Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y₁₂ inhibitor

Abstract

Aims

We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects.

Methods

CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open‐label, 2‐period cross‐over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7.

Results

After a loading dose, the AUC_0‐t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC_0‐t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28‐fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs.

Conclusions

CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs.

What is already known about this subject

• Administration of clopidogrel and aspirin is the standard treatment to prevent cardiovascular events in patients with acute coronary syndrome and percutaneous coronary intervention. However, the variability in patient responses to clopidogrel has become an increasingly important clinical issue. Genetic polymorphisms of CYP2C19 are associated with variations in response.

• Vicagrel is a novel thienopyridine P2Y₁₂ inhibitor that is now in Phase III development in China. It is an analogue of clopidogrel and has pharmacological effects that are based on the same active thiol metabolite as clopidogrel. However, vicagrel has a different metabolic pathway, which is designed to produce the active metabolite more efficiently and to be less influenced by CYP219 polymorphisms compared to clopidogrel.

What this study adds

• The predictions of more efficient active metabolite formation and decreased effects of CYP2C19 polymorphisms on vicagrel were confirmed in this randomized, open‐label, 2‐period cross‐over, clopidogrel‐controlled, multiple‐dose study.

• The plasma drug exposure and platelet inhibition were compared between vicagrel and clopidogrel in CYP2C19 extensive metabolizers, intermediate metabolizers (IMs), and poor metabolizers (PMs). Exposure to the active metabolite by vicagrel was higher than that by clopidogrel in either the CYP2C19 IM or the PM subjects, and it was comparable to clopidogrel in CYP2C19 extensive metabolizers. Consequently, the pharmacodynamic responses to vicagrel are greater than to clopidogrel in CYP2C19 IM and PM subjects.

1. INTRODUCTION

Cardiovascular disease is the leading cause of death worldwide, and acute coronary syndrome in many cardiovascular disease patients is a life‐threatening disorder with high morbidity and mortality. ¹ The combination of aspirin and a P2Y₁₂ receptor inhibitor is the standard treatment to prevent cardiovascular events in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. ² Of the available P2Y₁₂ receptor inhibitors, clopidogrel is most popularly used in clinic. Clopidogrel is a prodrug that needs hepatic bioactivation by primarily cytochrome P450 2C9 (CYP2C19) to form the pharmacologically active thiol metabolite, H4, which prevents platelet aggregation through irreversibly inhibiting the platelet receptor, P2Y_12. ³ , ⁴ , ⁵ There is significant interindividual variability in response to clopidogrel treatment. Some patients continue to have cardiovascular events despite receiving clopidogrel, which is known as clopidogrel resistance. ⁶ , ⁷ , ⁸ By contrast, some patients experience drug‐induced bleeding due to excessive platelet inhibition. ⁹ The mechanism of these variations in response to clopidogrel therapy is multifactorial, and genetic polymorphisms of CYP2C19 were found to have close associations with the observed variations. ¹⁰ , ¹¹ , ¹² Compared with wild type (*1/*1) individuals, CYP2C19 nonfunctional allele (*2 or *3) carriers exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation and, therefore, are at significantly higher risk for adverse cardiovascular events. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ On 12 March 2010, the US Food and Drug Administration changed the prescribing information for clopidogrel to highlight the impact of the CYP2C19 genotype on clopidogrel pharmacokinetics (PK), pharmacodynamics (PD) and clinical response. ¹⁹

To improve the formation of the active metabolite and decrease the influence of CYP2C19 polymorphisms, novel P2Y₁₂ receptor inhibitors are in development, and some of them, specifically prasugrel and ticagrelor, are currently on the market. Prasugrel and ticagrelor show more consistent platelet inhibition, but their risk of causing bleeding is increased compared to clopidogrel. ²⁰ , ²¹ Vicagrel, an analogue of clopidogrel, is being developed in China as a novel thienopyridine antiplatelet agent. ²² Vicagrel and clopidogrel have pharmacological effects based on the same active thiol metabolite, H4, which is formed through a 2‐step metabolic activation process (Figure 1). ¹² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ The second step, from 2‐oxo‐clopidogrel to the thiol metabolite, H4, is the same for both vicagrel and clopidogrel. However, for vicagrel, the first step is the rapid and complete hydrolysis of its ester function to form 2‐oxo‐clopidogrel, which is mediated by human carboxylesterase 2 and arylacetamide deacetylase in the gut instead of CYP2C19 in the liver. Therefore, it is promising that vicagrel will produce the active metabolite H4 more efficiently, and will be less influenced by polymorphisms of CYP219 than clopidogrel. In fact, the phase I clinical studies of vicagrel have shown that the AUC of the active metabolite H4 after oral administration of 5 mg vicagrel was similar to that after oral administration of 75 mg clopidogrel, which is consistent with the proposed hypothesis. ²⁷ , ²⁸ However, the influence of CYP2C19 polymorphisms on vicagrel's mechanism of action is unknown in humans. The current study was designed to evaluate the effects of CYP2C19 genetic polymorphisms on PK and PD of vicagrel in healthy Chinese subjects and separately compare the effects of vicagrel with clopidgrel in different CYP2C19 metabolizers.

FIGURE 1.

Metabolic pathways of clopidogrel and vicagrel in humans. hCE1, human carboxylesterase 1; hCE2, human carboxylesterase 2; AADAC, arylacetamide deacetylase

2. METHODS

2.1. Subjects

Subjects enrolled in this study were healthy male or female Chinese volunteers, aged 19–44 years, with body weights that ranged from 49.6 to 79.8 kg, and body mass index that ranged from 20.0 to 27.8 kg⋅m⁻². Before enrolment, we conducted CYP2C19 genotyping for alleles *1, *2, *3 and *17 to identify the subjects as CYP2C19 extensive metabolizers (EMs, genotype as *1/*1), CYP2C19 intermediate metabolizers (IMs, genotype as *1/*2, or *1/*3), or CYP2C19 poor metabolizers (PMs, genotype as *2/*2, *2/*3, or *3/*3). As the frequency of *17 is very low in Chinese population, *17 carriers were not enrolled in this study.

