A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

Abstract

Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population-specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady-state AUC_0-τ of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26-9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4-30.1] ng·h/ml, p < .001) population. In addition to CYP2C19-poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity.

Keywords: CYP2C19; PBPK modelling; clopidogrel; inter-ethnic differences; metabolites.

FIGURE 1

The metabolic pathways of clopidogrel

FIGURE 2

Workflow used for the PBPK model development and verification in populations of European ancestry, model application (extrapolation to a Japanese population) as well as simulations to investigate the effect of CYP2C19 activity, and other intrinsic factors on the pharmacokinetics of clopidogrel and its metabolites

FIGURE 3

Simulated and observed plasma concentration versus time profiles of clopidogrel and the primary carboxylic acid metabolite in healthy subjects of European ancestry (sim‐Healthy Volunteer) following single IV doses of clopidogrel. Four dose levels were used to develop the model (0.1 mg, 1 mg, 30 mg, and 300 mg), whereas two dose levels were used for model verification (10 mg and 100 mg). The circles represent observed concentrations, the solid blue lines represent the geometric means for the total virtual populations and the shaded areas represent the 90% prediction intervals

FIGURE 4

Simulated and observed concentration versus time profiles of the H4 metabolite stratified by CYP2C19 phenotype in the Japanese population following a single oral dose of 300 mg and 600 mg clopidogrel. The circles represent observed concentrations, solid blue lines represent the geometric means for the total virtual population and the shaded areas represent the 90% prediction intervals

FIGURE 5

Whisker‐box plots of AUC_0‐τ at steady‐state (Day 3, τ = 24 h) of clopidogrel, acyl glucuronide metabolite, and H4 metabolite in populations of European and Japanese ancestry following multiple doses of clopidogrel alone (300 mg loading dose, 75 mg daily) or coadministered with fluvoxamine (50 mg once daily) by CYP2C19 phenotype. The boxes represent the interquartile range with median shown as a solid line; whiskers represent the 10th and 90th percentiles

FIGURE 6

The effect of intrinsic factors on the steady‐state AUC_0‐τ (Day 3, τ = 24 h) of clopidogrel (300 mg oral loading dose, 75 mg daily). The reference line indicates the mean clopidogrel AUC_0‐τ for the Sim‐NEurCaucasian population, a general population of European ancestry (aged 20–50 years, 50% females. BMI 18–29 kg/m², normal hepatic function and healthy renal function >90 ml/min, CYP2C19 PM frequency = 2.4%). BMI, body mass index; GFR, glomerular filtration rate. Statistical significance compared to Sim‐NEurCaucasian population at ^*p < .001

FIGURE 7

The effect of intrinsic factors on the steady‐state AUC_0‐τ (Day 3, τ = 24 h) of the acyl glucuronide metabolite for a clopidogrel oral loading dose of 300 mg then 75 mg daily. The reference line indicates the mean acyl glucuronide AUC_0‐τ for the Sim‐NEurCaucasian population, a general population of European ancestry (aged 20–50 years, 50% females, BMI 18–29 kg/m², normal hepatic function and healthy renal function >90 ml/min, CYP2C19 PM frequency = 2.4%). BMI, body mass index; GFR, glomerular filtration rate. No groups were statistically different from the Sim‐NEurCaucasian population

FIGURE 8

The effect of intrinsic factors on the steady‐state AUC_0‐τ (Day 3, τ = 24 h) of the H4 metabolite following clopidogrel (300 mg oral loading dose, 75 mg daily). The reference line indicates the mean H4 metabolite AUC_0‐τ for the Sim‐NEurCaucasian population, a general population of European ancestry (aged 20–50 years, 50% females, BMI 18–29 kg/m², normal hepatic function and healthy renal function >90 ml/min, CYP2C19 PM frequency = 2.4%). BMI, body mass index; GFR, glomerular filtration rate. Statistical significance compared to the Sim‐NEurCaucasian population at ^*p < .01 and ^**p < .001