Alemtuzumab Pharmakokinetics (PK) in Pediatric Patients Undergoing Allogeneic Hematopoietic CELL Transplantation (HCT)

The aim of this study was to prospectively study the PK of alemtuzumab when given subcutaneously to pediatric patients undergoing allogeneic HCT in order to develop an optimal dosing strategy to maximize the therapeutic benefit of this agent. Based on our recent concurrent data on outcomes of 105 patients correlating with alemtuzumab concentration around day 0 (very limited PK), we have defined a potential optimal target for Day 0 alemtuzumab concentration in the range of 0.2-0.4ug/mL that will balance the risks of graft vs host disease (GVHD) and mixed chimerism, and maximize lymphocyte recovery. Children (n= 17, median age 7 yrs (range 0.5-18 yrs) with non-malignant disorders receiving subcutaneous alemtuzumab as a part of their preparative regimen were prospectively enrolled on this PK study. Subcutaneous alemtuzumab was administered starting on day -14 at a dose of 0.2mg/kg/day for 5 days (total 1mg/kg). Blood samples were drawn for PK measurement at pre-dose, 30 minutes, and 8 hours after each dose, followed by daily levels until day +2, and weekly levels for 8 weeks. Alemtuzumab concentrations were measured by a validated flow cytometric assay. Descriptive PK analysis was conducted using standard non-compartmental methods. The area under the plasma concentration versus time curve (AUC0-336h) was determined using the trapezoidal rule. Pre-transplant terminal half-life (T½) and elimination rate constant (ke) were calculated based on concentrations at -7 to 0 (transplant day). PK parameters are described in Table 1. Median alemtuzumab concentration at day 0 was 1.19ug/mL (range 0 to 2.34ug/mL). Fourteen patients had alemtuzumab concentrations of greater than 0.4ug/mL at day 0, 2 patients had concentrations within the predefined target range of 0.2-0.4ug/mL, and 1 patient had cleared alemtuzumab by Day 0. Day 0 levels correlated negatively with pre-dose ALC (p=0.0007). The median terminal t ½ was 124 hours (range 33.8 -1088.6 hours). Day 0 concentrations correlated positively with concentrations at Day -7 and AUC, and inversely with ke. This is a first report of the PK of alemtuzumab given subcutaneously to pediatric patients in the allogeneic HCT setting. Almost all patients had persistence of lytic levels of alemtuzumab beyond day 0, at levels which are in excess of that needed to reduce the risk of acute GVHD. These results will allow the development of a dosing algorithm to attain individualized optimal alemtuzumab levels at Day 0. This will lower the extent and duration of alemtuzumab exposure and in turn decrease the risk of mixed chimerism and maximize lymphocyte recovery following allogeneic HCT.Table 1PK parameters of alemtuzumab.ParameterMedian (25-75th percentiles)Maximum concentration (μg/mL)2.39 (1.97 – 3.25)Concentration at Day 0 (μg/mL)1.19 (0.32 – 1.59)T ½ (h) pre-transplant period125 (57 – 264)AUC0-336h (hr*mg/L)388 (319 – 608) Open table in a new tab