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

Figures

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  FIGURE 1. The metabolic pathways of clopidogrel

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  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

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  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, 28 the solid blue lines represent the geometric means for the total virtual populations and the shaded areas represent the 90% prediction intervals

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  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, 30 solid blue lines represent the geometric means for the total virtual population and the shaded areas represent the 90% prediction intervals

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  FIGURE 5. Whisker‐box plots of AUC0‐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

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  FIGURE 6. The effect of intrinsic factors on the steady‐state AUC0‐τ (Day 3, τ = 24 h) of clopidogrel (300 mg oral loading dose, 75 mg daily). The reference line indicates the mean clopidogrel AUC0‐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

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  FIGURE 7. The effect of intrinsic factors on the steady‐state AUC0‐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 AUC0‐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

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  FIGURE 8. The effect of intrinsic factors on the steady‐state AUC0‐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 AUC0‐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