28.6)
Predicted		2,579 (41.3)	1,816.9 (43.8)	0.84 (12.4)	322.5 (49.8)	102.4 (51.4)	1.45 (11.5)
Multiple	Ref	AUC (ng h/mL)b	Cmax (ng/mL)	Tmax (hours)	AUC (ng h/mL)b	Cmax (ng/mL)	Tmax (hours)
100 mg	^Citation41	1,773 (33.5)	761.0 (35.1)	0.48 (0.2–1.5)a
100 mg	^Citation42	1,443 (33.8)	781.6 (41.5)	0.70 (0.3–3.0)a	246.2 (30.7)	44.7 (43.4)	0.9 (0.3–3.0)a
100 mg	^Citation43	1,291 (31.7)	466.0 (39.8)	0.67 (0.3–3.0)a	267.2 (40.3)	43.9 (46.7)	0.7 (0.3–2.0)a
Predicted		1,951 (41.3)	502.9 (43.8)	0.90 (0.6–1.15)a	254.4 (54.9)	39.1 (51.1)	1.15 (0.8–1.6)a

Notes: Values are expressed as geometric mean (coefficient of variation, [%]).

a T_max data represent median (range).

b AUC from 0 to 24 hours.

Abbreviations: AUC, area under the curve; M-1, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol; Ref, reference; C_max, maximum plasma concentration; T_max, time to achieve C_max.

Table 2 Input parameters of sarpogrelate hydrochloride and M-1 used in the physiologically based pharmacokinetic model development

Parameter	Sarpogrelate hydrochloride		M-1
Physicochemical properties	Input parameters	Reference/comments	Input parameters	Reference/comments
Molecular weight (g/mol)	465.97	www.Chembase.cn	329.4333
Log P	1.12		3.58	Predicted from Simcyp^®
Compound type	Monoprotic acid		Monoprotic base
pKa	3.78		8.7	Predicted from Simcyp^®
B/P	0.55	Default in Simcyp^®	0.55	Default in Simcyp^®
fup	0.05	Reference ^Citation17	0.03	Reference ^Citation17
Absorption: ADAM model
PSA	85.3	www.Chembase.cn
Peff in man (10^−4 cm/s)	3.28	Predicted from Simcyp^®
fa	1.0	Assumed from Reference ^Citation21
Ka (1/h)	1.349	Predicted from Simcyp^®
Lag time (hours)	0	Assumed from Reference ^Citation21
Distribution: Full PBPK
Vss (L/kg)	0.100	Calculated using Simcyp^® (Method 2)	0.485	Calculated using Simcyp^® (Method 2)
Elimination: Enzyme kinetics model
CLpo (L/h)	140	Calculated from clinical data
CLint for M-1 formation (μL/min/mg protein)	32.6	Measured
Additional CLint in HLM (μL/min/mg protein)	17.4	Measured
Additional systemic clearance (L/h)	90	Optimized using back-calculated retrograde method from Simcyp^®
CLint by rUGT1A4/rUGT1A9/rUGT2B7rUGT2B4 (μL/min/mg protein)			0.63/1.30/0.32/1.56	Reference 40
Additional CLint in HLM (μL/min/mg protein)			150	Measured
fumic	0.969	Predicted from Simcyp^®	0.3	Reference ^Citation17
CLR (L/h)	0	Assumed based on clinical information
Interactions
CYP2D6 Ki (μM)a	1.24	Reference ^Citation17	0.12	Reference ^Citation17

Note:

a Competitive inhibition type.

Abbreviations: ADAM, advanced dissolution absorption metabolism; B/P, blood-to-plasma partition coefficient; CL_int, intrinsic clearance; CL_po, oral systemic clearance; CL_R, renal clearance; f_a, fraction absorbed in the gastrointestinal tract; fu_mic, fraction unbound in human liver microsomes; fu_p, fraction unbound in plasma; HLM, human liver microsomes; K_a, first-order absorption rate constant; K_i, reversible inhibition constant; Log P, log-transformed partition coefficient; M-1, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol; pKa, acid dissociation constant; PSA, polar surface area; P_eff, human jejunum permeability; V_ss, volume of distribution at steady state.

