Safe Co-Administration of Amenamevir with Calcineurin Inhibitors: Case Reports

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INTRODUCTION
Amenamevir (a non-nucleoside compound) blocks helicase-primase, a key enzyme complex involved in varicellazoster virus proliferation. Amenamevir 400 mg × 1 for 7 days is favorable in treating herpes zoster. 1) In vitro data suggest that 1.0 μM amenamevir potentially activates the drug-metabolizing enzyme CYP3A4/5 in human hepatocytes by 26.1% compared with rifampin (unpublished data; Maruho Co., Ltd.). Co-administration of amenamevir 400 mg for 10 days decreased exposure to midazolam (a CYP3A4 substrate) by approximately 50%. 2) Therefore, there is a concern that amenamevir may decrease the concentration of calcineurin inhibitors through CYP3A4 induction and diminish their immunosuppressive effects, however, the evidence for this topic is still lacking to the best of our knowledge. We illustrated two cases demonstrating the limited impact of amenamevir on the metabolism of calcineurin inhibitors at low concentrations.
Case presentation Written informed consent was obtained from the two patients for use in the study.

DISCUSSION
The short-term use of amenamevir can be co-administered with low concentrations of calcineurin inhibitors. The calculated gastrointestinal concentration of amenamevir is >3000 μM Fig. 1

. Summary of the Co-Prescription of Amenamevir and Calcineurin Inhibitors
The X-axis represents the day, and the left and right Y-axes represent the concentration and the concentration/dose-normalized body weight, respectively. Day 0 is the date at which amenamevir was administered. The closed and opened circles represent the concentration (ng/mL) and the concentration/dose-normalized body weight (ng/mL/mg/kg), respectively.
(a). Influence of amenamevir on trough concentration and C/D ratio of tacrolimus in case 1.
(b). Influence of amenamevir on C2 and C/D ratio of cyclosporine in case 2.
A 71-year-old female, BW 52.5 kg, BMI 21.9 kg/m 2 . Nephrotic syndrome (membranous nephropathy). CYP3A5 genotype: Unknown. The black and grey bars represent the administration of cyclosporine and amenamevir, respectively. The blood cyclosporine concentration was analyzed by the affinity chrome mediated Immunoassay (Siemens Healthineers Co., Ltd.). The calibration range was from 25.0 to 500.0 ng/mL with a quantitation limit of 25.0 ng/mL. *Trough concentration of CyA. Abbreviations: BW; body weight, BMI; body mass index, C2; concentration at 2 h post-dose, C/D; concentration/dose-normalized body weight, CyA; cyclosporine, AMN; amenamevir.

(a) (b)
(an oral dose of 400 mg with 250 mL water and molecular weight; 482.552), which is higher than a reported blood concentration (3.9 μM). 2) Conceptually, amenamevir can attain concentrations that induce CYP3A4/5; however, the induction of metabolism for calcineurin inhibitors was not observed. This finding is supported by physiologically-based pharmacokinetic simulation, which outputted that area under the plasma drug concentration-time curve ratio when given amenamevir at 400 mg × 1 was 0.890 (tacrolimus) and 0.843 (cyclosporine) based on the pharmacokinetic profile of amenamevir 3) (Appendix 1).
Tacrolimus is mainly metabolized by CYP3A4 in the loss of CYP3A5 function (case 1). Nonetheless, there was no significant change in tacrolimus pharmacokinetics. Amenamevir did not alter cyclosporine C2 (case 2), an alternative marker of the area under the plasma drug concentrationtime curve for nephrotic syndrome. 4) Strong CYP3A4 inducers (e.g., rifampin) have been reported to increase the clearance of calcineurin inhibitors by ≥50% in the range of tacrolimus >5.0 ng/mL. 5,6) Additionally, the dosing period of amenamevir was shorter in our cases than in a drug-drug interaction study (4 or 5 days vs. 10 days). 2) Furthermore, there were no influential factors affecting CYP metabolism including inflammatory disorders and concomitant use of CYP3A4 and/or P-glycoprotein inhibitors (e.g., azole antifungals, grapefruit, and St John's wort) in the medical records from two cases. Notably, Adeloye et al. reported that co-administered amenamevir with cyclosporine decreases amenamevir exposure, and they hypothesized auto-induction by amenamevir, but this remains clarified. 2) Consequently, our data indicated that amenamevir has a limited effect on the metabolism of calcineurin inhibitors at low concentrations.