The enrolled subjects were considered to be in good health based on their medical history, physical examination, electrocardiograms (ECGs), and routine laboratory tests. The subjects did not take any medications for a minimum of 2 weeks prior to the study, and alcohol was forbidden for 72 hours prior to drug administration.

2.2. Ethics

The study was approved by the Independent Ethics Committee of the First Hospital, Jilin University and was in full compliance with the principles of the Declaration of Helsinki (current revision) and Good Clinical Practice guideline. Written informed consent was obtained from each subject before the study.

2.3. Genotype assay

Genomic DNA was extracted from 0.5 mL of peripheral blood drawn into EDTA‐coated tubes using QIAamp DNA Blood Mini Kit (Qiagen, Germany). Three single nucleotide polymorphisms (SNPs)—CYP2C19*2 (rs4244285), *3 (rs4986893) and *17 (rs12248560)—were genotyped using Sequenom MassARRAY platform integrating iPLEX (Sequenom Inc, San Diego, CA, USA) based on a previously described method. ²⁹ The assay consists of an initial locus‐specific polymerase chain reaction amplification followed by single base extension reaction using mass‐modified dideoxynucleotide terminators of an oligonucleotide primer that anneals immediately upstream of the target polymorphic site. The polymerase chain reaction extension products were separated onto a 384‐well sepctroCHIP and placed into the matrix assisted laser desorption/ionization time‐of‐flight mass spectrometer. The distinct mass of extended primer traces the alternative alleles using MassARRAY Typer 4.0.20. For quality control step, data missing rate per individuals and missing rate per SNP were determined. In addition, for quality control of SNP genotyping, positive and negative template control samples were included in each assay plate. Any assay found as positive in negative template control was removed from the study. All these procedures were performed in KingMed Diagnostics Group Co., Ltd. (Guangzhou, China).

2.4. Study design

This study was a single centre, randomized, open‐label, 2‐period cross‐over, clopidogrel‐controlled, multiple‐dose study. Three CYP2C19‐predicted phenotype groups were identified (CYP2C19 EM, IM and PM) with 16 subjects in each group. Each study period lasted 7 days, starting with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and daily maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel, from day 2 to day 7. The 2 study periods were separated by a washout phase of 14 days. The PK and PD samples were collected on day 1 and day 7 for each study period. The flow chart of the study is seen in Figure 2.

FIGURE 2.

Study design and flow chart. EMs, extensive metabolizers; IMs, intermediate metabolizers; PMs, poor metabolizers; V, vicagrel; C, clopidogrel

On day 1 and day 7 of each study period, all subjects fasted for a minimum of 10 hours prior to administration of the study drugs and continued to fast for at least 4 hours more. Standard meals were provided at 4 and 10 hours after drug administration. Alcohol, caffeine‐containing beverages, and grape juice were forbidden starting 72 hours prior to drug administration and throughout the study period as well.

2.5. PK assessment

In each study period, venous blood samples were collected from each subject before dosing (0 h) and at 10, 20, 30, 45 minutes, 1, 1.25, 1.5, 2, 2.5, 3, and 4 hours after drug administration on day 1 and day 7. A 3.0‐mL aliquot of each blood sample was collected into an EDTA tube that was pretreated with a derivatization agent, specifically, 30 μL 0.5 M 2–bromo‐3′‐methoxyacetophenone. The blood samples were immediately mixed by inversion and kept at room temperature for 10 minutes. Then the plasma samples were separated by centrifugation at 2000 × g at 4°C for 5 minutes and stored at −70°C until analysis.

Plasma concentrations of derivatized H4 (MP‐H4) and derivatized H3 (MP‐H3) were determined simultaneously using a validated HPLC–MS/MS method that was based on a previously reported method. ³⁰ After protein precipitation the samples were analysed using a UHPLC system (Shimadzu Corporation, Kyoto, Japan) and an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 μm; Waters, Milford, MA, USA), coupled with an Sciex Triple Quad 6500 mass spectrometer (Applied Biosystems, Foster City, CA, USA). The calibration ranges for the assay were 0.100–200 ng·mL⁻¹ for MP‐H4 and MP‐H3, with the lower limit of quantitation (LLOQ) set at 0.100 ng·mL⁻¹. MP‐H4 and MP‐H3 were used as reference standards for H4 and H3, respectively, and the plasma concentrations of the PK samples were corrected to H4 and H3.

PK parameters for H4 and H3 were calculated using standard noncompartmental methods with WinNonlin 7.0 (Certara, Princeton, NJ, USA). Maximum concentration (C_max) and the time to reach C_max (T_max) were determined by inspection of the plasma concentration–time curves. The elimination rate constant (k) was determined using linear regression of the terminal linear portion of the ln‐concentration–time curve, and the apparent elimination half‐life (t_1/2) was calculated as 0.693/k. The area under the plasma concentration–time curve from zero to the last point (AUC_0‐t) was calculated using the linear trapezoidal method. The AUC from zero to infinity (AUC_0‐∞) was calculated as AUC_0‐t + C_t/k, where C_t was the last measurable concentration.

2.6. PD measurements

Blood samples for PD assessment were collected into 2‐mL vacutainer tubes containing 3.2% sodium citrate. The samples were drawn before dosing (0 h) and at 4 and 24 hours after dosing on day 1 and day 7. The platelet reactivity was assessed using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA) according to the manufacturer's instructions. This assay measured adenosine diphosphate‐induced aggregation as an increase in light transmittance and reports results in P2Y12 reaction units (PRUs). The inhibition of platelet aggregation (IPA) was represented by the percent change from baseline aggregation, which was calculated using the mathematical formula: IPA (%) = (BASE–PRU)/BASE × 100%.