Table 3 The predicted AUC and C_max fold ratios of CYP2D6 substrates with or without sarpogrelate hydrochloride in DDI study simulations for the ten trials with ten subjects each. For multiple dose administration, after pretreatment of sarpogrelate hydrochloride for 3 days (100 mg tid) and each CYP2D6 substrate were coadministered with sarpogrelate hydrochloride on day 4

CYP2D6 substrates			Sarpogrelate hydrochloride
Compound	Dose (mg)	Dosage regimen	Single dose, day 1		Multiple doses, day 4
			AUC ratio	Cmax ratio	AUC ratio	Cmax ratio
Metoprolol	100	qd	1.33 (1.29–1.37)	1.35 (1.30–1.39)	1.35 (1.31–1.39)	1.35 (1.31–1.39)
Desipramine	50	qd	1.26 (1.24–1.28)	1.28 (1.26–1.30)	1.27 (1.25–1.29)	1.28 (1.26–1.30)
Imipramine	50	qd	1.29 (1.27–1.31)	1.30 (1.27–1.33)	1.32 (1.29–1.36)	1.33 (1.30–1.36)
Dextromethorphan	30	qd	1.79 (1.62–1.96)	1.93 (1.77–2.10)	1.94 (1.78–2.12)	2.09 (1.94–2.26)
Tolterodine	2	bid	1.43 (1.38–1.49)	1.37 (1.32–1.42)	1.46 (1.43–1.50)	1.39 (1.36–1.42)

Note: Values were expressed as simulated geometric mean ratio (95% CI).

Abbreviations: AUC, area under the curve; CI, confidence interval; CYP, cytochrome P450; qd, once daily; bid, twice daily; DDI, drug–drug interaction; C_max, maximum plasma concentration.

Table 4 Inhibition of sarpogrelate and M-1 on loperamide transport in MDCK-II-P-gp and loperamide transport in MDCK-II-BCRP cells

Cells	Inhibitor		Permeability (×10^−6 cm/s)		Inhibition (%)
	Compounds	Concentration (µM)	Papp,ABa	Papp,BAb
MDCK-II-P-gp	Controlc	10	0.144±0.0292	2.05±0.133
	Cyclosporine A	10	0.373±0.0577*	0.329±0.00822*	102
	Sarpogrelate	0.2	0.109±0.00601	1.84±0.00493	9.18
		2	0.108±0.00187	1.83±0.00447	9.72
		10	0.120±0.00365	1.83±0.147	9.95
	M-1	0.2	0.0894±0.0188	1.95±0.0443	2.00
		2	0.0822±0.0192	1.84±0.0249	7.82
		10	0.104±0.0243	1.95±0.0403	2.91
MDCK-II-BCRP	Controld	10	0.813±0.0548	3.33±0.274
	Ko143	10	0.968±0.0510	1.67±0.137*	72.3
	Sarpogrelate	0.2	0.697±0.109	3.15±0.205	2.69
		2	0.775±0.110	3.09±0.233	9.62
		10	0.813±0.0548	3.34±0.0411	0.380
	M-1	0.2	0.891±0.0355	3.42±0.0237	0.380
		2	0.813±0.0547	3.31±0.0467	0.771
		10	0.811±0.0111	3.32±0.0139	0.381

Notes: Each value represents the mean ± SD (n=3).

* Significantly different from the control value by Dunnett’s test (P<0.05).

a P_app,AB represents apparent permeability of apical to basolateral transport of loperamide (prazosin) in MDCK-II-P-gp (MDCK-II-BCRP) cells.

b P_app,BA represents apparent permeability of basolateral to apical transport of loperamide (prazosin) in MDCK-II-P-gp (MDCK-II-BCRP) cells.

c Control represents loperamide alone without the addition of P-gp inhibitors.

d Control represents prazosin alone without the addition of BCRP inhibitors.

Abbreviations: MDCK, Madin-Darby canine kidney; BCRP, breast cancer resistance protein; SD, standard deviation; M-1, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol.

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;²⁰ black;²¹ green;²² gray;²³ orange²⁴) represent mean plasma concentration-time curves of sarpogrelate (A) and M-1 (B) observed clinical data from the references.^20–24 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):42–49.²⁰ Adapted from the package insert of Anplag^® with permission of Yuhan Corporation.²¹ 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):391–398.²² 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.²³ 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.²⁴

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.²⁵ 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.²⁵
Abbreviations: AUC, area under the curve; tid, three times daily.

Anplag^® (sarpogrelate hydrochloride) [package insert]OsakaMitsubishi Tanabe Pharma Corporation2012

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