Variations in prothrombin time-international normalized ratio caused by drug-drug interaction in patients receiving warfarin: A retrospective observational study

Objectives: Drug-drug inter-actions between warfarin and cytochrome P450 (CYP) 2C9 inhibitors and inducers are well known. Few studies have clarified the clinical impact of CYP2C9 inhibitors and in-ducers on warfarin therapy. Here, we evalu-ated the clinical impact of CYP2C9-mediated interactions on the pharmacodynamics of warfarin. Materials and methods: This ret-rospective observational study enrolled patients who received warfarin between 2008 and 2020 at Mie University Hospital. We defined prothrombin time-international normalized ratio/daily warfarin dose (PT-INR/dose) as the primary outcome and conducted a multiple linear regression analysis to clarify the factors that affected the primary outcome. Additionally, we ex-amined the clinical features of patients who received CYP2C9 inducers. Results: Out of 1,393 patients, 17 (1.2%) received carbam-azepine, rifampicin, phenobarbital, or phe-nytoin as CYP2C9 inducers. Multiple linear regression analysis indicated that age, body mass index (BMI), serum albumin (Alb), es-timated glomerular filtration rate (eGFR), and CYP2C9 inducers were associated with PT-INR/dose. The multiple regression equa-tion was as follows: PT-INR/dose = 1.590 + 0.004 x age - 0.020 x BMI - 0.141 x Alb - 0.001 x eGFR - 0.149 x (if concomitant use of CYP2C9 inducers) (adjusted coefficient of determination = 0.106, Akaike informa-tion criterion = 267.3, p < 0.001). In patients receiving CYP2C9 inducers, lower PT-INR/ dose values were observed regardless of co-administered CYP2C9 inhibitors. Conclu-sion: In addition to age, BMI, Alb, and eGFR, concomitant use of CYP2C9 inducers should be considered when adjusting the warfarin dose and PT-INR.