2.7. Safety assessment

Safety was evaluated based on assessments obtained from the physical examinations, vital signs (blood pressure, pulse, respiration rate, and body temperature), 12‐lead ECG, laboratory tests (biochemistry, haematology, urinalysis, coagulation convention, routine stool assessment and occult blood), and the occurrence of any adverse events (AEs). Vital signs for all subjects were assessed at least once during each study day. Physical examinations were performed before and after each study period. The 12‐lead ECGs and laboratory tests were conducted after each study period. AEs were recorded throughout the study period and at the follow‐up assessment.

2.8. Statistical analysis

The PK parameters C_max and AUC were ln‐transformed prior to statistical analysis. An analysis of variance model was used to detect differences in PK parameters among the predicted phenotype groups, and the geometric mean ratio of IMs or PMs to EMs and its 90% confidence intervals were given. In each phenotype group, the differences in PK parameters between vicagrel and clopidogrel were assessed using a linear mixed effects model, and the geometric mean ratio and its 90% confidence intervals were given. For PD analysis, the differences of IPA among the groups were assessed separately at 4 and 24 hours. The statistical method was similar to the PK analysis. The differences between vicagrel and clopidogrel were assessed separately using a linear mixed effects model for each phenotype group. For all analyses, P < 0.05 was considered statistically significant. Statistical analysis was performed using the software SAS 9.4.

3. RESULTS

3.1. Subjects demography

A total of 357 subjects were genotyped for CYP2C19 alleles during the screening period. Forty‐eight subjects, with 16 subjects included in each of the 3 CYP2C19‐predicted phenotype groups were enrolled in and completed the study. The demographics of these subjects are summarized in Table 1.

TABLE 1.

Summary of demographics of the subjects

	CYP1C19‐predicted phenotype
	EMs	IMs	PMs
CYP2C19 genotype	* 1/ * 1	* 1/ * 2 or * 1/ * 3	* 2/ * 2, * 3/ * 3 or * 2/ * 3
n	16	16	16
Female/male	9/7	8/8	7/9
Age (y)
Mean (SD)	36.69(5.55)	33.69(6.84)	35.00(4.75)
Range	24–43	19–42	29–44
Body weight (kg)
Mean (SD)	64.79(8.43)	62.76(6.54)	63.74(6.64)
Range	51.3–79.8	51.4–78.6	49.6–76.8
BMI (kg⋅m−2)
Mean (SD)	23.58(2.50)	23.58(2.38)	23.48(2.41)
Range	20.0–27.8	20.1–27.2	20.4–27.8

EMs, extensive metabolizers (phenotype ^*1/^*1); IMs, intermediate metabolizers (phenotype ^*1^/*2 & ^*1^/*3); PMs, poor metabolizers (phenotype ^*2/^*2, ^*2/^*3, and ^*3/^*3); SD, standard deviation; BMI, body mass index;

3.2. PK results

The mean plasma concentration–time curves for the active metabolite H4 and the inactive metabolite H3 after vicagrel and clopidogrel administration are shown in Figures 3 and 4, respectively. The calculated parameters of H4 and H3 are summarized in Tables 2A, 2B and Tables 3A, 3B, respectively. Figure 5 shows the comparison in the exposure of H4 between vicagrel and clopidogrel treatments.

FIGURE 3.

The mean plasma concentration–time curves of the active metabolite H4 in CYP2C19‐predicted phenotype groups (16 subjects in each group) after vicagrel (loading dose of 24 mg on day 1 and maintenance doses of 6 mg·d⁻¹ from day 2 to day 7) and clopidogrel (loading dose of 300 mg on day 1 and maintenance doses of 75 mg·d⁻¹ from day 2 to day 7) administration. Each data indicates mean ± SD. Vicagrel EMs (◇); vicagrel IMs (△); vicagrel PMs (□); clopidogrel EMs (◆); clopidogrel IMs (▲); clopidogrel PMs (■); EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3)

FIGURE 4.

The mean plasma concentration–time curves of the inactive metabolite H3 in CYP2C19‐predicted phenotype groups (16 subjects in each group) after vicagrel (loading dose of 24 mg on day 1 and maintenance doses of 6 mg·d⁻¹ from day 2 to day 7) and clopidogrel (loading dose of 300 mg on day 1 and maintenance doses of 75 mg·d⁻¹ from day 2 to day 7) administration. Each data indicates mean ± SD. Vicagrel EMs (◇); cicagrel IMs (△); vicagrel PMs (□); clopidogrel EMs (◆); clopidogrel IMs (▲); clopidogrel PMs (■); EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3)

TABLE 2A.

Pharmacokinetic parameters of H4 following loading dose administration of vicagrel (24 mg) or clopidogrel (300 mg) in CYP2C19‐predicted phenotype groups

Phenotype groups	Parameters	LS geometric mean		P value and ratio to EMs (90%CI)		Vicagrel/clopidogrel
		Vicagrel	Clopidogrel	Vicagrel	Clopidogrel	P value and GMR (90%CI)
CYP2C19 EMs (n = 16)	AUC0‐∞ (ng⋅mL−1⋅h)	39.8	30.0			P < 0.001, 1.32 (1.18, 1.48)
	AUC0‐t (ng⋅mL−1⋅h)	39.4	29.6			P < 0.001, 1.33 (1.19, 1.49)
	Cmax (ng⋅mL−1)	45.3	22.5			P < 0.001, 2.02 (1.70, 2.40)
	Tmax (h)	0.5 (0.333–1.5)	0.75 (0.5–1.5)
	t1/2 (h)	0.572	0.544
CYP2C19 IMs (n = 16)	AUC0‐∞ (ng⋅mL−1⋅h)	31.5	19.4	0.041 0.79 (0.68, 0.92),	0.004, 0.65 (0.52, 0.80)	P < 0.001, 1.62 (1.45, 1.81)
	AUC0‐t (ng⋅mL−1⋅h)	31.3	19.2	0.042, 0.79 (0.68, 0.92)	0.004, 0.65 (0.52, 0.80)	P < 0.001, 1.63 (1.46, 1.83)
	Cmax (ng⋅mL−1)	37.4	15.1	0.612, 0.82 (0.64, 1.06)	0.045, 0.67 (0.52, 0.87)	P < 0.001, 2.48 (2.02, 3.04)
	Tmax (h)	0.5 (0.333–1)	0.75 (0.5–1.5)
	t1/2 (h)	0.555	0.539
CYP2C19 PMs (n = 16)	AUC0‐∞ (ng⋅mL−1⋅h)	28.9	12.9	0.003, 0.73 (0.62, 0.85)	P < 0.001, 0.43 (0.34, 0.53)	P < 0.001, 2.24 (1.94, 2.59)
	AUC0‐t (ng⋅mL−1⋅h)	28.7	12.6	0.003, 0.73 (0.62, 0.85)	P < 0.001, 0.42 (0.34, 0.52)	P < 0.001, 2.28 (1.99, 2.62)
	Cmax (ng⋅mL−1)	35.3	8.53	0.306, 0.78 (0.61, 1.00)	P < 0.001, 0.38 (0.29, 0.50)	P < 0.001, 4.14 (3.46, 4.95)
	Tmax (h)	0.5 (0.333–1)	0.75 (0.5–3)
	t1/2 (h)	0.627	0.523

