Pharmacokinetics of cyclosporine A at a high-peak concentration of twice-daily infusion and oral administration in allogeneic haematopoietic stem cell transplantation

Abstract

The most appropriate immunosuppressive strategy with calcineurin inhibitors for the prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) has not yet been established. To estimate the safety and efficacy of a new strategy, we investigated the pharmacokinetics of cyclosporine A (CyA) delivered by twice-daily infusion and oral administration maintained with a peak level above 1000 ng/mL to keep 24 h area under the concentration-time curve (AUC0-24) higher than 10 000 ng·h/mL in 12 patients. Cyclosporine A was started as a twice-daily infusion at 1·5 mg/kg and then orally administered at twice the infusion dose to maintain the trough blood concentration between 200 and 500 ng/mL, and with a peak level above 1000 ng/mL. Serial blood samples were collected at 0, 1, 2, 3, 5, 8 and 12 h after CyA dosing (C0, C1, C2, C3, C5, C8 and C12) on days 14-21 after transplantation and on days 7-14 after switching to oral administration, and the AUC was calculated. In all patients, the AUC0-24 for both twice-daily infusion and oral administration was higher than 10 000 ng·h/mL. Two close relationships were observed between AUC0-12 and the C3 for infusion and between AUC0-12 and the C8 for oral administration. None of the patients had grades 3-4 aGVHD or other serious complications. This strategy was well tolerated, and the C3 for twice-daily infusion and the C8 for oral administration were the optimal points for monitoring of CyA concentration in the early phase of transplantation.