An 81-year-old Japanese woman who had been diagnosed with RA-associated interstitial lung disease was followed up at The University of Tokyo Hospital. The patient had a history of secondary Sjögren's syndrome, dementia, diabetes, and hypertension and was treated with prednisolone (3 mg per os (PO), once daily after breakfast), abatacept (500 mg intravenous injection (IV), once monthly), and oral TAC. TAC was started 4 years ago at a dose of 2 mg daily, achieving a TAC trough level of 6.6 ng/mL after 5 days. The dose was reduced to 1.5 mg daily five months later due to increased serum creatinine (Scr). Subsequently, TAC dose was maintained at 1.5 mg daily without obvious adverse effects, and Scr levels were maintained within normal range (0.75—1.0 mg/dL). On day -30 (30 days before the start of ensitrelvir treatment), the patient complained of fatigue, sore throat, and productive cough at a routine outpatient visit. The patient tested positive for SARS-CoV2 antigen and was admitted emergently with clinically and radiologically confirmed pneumonia.

On admission, the patient had a temperature of 36.4℃, oxygen saturation (SpO2) of 97% on room air, blood pressure of 108/70 mmHg, and heart rate of 89 beats per minute. On the day of admission, the patient was started on a five-day course of remdesivir (200 mg IV once, followed by 100 mg IV every 24 h for 4 days). The patient was also administered corticosteroid (day -30 to -21, dexamethasone 6 mg PO, once daily after breakfast; day -20 to -17, prednisolone 30 mg PO, once daily after breakfast). On day -23, baricitinib (2 mg PO, once daily after breakfast for 6 days) was administered. On day -17, methylprednisolone (1,000 mg IV, once daily for 5 days) was administered, followed by dexamethasone (6 mg IV, once daily after breakfast). The cycle threshold (Ct) value from the SARS-CoV2 PCR after treatment (day 15) was 25.73, indicating persistent viral presence; therefore, a second five-day course of remdesivir was administered. On day -13, tocilizumab (360 mg IV, once daily) was administered. On day -7, the Ct value was 26.18, the viral load remained high, and a computed tomography (CT) scan showed worsening of pneumonia and respiratory status. Consequently, a third course of remdesivir was initiated on day -2 (200 mg IV once, followed by 100 mg IV daily for 9 days). On day 0, the patient was started on ensitrelvir treatment (375 mg PO once, followed by 125 mg PO for 4 days) in combination with remdesivir. At the time of the start of ensitrelvir therapy (day 0), the patient was taking the following medications: TAC (1.5 mg PO, once daily after dinner), dexamethasone (6 mg IV, once daily), sulfamethoxazole/trimethoprim (400 mg/80 mg PO, once daily after breakfast), rosuvastatin (5 mg PO, once daily after breakfast), nicorandil (5 mg PO, 3 times daily after meals), aspirin (100 mg PO, once daily after breakfast), esomeprazole (20 mg PO, once daily after breakfast), rivastigmine patch (18 mg, once daily), and subcutaneous denosumab (60 mg, every six months). The patient had received a COVID-19 vaccine approximately one year ago. The patient had no supplements or over-the-counter drugs. Grapefruit was not offered during the hospital stay. Before the start of ensitrelvir therapy, a clinical pharmacist informed the attending physician regarding the potential DDI between ensitrelvir and TAC or rosuvastatin (BCRP substrate) and recommended avoiding the concomitant use. Consequently, TAC was discontinued from the day before the start of ensitrelvir (day -1), and TAC blood levels were frequently monitored using a Siemens Dimension EXL200 with Flex Cartridge Tacrolimus (ACMIA method, Siemens). Rosuvastatin treatment was discontinued on day 0. Given that ensitrelvir is metabolized by CYP3A [17], dexamethasone, which reportedly induces CYP3A [18], was replaced with methylprednisolone on day 1.

On day -1, TAC level at 17:00 (21.5 h after the last dose) was 3.6 ng/mL. On day 0, TAC level was 2.7 ng/mL at 7:00 (35.5 h after the last dose), while on day 2, TAC level was 1.7 ng/mL at 7:00 (83.5 h after the last dose). TAC level on day 5 (the next day after the end of ensitrelvir treatment) was reduced to 1.1 ng/mL at 7:00 (155.5 h after the last dose) (Fig. 1). As TAC level decreased to below the target range, the attending physician decided to restart TAC. Based on previous reports on DDI between NMV/RTV and TAC [14, 15], we considered that ensitrelvir inhibits CYP3A and P-gp not only in the liver but also in intestine and increases the bioavailability (F) of TAC: Therefore, the clinical pharmacist recommended a TAC dose of 0.2 mg PO daily, assuming a volume of distribution (Vd) of 42 L (1 L/kg, based on a body weight of 42 kg) [19], and F of 100% (assuming complete inhibition of intestinal CYP3A and P-gp), allowing an increase in TAC blood level up to 5 ng/mL Following the suggestion by the clinical pharmacist, 0.2 mg of TAC was administered orally after dinner (19:00) on day 5. On day 7 at 7:00, TAC level was 1.0 ng/mL. Because TAC blood level did not increase as calculated, the inhibitory effects of ensitrelvir on CYP3A and P-gp in the gastrointestinal tract seemed to be minimal. Therefore, 1.0 mg of TAC was administered orally at 19:00 on day 7. On day 8, TAC level at 7:00 was 3.9 ng/mL, which was similar to that before ensitrelvir treatment (day -1); thus, TAC was continued at a dose of 1.0 mg daily until day 14. TAC levels were 6.5 ng/mL at 7:00 on day 12 (12 h after the last dose) and 3.7 ng/mL at 15:00 on day 14 (20 h after the last dose). On day 15, assuming that ensitrelvir was almost completely cleared from the body and that the effects of the DDI had resolved, we reset TAC dose to 1.5 mg daily. During ensitrelvir treatment, alanine aminotransferase (ALT) and Scr levels remained within normal ranges (Fig. 1). The SARS-CoV-2 PCR Ct values on days 0, 5, 12, and 19 were 25.88, 30.03, 34.36, and 34.89, respectively, indicating a decrease in the viral load. On day 18, CT imaging showed improved inflammation in both lung fields. However, oxygen demand showed little improvement.

Tacrolimus blood levels in a rheumatoid arthritis patient treated with ensitrelvir. TAC and ensitrelvir doses, and laboratory parameters are presented. TAC, tacrolimus; Scr, serum creatinine; ALT, alanine aminotransferase. The time (h) in parentheses indicates the interval between the last TAC dose and the TDM measurement

Assuming a one-compartment model, the elimination rate constant (ke), elimination half-life (t1/2), and maximum plasma concentration (Cmax) of TAC were calculated as follows:

$$_\;=\ln\;\left(_1/_2\right)\;/\;\left(_2-_1\right)$$

$$_=_}+\mathrm F\ast\mathrm\ _$$

where C1 and C2 represent the TAC blood levels at times T1 and T2 in the same dosing interval (T2 > T1), respectively. Ctrough represents TAC blood levels immediately before administration and dose represents the TAC dose. The volume of distribution (Vd) was assumed to be 42 L (1 L/kg based on a body weight of 42 kg). If the Ctrough was unavailable, Ctrough was estimated using ke.

The calculated t1/2 of TAC was 33.7, 71.9, and 114.6 h from day -1 to 0, day 0 to 2, and day 2 to 5, respectively.