Abstract
Objectives
The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans.
Methods
Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.4. The ke of warfarin given a cytochrome P450 2C9 (CYP2C9) genotype ranged from 0.0189 to 0.0075 h−1. Ka and Vd parameters were taken from literature. Data from 128 subjects were divided into two groups (i.e., wild-types and carriers) and statistical analyses of PK parameters were performed by unpaired t-tests.
Results
In the carrier group (n=64), 53 subjects were single-carriers and 11 double-carriers (i.e., *2/*2, *2/*3, *2/*5, *3/*5, and *3/*8). The mean peak concentration (Cmax) was higher for wild-type (0.36±0.12 vs. 0.32±0.14 mg/L). Likewise, the average clearance (CL) parameter was faster among non-carriers (0.22±0.03 vs. 0.17±0.05 L/h; p=0.0001), with also lower area under the curve (AUC) when compared to carriers (20.43±6.97 vs. 24.78±11.26 h mg/L; p=0.025). Statistical analysis revealed a significant difference between groups with regard to AUC and CL, but not for Cmax. This can be explained by the variation of ke across different genotypes.
Conclusions
The results provided useful information for warfarin dosing predictions that take into consideration important individual PK and genotyping data.
Funding source: NASA EPSCoR Program
Award Identifier / Grant number: # 80 NSSC19M0148
Funding source: National Institute on Minority Health and Health Disparities
Award Identifier / Grant number: #2U54 MD007600-31
Acknowledgments
We want to thanks the patients for voluntarily participating in this survey. A special acknowledgement to Drs. Ricardo Jiménez and Jamie Rivera for their help with data collection and analysis, as well as the personnel at the Veteran Affairs Caribbean Healthcare System (VACHS) at San Juan, PR for their support in this project.
Research funding: This work was supported in part by CCRHD-RCMI grant #2U54 MD007600-31 from the National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health and grant # 80 NSSC19M0148 from the NASA EPSCoR program.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Disclaimer: The contents of this manuscript do not represent the views of the National Institutes of Health, NASA or the United States Government. No funded writing assistance was utilized in the production of this manuscript.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The study was approved by the Institutional Review Board (#A4070109). The study was conducted following the Helsinki’s declaration for human subject protection in clinical surveys.
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/dmpt-2020-0135).
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