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Population pharmacokinetic analysis for dabigatran etexilate in Chinese patients with non-valvular atrial fibrillation



doi: 10.3389/fcvm.2022.998751.


eCollection 2022.

Affiliations

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Ya-Ou Liu et al.


Front Cardiovasc Med.


.

Abstract

We aimed to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model from healthy Chinese subjects and real-world non-valvular atrial fibrillation (NVAF) patients. We also investigated meaningful intrinsic and extrinsic factors and related biomarkers for bleeding events. We characterized the integrated PK/PD models based on rich PK/PD data [dabigatran concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), and anti-factor IIa (anti-FIIa) activity] from 118 healthy volunteers and sparse PD data [APTT, PT, and anti-FIIa] from 167 patients with NVAF after verifying the model extrapolation performance. We also documented the correlations between PD biomarkers and clinically relevant bleeding events over one year. Next, we used the final integrated PK/PD model (a two-compartment, linear model with first-order absorption) to evaluate the influence of dosage and individual covariates on PD parameters. The age, high-density liptein cholesterol (HDL-C), and creatinine clearance (CrCL) improved the PK model fit. The linear direct-effects PD model described the correlation between APTT, PT, and anti-FIIa and plasma concentration. CrCL improved the PD model fit. Anti-FIIa was more sensitive to the increase in dabigatran exposure than APTT and PT in the PD model. Therefore, fixed dabigatran doses could be prescribed for patients with NVAF without adjusting for age and HDL-C. We observed an elevated bleeding tendency with higher peak and trough values of APTT, PT, and anti-FIIa. Randomized studies should be performed to evaluate the efficacy and safety of low-dose dabigatran in Chinese patients with NVAF.


Keywords:

bleeding; dabigatran; non-valvular atrial fibrillation; pharmacodynamics; population pharmacokinetics.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures



Figure 1

GoF plots for the integrated PK/PD model. (A) APTT. (B) PT. (C) Anti-FIIa. Annotation: The standard goodness-of-fit plots for APTT, PT, and anti-FIIa in the integrated PK/PD model.


Figure 2


Figure 2

pcVPC of the integrated PK/PD model. (A) APTT. (B) PT. (C) Anti-FIIa. Annotation: The prediction-corrected visual prediction test (pcVPC) for APTT, PT, and anti-FIIa in the integrated PK/PD model.


Figure 3


Figure 3

Correlation between peak APPT, PT, and anti-FIIa values and bleeding events. (A) APTT. (B) PT. (C) Anti-FIIa. Annotation: The blue circle represents the standard dose. Boxes indicate the 25th−75th percentiles, whiskers represent 1.5 times the interquartile range, and black horizontal lines represent the median. The blue circles are individual predicted values for the standard dose or overdose.


Figure 4


Figure 4

Correlation between trough APPT, PT, and anti-FIIa values and bleeding events. (A) APTT. (B) PT. (C) Anti-FIIa. Annotation: The blue circle represents the standard dose. Boxes indicate the 25th-75th percentiles, whiskers represent 1.5 times the interquartile range, and black horizontal lines represent the median. The blue circles are individual predicted values for the standard dose or overdose.


Figure 5


Figure 5

Predicted APTT, PT, and anti-FIIa PD-time profiles. (A) APTT. (B) PT. (C) Anti-FIIa. Annotation: The black dot represents a patient with mean characteristics (dose = 110 mg bid, HDL = 1.4 mmol/L, age = 24 y, CrCL = 30 mL/min). The black cross represents a patient with mean characteristics (dose = 150 mg bid, HDL = 1.4 mmol/L, age = 24 y, CrCL = 50 mL/min). The black solid line represents a patient with mean characteristics (dose = 150 mg bid, HDL = 1.4 mmol/L, age = 24 y, CrCL = 118.76 mL/min) and the black dotted line 1 represents the corresponding 95% confidence interval. The black dotted line 2 represents the 95% confidence interval of a patient with mean characteristics (dose = 110 mg bid, HDL = 1.4 mmol/L, age = 24 y, CrCL = 118.76 mL/min). The red shaded area represents the predicted peak concentration ranges of APTT, PT, and anti-FIIa. The green shaded area represents the predicted trough concentration ranges of APTT, PT, and anti-FIIa. The yellow shaded area represents the predicted overlap of the trough and peak concentration ranges of APTT, PT, and anti-FIIa.

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