The patient was a 68-year-old man weighing 55.5 kg. The patient had pancreatic cancer and was admitted to Hirosaki University hospital to undergo a pancreatoduodenectomy. Written informed consent was obtained from this patient for the measurement of each biomarker and polymorphisms of pharmacokinetics-related genes. The patient had been taking edoxaban tablets (Lixiana®), 60 mg once per day after breakfast for 6 months prior to admission to prevent recurrence of thrombus formation due to NVAF. The dose of edoxaban was determined based on the patient's weight at the start of edoxaban administration (> 60 kg), and the dose remained constant throughout the treatment. In addition, two months after the start of edoxaban therapy, the patient began a three-drug regimen for the treatment of MAC lung disease. This regimen involved taking CAM 400 mg twice per day after breakfast and supper, RFP 450 mg once per day after breakfast, and ethambutol 750 mg once per day. Other concomitant medications administered to this patient are shown in Fig. 1.

Schedule of drug administration and blood collection. Vertical black arrows indicate blood collection for plasma drug concentration measurements. CAM, clarithromycin; RFP, rifampin

As shown in Fig. 1, edoxaban was discontinued three days before surgery, and all other drugs were discontinued on the day before surgery. All other medications, including edoxaban, RFP, and CAM, were resumed on POD8.

From POD9 through POD11, the patient developed AKI with dehydration due to insufficient water intake. As shown in Table 1, over those three days, the patient’s serum creatinine (S-CRE) level increased from 1.20 to 2.32 mg/dL. On the other hand, no abnormal liver function test values such as aspartate transaminase, alanine transaminase, or serum total bilirubin were observed after POD6. All oral medications were discontinued after administration on POD10 due to delayed gastric emptying. Although the patient developed a small area of subcutaneous haemorrhage in the left leg on POD10, the patient did not develop major bleeding during the observation period up to POD233. On POD15, the treatment regimen involving CAM, RFP, and ethambutol was resumed at the same doses as before discontinuation. Treatment with edoxaban tablets was resumed at the reduced dose of 30 mg/day on POD22, and the patient was discharged on POD22.

The plasma concentrations of edoxaban and M-4 and the plasma concentration ratios of M-4 to edoxaban (M-4 ratio) after surgery are shown in Fig. 1 and Table 1. On POD9, the trough concentrations of edoxaban and M-4 (C0h-Edo and C0h-M-4) were 131.1 and 115.8 ng/mL, respectively, and the M-4 ratio was 88.3%. On POD10, the plasma concentrations of edoxaban and M-4 at 8 h after administration of an edoxaban tablet (C8h-Edo and C8h-M-4) were 796.2 and 878.5 ng/mL, respectively, and the M-4 ratio was 110.3%. On POD11, C0h-Edo was 116.1 ng/mL, but C0h-M-4 and the M-4 ratio increased to 216.2 ng/mL and 186.2%, respectively. During an outpatient follow-up on POD131, C0h-Edo and C0h-M-4 were determined to be below the lower limits of quantification; interviews with the patient on POD131 confirmed that edoxaban was taken the previous morning. On POD233, the plasma concentrations of edoxaban and M-4 at 2 h after administration (C2h-Edo and C2h-M-4) were 413.2 and 189.7 ng/mL, respectively, and the M-4 ratio was 45.9%.

Coproporphyrin-I (CP-I), valsartan, and IL-6 were measured in the same blood samples used to measure plasma concentrations of edoxaban and M-4. Plasma concentrations of CP-I at trough on POD6, 9, 11, and 131 were 2.4, 4.6, 6.0, and 0.6 ng/mL, respectively. Plasma concentrations of valsartan at the same trough were 2.4, 5.7, 10.4, and 1.0 µg/mL, respectively. Plasma concentrations of IL-6 on POD6, 9, 10, and 11 were 18.0, 20.1, 76.0, and 23.6 pg/mL, respectively.

The drug metabolizing enzyme and transporter gene polymorphisms of this patient were determined with real-time PCR using TaqMan probes. These polymorphisms were found to be CYP3A5*1/*3; SLCO1B1 521 T/C and 388G/G; and ABCB1 1236 T/T, 2677G/T, and 3435C/C. The patient's SLCO1B1 haplotype was classified as *1b (c.388G – c.521 T)/*15 (c.388G – c.521C).