T_max was presented by median (range); LS, least squares; CI, confidence interval; GMR, geometric mean ratio; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3); AUC_0‐∞, area under the plasma concentration–time curve from zero to infinity;AUC_0‐t, area under the plasma concentration–time curve from zero to the last point; C_max, maximum concentration; T_max, time to reach C_max

t_1/2, apparent elimination half‐life.

TABLE 2B.

Pharmacokinetic parameters of H4 following maintenance doses administration of vicagrel (6 mg·day^‐1) or clopidogrel (75 mg·day^‐1) in CYP2C19‐predicted phenotype groups

Phenotype groups	Parameters	LS Geometric mean		P value and ratio to EMs (90%CI)		Vicagrel/Clopidogrel
		Vicagrel	Clopidogrel	Vicagrel	Clopidogrel	P value and GMR (90%CI)
CYP2C19 EMs (N = 16)	AUC0‐∞ (ng⋅mL‐1⋅h)	10.1	9.61			P = 0.516, 1.05 (0.92, 1.19)
	AUC0‐t (ng⋅mL‐1⋅h)	10.0	9.38			P = 0.379, 1.07 (0.94, 1.21)
	Cmax (ng⋅mL‐1)	11.5	9.58			P = 0.202, 1.20 (0.94, 1.53)
	Tmax (h)	0.5(0.333,1)	0.75(0.5,2.5)
	t1/2 (h)	0.590	0.546
CYP2C19 IMs (N = 16)	AUC0‐∞ (ng⋅mL‐1⋅h)	8.18	5.51	P = 0.143, 0.81 (0.68, 0.96)	P < 0.001, 0.57 (0.46, 0.71)	P < 0.001, 1.48 (1.31, 1.69)
	AUC0‐t (ng⋅mL‐1⋅h)	8.08	5.41	P = 0.152, 0.81 (0.68, 0.97)	P < 0.001, 0.58 (0.47, 0.71)	P < 0.001, 1.50 (1.31, 1.70)
	Cmax (ng⋅mL‐1)	12.5	5.59	P = 1.00, 1.08 (0.83, 1.41)	P = 0.010, 0.58 (0.44, 0.78)	P < 0.001, 2.23 (1.83, 2.72)
	Tmax (h)	0.5(0.333,0.75)	0.584(0.5,2)
	t1/2 (h)	0.660	0.524
CYP2C19 PMs (N = 16)	AUC0‐∞ (ng⋅mL‐1⋅h)	7.07	4.15	P = 0.004, 0.70 (0.59, 0.83)	P < 0.001, 0.43 (0.35, 0.53)	P < 0.001, 1.69 (1.45, 1.97)
	AUC0‐t (ng⋅mL‐1⋅h)	6.98	4.03	P = 0.004, 0.70 (0.58, 0.83)	P < 0.001, 0.43 (0.35, 0.53)	P < 0.001, 1.73 (1.51, 1.99)
	Cmax (ng⋅mL‐1)	9.05	3.95	P = 0.392, 0.79 (0.60, 1.02)	P < 0.001, 0.41 (0.31, 0.55)	P < 0.001, 2.29 (1.77, 2.96)
	Tmax (h)	0.5(0.333,1)	0.75(0.333,2.5)
	t1/2 (h)	0.526	0.486

T_max was presented by median (range); LS, least squares; CI, confidence interval; GMR, geometric mean ratio; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3); N, number of subjects; AUC_0‐∞, area under the plasma concentration‐time curve from zero to infinity;AUC_0‐t, area under the plasma concentration‐time curve from zero to the last point; C_max, maximum concentration; T_max, time to reach C_max

t_1/2, apparent elimination half‐life.

TABLE 3A.

Pharmacokinetic parameters of H3 following loading dose administration of vicagrel (24 mg) or clopidogrel (300 mg) in CYP2C19‐predicted phenotype groups

