VKORC1 and CYP2C9 Genetic Variant-Associated Warfarin Treatment Outcomes and Artificial Intelligence-Based Dosing Optimization Among Chinese Patients

Background: As warfarin therapy outcomes in Chinese patients can differ from those in other populations owing to differences in genotype frequencies and demographic characteristics (e.g., weight and height), this study was developed to investigate warfarin treatment patterns among Chinese patients and to propose dose optimization. Methods: This study recruited adults undergoing heart valve replacement surgery who received warfarin treatment. Several anticoagulation response-related parameters were measured in these patients and compared among major genotype subgroups. These data were used to construct a population-based pharmacometric model, and warfarin initiation dosing regimens were proposed using generative artificial intelligence (GAI)-assisted model simulation. Results: We found that those patients carrying the Vitamin K epoxide reductase complex subunit 1 (VKORC1) AA & Cytochrome P450 family 2 subfamily C member 9 (CYP2C9)*1/*1 genotype, which accounted for the majority of patients (73.3%), achieved 39% time in the therapeutic range (%TTR) within the first week of treatment, stabilizing to approximately 50% within four weeks after initiating warfarin therapy. In contrast, those patients carrying the VKORC1 AA & CYP2C9*1/*3 genotype (8.9%) exhibited more pronounced fluctuations in %TTR, while those with the VKORC1 GA & CYP2C9*1/*1 genotype (15.1%) tended to exhibit subtherapeutic %TTR. The GAI-based dosing regimen proposed in this study, consisting of higher loading doses on Days 1–5 and lower maintenance doses thereafter, was found to enable patients to achieve target international normalized ratio (INR) range within one week. Conclusion: As over 70% of Chinese patients have the VKORC1 AA/CYP2C9*1/*1 genotype, this means that most carry more than one VKORC1/CYP2C9 variant allele. On average, those patients with >1 VKORC1/CYP2C9 variant allele required lower warfarin doses and reached the therapeutic INR range more quickly than those with ≤1 variant allele. GAI-based approaches can provide value as a means of facilitating dose optimization based on modeling and simulation.