Higher Starting Dose of Ciclosporin Optimized Therapeutic Levels in Patients Receiving Phenytoin for Busulfan-induced Seizure Prophylaxis.

Abstract

Despite understanding the drug-drug interaction between phenytoin and ciclosporin (CsA), there is no recommended CsA dosing in patients receiving phenytoin as seizure prophylaxis in busulfan-based conditioning regimens. This drug-drug interaction has resulted in patients with sub-therapeutic levels at day 0 (D0) of allogeneic hematopoietic stem cell transplantation (alloHSCT) and at risk for acute graft-versus-host disease (aGVHD). A single-center historical-control study was conducted at Singapore General Hospital between March 2010 and July 2019 to evaluate a new dosing strategy. Patients with phenytoin received a higher starting dose of intravenous CsA (4 mg/kg/dose twice daily instead of 3 mg/kg/dose twice daily). The primary endpoint of this study was to determine the proportion of patients with therapeutic CsA levels at D0. Secondary endpoints included median CsA level on D-1 and D0, time to the therapeutic target, incidence and severity of aGVHD, and safety profile. A total of 91 patients were included in this study. Patients with therapeutic CsA at D0 was higher (66.7%) in the study arm than in the control arm (24.7 %) (p = 0.006). The median CsA concentration at D0 in the study arm was 284 ng/mL (range, 144-441 ng/mL) as compared to the control arm, 255 ng/mL (range, 104-580). There was no difference in the time to therapeutic range and the cumulative incidence of aGVHD. There were no significant differences in the safety outcomes. The new strategy with higher dosing based on the actual body weight should be adopted as it resulted in a higher proportion of patients with therapeutic CsA at D0, without an increase in CsA-related adverse events.