Phenotype groups	Parameters	LS geometric mean		P value and ratio to EM (90%CI)		Vicagrel/clopidogrel
		Vicagrel	Clopidogrel	Vicagrel	Clopidogrel	P value and GMR (90%CI)
CYP2C19 EMs (n =16)	AUC0‐∞ (ng⋅mL−1⋅h)	54.6	30.2			P < 0.001, 1.81 (1.62, 2.01)
	AUC0‐t (ng⋅mL−1⋅h)	54.3	29.8			P < 0.001, 1.82 (1.64, 2.03)
	Cmax (ng⋅mL−1)	64.0	23.9			P < 0.001, 2.68 (2.32, 3.09)
	Tmax (h)	0.5 (0.5–1.5)	0.75 (0.5–1.5)
	t1/2 (h)	0.545	0.502
CYP2C19 IMs (n = 16)	AUC0‐∞ (ng⋅mL−1⋅h)	49.3	21.1	0.668, 0.90 (0.79, 1.04)	0.010, 0.70 (0.57, 0.85)	P < 0.001, 2.34 (2.13, 2.57)
	AUC0‐t (ng⋅mL−1⋅h)	49.2	20.0	0.688, 0.90 (0.79, 1.04)	0.009, 0.70 (0.58, 0.85)	P < 0.001, 2.36 (2.15, 2.59)
	Cmax (ng⋅mL−1)	61.00	17.1	1.00, 0.95 (0.76, 1.19)	0.058, 0.72 (0.57, 0.90)	P < 0.001, 3.57 (2.96, 4.30)
	Tmax (h)	0.5 (0.5–1)	0.75 (0.5–1.25)
	t1/2 (h)	0.461	0.506
CYP2C19 PMs (n = 16)	AUC0‐∞ (ng⋅mL−1⋅h)	54.6	17.4	1.00, 1.00 (0.87, 1.15)	P < 0.001, 0.58 (0.47, 0.70)	P < 0.001, 3.12 (2.76, 3.52)
	AUC0‐t (ng⋅mL−1⋅h)	54.4	17.1	1.00, 1.00 (0.87, 1.15)	P < 0.001, 0.57 (0.47, 0.69)	P < 0.001, 3.19 (2.84, 3.58)
	Cmax (ng⋅mL−1)	66.0	11.9	1.00, 1.03 (0.83, 1.29)	P < 0.001, 0.50 (0.39, 0.63)	P < 0.001, 5.57 (4.67, 6.64)
	Tmax (h)	0.5 (0.5–1)	1 (0.75–3)
	t1/2 (h)	0.470	0.458

T_max was presented by median (range); LS, least squares; CI, confidence interval; GMR, geometric mean ratio; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3); AUC_0‐∞, area under the plasma concentration–time curve from zero to infinity;AUC_0‐t, area under the plasma concentration–time curve from zero to the last point; C_max, maximum concentration; T_max, time to reach C_max

t_1/2, apparent elimination half‐life.

TABLE 3B.

Pharmacokinetic parameters of H3 following maintenance doses loading dose administration of vicagrel (6 mg·day^‐1) or clopidogrel (75 mg·day^‐1) in CYP2C19‐predicted phenotype groups

Phenotype groups	Parameters	LS Geometric mean		P value and ratio to EM (90%CI)		Vicagrel/Clopidogrel
		Vicagrel	Clopidogrel	Vicagrel	Clopidogrel	P value and GMR (90%CI)
CYP2C19 EMs (n = 16)	AUC0‐∞ (ng⋅mL‐1⋅h)	15.6	14.7			P = 0.400, 1.06 (0.94, 1.19)
	AUC0‐t (ng⋅mL‐1⋅h)	15.5	14.5			P = 0.322, 1.07 (0.95, 1.20)
	Cmax (ng⋅mL‐1)	16.8	13.8			P = 0.108, 1.21 (1.00, 1.48)
	Tmax (h)	0.75(0.333,1)	0.75(0.5,2.5)
	t1/2 (h)	0.414	0.465
CYP2C19 IMs (n = 16)	AUC0‐∞ (ng⋅mL‐1⋅h)	15.5	9.47	P = 1.00, 0.99 (0.86, 1.14)	P < 0.001, 0.65 (0.54, 0.78)	P < 0.001, 1.63 (1.47, 1.81)
	AUC0‐t (ng⋅mL‐1⋅h)	15.4	9.35	P = 1.00, 0.99 (0.86, 1.15)	P < 0.001, 0.65 (0.54, 0.77)	P < 0.001, 1.64 (1.48, 1.82)
	Cmax (ng⋅mL‐1)	21.3	8.96	P = 0.184, 1.27 (1.03, 1.56)	P = 0.007, 0.65 (0.52, 0.81)	P < 0.001, 2.37 (1.96, 2.87)
	Tmax (h)	0.5(0.333,0.75)	0.75(0.5,2)
	t1/2 (h)	0.382	0.373
CYP2C19 PMs (n = 16)	AUC0‐∞ (ng⋅mL‐1⋅h)	15.2	8.43	P = 1.00, 0.98 (0.85, 1.12)	P < 0.001, 0.58 (0.48, 0.69)	P < 0.001, 1.80 (1.54, 2.09)
	AUC0‐t (ng⋅mL‐1⋅h)	15.1	8.34	P = 1.00, 0.97 (0.85, 1.12)	P < 0.001, 0.58 (0.48, 0.69)	P < 0.001, 1.81 (1.56, 2.09)
	Cmax (ng⋅mL‐1)	16.5	7.18	P = 1.00, 0.98 (0.80, 1.21)	P < 0.001, 0.52 (0.41, 0.65)	P < 0.001, 2.30 (1.88, 2.82)
	Tmax (h)	0.5(0.333,1.25)	0.75(0.5,2.5)
	t1/2 (h)	0.423	0.363

T_max was presented by median (range); LS, least squares; CI, confidence interval; GMR, geometric mean ratio; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3); N, number of subjects; AUC_0‐∞, area under the plasma concentration‐time curve from zero to infinity;AUC_0‐t, area under the plasma concentration‐time curve from zero to the last point; C_max, maximum concentration; T_max, time to reach C_max

t_1/2, apparent elimination half‐life.

FIGURE 5.

Comparison of the exposure for the active metabolite H4 and the platelet response between vicagrel (■) and clopidogrel (■) treatments after the loading dose (A, 24 mg of vicagrel vs 300 mg of clopidogrel) and the maintenance doses (B, 6 mg·d⁻¹ of vicagrel vs 75 mg·d⁻¹ of clopidogrel) in CYP2C19‐predicted phenotype groups (16 subjects in each group). AUC_0‐t, area under the plasma concentration–time curve from zero to the last point; C_max, maximum concentration; IPA, inhibition of platelet aggregation; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3)

H4 formation was significantly decreased for clopidogrel in the CYP2C19 IM (P < 0.05) and PM (P < 0.001) subjects when compared with the EM subjects. After receiving the loading dose, the AUC_0‐t for H4 decreased by 35 and 58% in CYP2C19 IM and PM subjects, and the C_max decreased by 33 and 62%, respectively. After receiving the maintenance doses, the AUC_0‐t of H4 decreased by 42 and 57% in CYP2C19 IM and PM subjects, and the C_max decreased by 42 and 59%, respectively.

