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

Abstract

Although co-administration of amenamevir (a helicase–primase inhibitor) reportedly decreases exposure to midazolam, a CYP3A4 substrate, it remains unclear whether amenamevir induces the metabolism of calcineurin inhibitors (tacrolimus and cyclosporine) metabolized by CYP3A4. Herein, we illustrated two cases of induction of metabolism for calcineurin inhibitors by amenamevir. The concentration/dose normalized by body weight was defined as exposure to calcineurin inhibitors. The first case is a 63-year-old female (CYP3A5*3/*3 in both the recipient and donor) who received sustained-release tacrolimus 1.0 mg × 1 after living-donor liver transplantation. Although she temporarily withdrew tacrolimus on days 1 and 2 (from the initiation of combination), the same dosage was restarted from day 3. There was no significant difference in the C/D ratio regardless of co-administration of amenamevir 400 mg × 1 for 4 days (day -16: 4.5 ng/mL, 277.2 ng/mL/mg/kg vs. day 5: 3.6 ng/mL, 221.8 ng/mL/mg/kg). The second case is a 71-year-old female who received an induction therapy of microemulsion cyclosporine 50 mg × 2 from day -2 for nephrotic syndrome. The genotype of CYP3A5 was unknown. Blood cyclosporine concentrations at 2 h post-dose were 153.5 ng/mL (80.6 ng/mL/mg/kg) on day 2 and 166.8 ng/mL (87.6 ng/mL/mg/kg) on day 4 when administered amenamevir 400 mg × 1 for 5 days from day 0. After the discontinuation of amenamevir, blood cyclosporine concentration at 2 h post-dose on day 19 remained unchanged (170.4 ng/mL, 89.5 ng/mL/mg/kg). In conclusion, amenamevir co-administered for ≤5 days had less impact on the pharmacokinetics of tacrolimus and cyclosporine at low concentrations.