For vicagrel, the difference in H4 levels in CYP2C19‐predicted phenotype groups was much less. After receiving the loading dose, the AUC_0‐t for H4 decreased by 21 and 27% in CYP2C19 IM and PM subjects, respectively, as compared with the EM subjects. No significant differences were observed in C_max. Similar results were found after subjects received the maintenance doses. In CYP2C19 IM subjects, the C_max of H4 slightly increased by 8%, when compared with the EM subjects.

When the profiles of H4 by vicagrel were compared separately with H4 profiles by clopidogrel in each CYP2C19‐predicted phenotype group, we observed that in CYP2C19 EM subjects, the AUC_0‐t for H4 by vicagrel was slightly higher (a 33% increase) compared to that by clopidogrel after the loading dose, and they were comparable (90% confidence interval 0.94–1.21) after the maintenance doses. However, in IM and PM subjects, the AUC_0‐t of H4 by vicagrel was much higher than that by clopidogrel. In PM subjects, it was 2.28‐fold (loading dose) and 1.73 fold (maintenance doses) of that by clopidogrel (P < 0.001). The differences in C_max were even more remarkable. The C_max of H4 by vicagrel was 4.14‐fold (loading dose) and 2.29‐fold (maintenance doses) of that by clopidogrel (P < 0.001).

We also assessed another thiol metabolite, H3, which is pharmacologically inactive, in the present study. After the administration of clopidogrel, the formation of H3 seemed less influenced by CYP2C19 polymorphisms compared to H4. After the loading and maintenance doses, the AUC of H3 in CYP2C19 PM subjects decreased by approximately 40%, while the AUC of H4 decreased by almost 60%. It is interesting that after the administration of vicagrel, there were no significant differences in the exposure of H3 in any of the CYP2C19 EM, IM or PM subjects. The parameters AUC_0‐t and C_max were comparable in these 3 groups after either the loading dose or the maintenance doses, which indicates that CYP2C19 polymorphisms had no effect on the formation of H3 by vicagrel.

3.3. PD results

The calculated IPA at 4 and 24 hours after vicagrel and clopidogrel administration are summarized in Tables 4A and 4B. The comparison in PD between vicagrel and clopidogrel are shown together with the PK in Figure 5.

TABLE 4A.

Summary of IPA following loading dose administration of vicagrel (24 mg) or clopidogrel (300 mg) in CYP2C19‐predicted phenotype groups

Time point	Phenotype groups	LS mean of IPA(90%CI)		P values compared to EMs		(Vicagrel – clopidogrel)
		Vicagrel	Clopidogrel	Vicagrel	Clopidogrel	Difference (90%CI)	P value
4 h	CYP2C19 EMs	47.6 (39.7–55.4)	33.3 (25.4–41.1)			14.3 (7.1–21.5)	0.004
	CYP2C19 IMs	39.0 (31.4–46.7)	23.5 (15.9–31.1)	0.531	0.173	15.5 (9.8–21.3)	<0.001
	CYP2C19 PMs	28.2 (22.9–33.5)	12.4 (7.1–17.7)	0.009	<0.001	15.8 (8.5–23.0)	0.002
24 h	CYP2C19 EMs	54.4 (47.8–61.0)	45.8 (39.2–52.4)			8.6 (1.2–16.0)	0.060
	CYP2C19 IMs	47.5 (40.8–54.2)	28.2 (21.5–34.9)	0.866	0.002	19.3 (14.4–24.1)	<0.001
	CYP2C19 PMs	40.8 (35.0–46.5)	15.9 (10.2–21.7)	0.118	<0.001	24.8 (18.2–31.5)	<0.001

IPA, inhibition of platelet aggregation; LS, least squares; CI, confidence interval; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3).

TABLE 4B.

Summary of IPA following maintenance doses administration of vicagrel (6 mg·d⁻¹) or clopidogrel (75 mg·d⁻¹) in CYP2C19‐predicted phenotype groups

Time point	Phenotype groups	LS mean of IPA(90%CI)		P values compared to EMs		(Vicagrel – clopidogrel)
		Vicagrel	Clopidogrel	Vicagrel	Clopidogrel	Difference (90%CI)	P value
4 h	CYP2C19 EMs	60.6 (51.6–69.7)	58.4 (49.4–64.2)			14.3 (7.1–21.5)	0.602
	CYP2C19 IMs	52.1 (45.7–58.5)	38.9 (32.6–45.3)	0.352	0.013	15.5 (9.8–21.3)	<0.001
	CYP2C19 PMs	42.8 (37.2–48.4)	24.6 (18.9–30.2)	0.005	<0.001	15.8 (8.5–23.0)	<0.001
24 h	CYP2C19 EMs	57.4 (49.5–65.3)	56.3 (48.4–64.2)			1.1 (−4.4–6.5)	0.732
	CYP2C19 IMs	50.6 (45.4–55.7)	42.9 (37.8–48.1)	0.396	0.089	7.7 (1.2–14.2)	0.055
	CYP2C19 PMs	40.9 (35.7–46.1)	32.5 (27.3–37.7)	0.002	<0.001	8.4 (2.9–13.9)	0.018

IPA, inhibition of platelet aggregation; LS, least squares; CI, confidence interval; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 and *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3).

At 4 hours after the loading dose of clopidogrel, the mean IPA decreased by 29.3 and 62.6% in the CYP2C19 IM and PM subjects, respectively, when compared to the EM subjects. After the maintenance doses, the mean IPA decreased by 33.4 and 58.0%, respectively. At 4 hours after the loading dose, the IPA for vicagrel decreased by 17.9 and 40.7% in the CYP2C19 IM and PM subjects, respectively, and decreased by 14.0 and 29.3%, respectively, after the maintenance doses.

The comparison of IPA between vicagrel and clopidogrel demonstrated that the IPA at 4 hours for vicagrel was higher than for clopidogrel after the loading dose in CYP2C19 EM subjects (P < 0.01). However, the IPA for vicagrel was comparable with that of clopidogrel after the maintenance doses. In both CYP2C19 IM and PM subjects, the IPA at 4 hours for vicagrel was significantly higher than that for clopidogrel after both the loading dose (P < 0.01) and the maintenance doses (P < 0.001). Similar results were observed for the IPAs at 24 hours. For vicagrel, the IPA was 40.8% at 24 hours after a loading dose on day1, and it remained over 40% after the 6‐days of maintenance doses in CYP2C19 PM subjects. However, for clopidogrel, the 24 hours IPA after the loading dose was only 15.9% in the same subjects, although the clopidogrel IPA increased to 32.5% at 24 hours after the 6th day maintenance dose. As noted in Figure 5, we observed that the IPA responses to vicagrel in PM subjects were even higher than the responses to clopidogrel in IM subjects. These results indicate that the impact of CYP2C19 polymorphisms on the PD of vicagrel was less compared to the impact on clopidogrel and vicagrel was faster to take effect than clopidogrel, which were in accordance with the findings in PK.

The relationship between IPA and AUC_0‐t of H4 was investigated. The correlations of the IPA to the AUC_0‐t of H4 are shown in Figure 6. A better correlation overall was observed for clopidogrel. The correlation for vicagrel was better at 4 hours than at 24 hours, which indicates that IPA at 4 hours may be more sensitive for vicagrel PD assessment.

FIGURE 6.

The correlation of IPA at 4 hours (A) and 24 hours (B) to AUC_0‐t of H4 after vicagrel (loading dose of 24 mg on day 1 and maintenance doses of 6 mg·d⁻¹ from day 2 to day 7) and clopidogrel (loading dose of 300 mg on day1 and maintenance doses of 75 mg·day⁻¹ from day 2 to day 7) administration. AUC_0‐t, area under the plasma concentration–time curve from zero to the last point; IPA, inhibition of platelet aggregation; vicagrel loading dose (△); clopidogrel loading dose (○); vicagrel maintenance doses (▲); clopidogrel maintenance dose (●)

3.4. Safety assessment

A total of 22 AEs were reported by 14 subjects from all 3 CYP2C19‐predicted phenotype groups. The AEs that were possibly related to the study drugs included, positive occult blood (3/48), increased bilirubin (3/48), decreased neutrophil account (3/48), decreased white blood account (2/48), hypertriglyceridaemia (2/48), increased amylase (2/48), hyperuricaemia (1/48) and increased lipase (1/48). Of these AEs, 8 were reported by 6 subjects (12.5%) following vicagrel administration, and 9 were reported by 8 subjects (16.7%) following clopidogrel administration. There were no apparent correlations between the incidence of any of the adverse events and the subject phenotype for either vicagrel treatment or clopidogrel treatment. All of the AEs reported in this study were mild in severity and resolved without treatment. None of the subjects withdrew from the study because of an AE. Therefore, both vicagrel and clopidogrel were considered to be well tolerated in CYP2C19 EM, IM and PM subjects when administered at the loading dose or the maintenance doses.

4. DISCUSSION

Kelly et al. assessed the PK and PD of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants, and prasugrel was found not relevant to CYP2C19 genotype at all. ¹⁸ We adopted a similar study design to the trial by Kelly et al., which is useful when making comparisons between the results of the Kelly et al. study¹⁸ and our study. In both studies, clopidogrel was considered to be the control drug, and the maintenance doses for clopidogrel were set at 75 mg·day⁻¹ in both studies. In our study, the active metabolite exposure associated with the clopidogrel maintenance dose in IM and PM subjects was 58% and 43% of that in EM subjects, respectively. The PD response (IPA) at 24 hours on day 7 was 56.3%, 42.9%, and 32.5% in EM, IM and PM subjects, respectively, which were similar to observations reported by Kelly et al. Unlike prasugrel, vicagrel has pharmacological effects based on the same active metabolite as clopidogrel, so the PD response to vicagrel was similar to clopidogrel using doses we reported in EM subjects. These dose levels ensure the safety and efficacy of vicagrel in future clinical use.

In this study, we observed that the PK impact and subsequent PD response of CYP2C19 polymorphisms on vicagrel were less than for clopidogrel. These observations are due to the specialized metabolic pathway of vicagrel, which, in part, avoids involvement of the CYP2C19 enzyme in the formation of the active metabolite H4. Although the H4 formation after vicagrel administration decreased slightly in CYP2C19 IM and PM subjects, when compared with EM subjects, the extent of the decrease was much less than that observed for clopidogrel. In CYP2C19 PM subjects, the exposure of H4 by vicagrel was approximately 2‐fold of that by clopidogrel after both the loading dose and the maintenance doses. Consequently, the PD responses to vicagrel were significantly higher compared to clopidogrel in PM subjects (P < 0.05). The mean IPAs at 4 and 24 hours were 28.2 and 40.8% after the vicagrel loading dose, whereas the IPAs were <20% (a nonresponse criterion) after loading with clopidogrel. The PD response to clopidogrel was still lower than to vicagrel, although it increased after the maintenance doses. When the individual data were analysed (Figure S1), we observed that most subjects had a PD response >20% IPA to vicagrel at 24 hours after the loading dose; however, only the EM subjects and some of the IM subjects demonstrated a PD response to the clopidogrel loading dose. Most PM subjects displayed no PD response to clopidogrel (<20% IPA). The 2017 Food and Drug Administration‐approved drug label for clopidogrel includes a box warning of the reduced antiplatelet effect of clopidogrel in patients who are CYP2C19 poor metabolizers, and advising healthcare professionals to consider use of other antiplatelet medications in these patients. ¹⁹ In the present study, it was found that the antiplatelet effects of vicagrel in CYP2C19 PM subjects were even higher than those of clopidogrel in IM subjects. Thus, based on the results of our study, it is not necessary to consider alternative therapy in vicagrel treatment. CYP2C19 genotyping might be useful and depends on further analysis of clinical data.

In this study, we assessed the PK of another thiol metabolite, H3, which is pharmacologically inactive. It was interesting that no differences were found in the exposure of H3 in any of the 3 CYP2C19‐predicted phenotype groups after vicagrel administration. The C_max and AUC_0‐t of H3 in IM and PM subjects were comparable to those observed in EM subjects after both the loading dose and the maintenance doses. This indicates that the formation of H3 from vicagrel is unaffected by CYP2C19 genetic variations. Some in vitro studies have reported that CYP2B6, CYP2C19 and CYP3A4 were involved in the formation of H3 and H4 from 2‐oxo‐clopidogrel. ⁴ , ³¹ Our previous study confirmed the findings reported above and found that the dominant contribution was from CYP3A4. ²⁴ Furthermore, we found that the formation of H3 and H4 from 2‐oxo‐clopidogrel was stereoselective and that the contribution of CYP2C19 to H3 was less than to H4 (16.5 vs 26.1%), which might be a possible explanation for our findings in the present in vivo study.

Previous studies have proven that vicagrel produces the active metabolite more efficiently than clopidogrel. ²⁷ , ²⁸ However, those studies failed to provide precise comparison data due to small sample size, or other factors, such as the occurrence of CYP2C19 genetic polymorphisms. In this study, the production of the active metabolite of vicagrel and clopidogrel was compared quantitatively using a single dose as well as multiple‐doses, in a cross‐over study that included CYP2C19 EM, IM and PM subjects. Based on previous studies, we chose a loading dose of 24 mg and a maintenance dose of 6 mg·day⁻¹ for vicagrel, and a loading dose of 300 mg and a maintenance dose of 75 mg·day⁻¹ for clopidogrel. In the CYP2C19 EM subjects, the AUC of the active metabolite H4 after the maintenance doses was comparable for vicagrel and clopidogrel (90% confidence interval of 0.94–1.21). However, the active metabolite H4 was somewhat higher (33%) for vicagrel than for clopidogrel after the loading dose. When the dose proportionality was assessed for these 2 drugs, it was found that for vicagrel, the AUC of H4 after the loading dose was approximately 3.9‐fold of that after the maintenance doses while for clopidogrel, it was only 3.2‐fold, although the ratio of the loading dose to the maintenance dose was the same (4‐fold) for both drugs. Vicagrel exhibited good dose‐proportionality in the range from 6 to 24 mg, while clopidogrel showed less dose‐proportionality in the range from 75 to 300 mg. This difference in dose proportionality might explain why the exposure of H4 for clopidogrel was less than that of vicagrel after the loading dose. Our study also indicated that there was an excellent correlation between the exposure of H4 and platelet aggregation inhibition. Therefore, based on these results, it would be better to reduce the vicagrel loading dose from 24 to 20 mg to obtain the same pharmacological effects observed with clopidogrel.

Sim et al. found the variant allele CYP2C19*17, which is associated with elevated enzyme activity as it increases expression of CYP2C19. ³² However, the frequency of *17 is very low (<4%) in East and Southeastern Asian populations. ³³ , ³⁴ , ³⁵ More reports have shown that it is only 1–1.5% in Chinese. ³⁶ , ³⁷ , ³⁸ The low frequency of *17 leads to difficulty in assessing the effect of *17 on CYP2C19 metabolised medicines in Chinese populations. Additionally, the clinical relevance of *17 to clopidogrel remains unclear. Some studies have demonstrated increased active metabolite formation and enhanced antiplatelet effect in *17 carriers, and some have reported a higher bleeding risk. ³⁹ , ⁴⁰ However, associations with higher bleeding risk have not been widely validated. Considering these points, no CYP2C19*17 carriers were enrolled and the effects of *17 on the PK and PD of vicargel were not assessed in the present study. Nevertheless, based on the low frequency of *17 and the results from *2 and *3 subjects, we have reason to speculate that CYP2C19*17 probably plays a minor role with respect to vicagrel in Chinese population.

In summary, the present study showed that CYP2C19 genetic polymorphisms had a significant impact on clopidogrel with respect to both PK and PD, but less impact on vicagrel. The drug exposure and response to vicagrel in PM subjects were even higher than those observed for clopidogrel in IM subjects. The production of the active metabolite and platelet responses to a maintenance dose of 6 mg·day⁻¹ of vicagrel were comparable to a maintenance dose of 75 mg·day⁻¹ of clopidogrel.

COMPETING INTERESTS

Yongqiang Liu, Xiaojuan Lai, Yanchun Gong and Xuefang Liu are employees of Jiangsu Vcare PharmaTech Co., Ltd., and Hongbin Sun and Yanchun Gong hold stock options or shares in the company. The other authors have no conflicts of interest directly relevant to the content of this article.

CONTRIBUTORS

Yifan Zhang designed the study, analysed the data and wrote the article. Xiaoxue Zhu, Yanhua Ding andDafang Zhong designed the study. Yan Zhan, Xiaojiao Li, Cai Liu, Yunting Zhu, Hong Zhang, Haijing Wei, andYu Xia performed the study. Hongbin Sun, Yongqiang Liu, Xiaojuan Lai, Yanchun Gong, Xuefang Liu, andYongguo Li contributed the new reagents.

Supporting information

FIGURE S1 The individual IPA at 4 and 24 hours after vicagrel (loading dose of 24 mg on day 1 and maintenance doses of 6 mg·d⁻¹ from day 2 to day 7) and clopidogrel (loading dose of 300 mg on day 1 and maintenance doses of 75 mg·d⁻¹ from day 2 to day 7) administration in CYP2C19‐predicted phenotype groups. IPA, inhibition of platelet aggregation; V, vicagrel; C, clopidogrel; EMs, extensive metabolizers (phenotype *1/*1); IMs, intermediate metabolizers (phenotype *1/*2 & *1/*3); PMs, poor metabolizers (phenotype *2/*2, *2/*3, and *3/*3).

Zhang Y, Zhu X, Zhan Y, et al. Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y₁₂ inhibitor. Br J Clin Pharmacol. 2020;86:1860–1874. 10.1111/bcp.14296

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.