title: Pretransplant Absolute Lymphocyte Counts Impact the Pharmacokinetics of Alemtuzumab.
abstract: Alemtuzumab is frequently used as part of reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (HCT) in pediatric patients with nonmalignant diseases. We previously suggested an optimal day 0 targeted range of alemtuzumab, but there are no pediatric data regarding the pharmacokinetics (PK) of subcutaneous alemtuzumab to guide precision dosing trials. The goal of this study was to prospectively characterize alemtuzumab PK and to explore absolute lymphocyte count (ALC) as a predictor of interindividual variability. We prospectively enrolled 23 patients who received an alemtuzumab, fludarabine, and melphalan RIC regimen. Seventeen patients completed study and received 1 mg/kg alemtuzumab divided over 5 days subcutaneously, starting on day -14. The median age was 7 years (range, .5 to 18). Blood sampling for PK measurements and descriptive PK analyses were performed. The median maximum alemtuzumab concentration was 2.39 µg/mL (interquartile range, 1.98 to 2.92). The median terminal half-life was 5.2 days (interquartile range, 2.7 to 7.8). The median concentration at day 0 was 1.27 µg/mL (interquartile range, .35 to 1.51). Importantly, day 0 alemtuzumab levels and area under the curve negatively correlated with predose ALC and ALC area-time, respectively. In conclusion, we reported the PK of subcutaneous alemtuzumab given to pediatric allogeneic HCT patients and observed that almost all patients have persistence of lytic levels of alemtuzumab beyond day 0, at levels in excess of that needed to reduce the risk of acute graft-versus-host disease. Additionally, levels correlate with pretransplant ALC. These results will allow the development of population PK models for precision dosing trials.
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio. Electronic address: Rebecca.marsh@cchmc.org.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Marsh
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Pharmacology, Cincinnati Children's Hospital, Cincinnati, Ohio.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Pharmacology, Cincinnati Children's Hospital, Cincinnati, Ohio.
authors.forename: Chie
authors.initials: C
authors.lastname: Emoto
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Lisa
authors.initials: L
authors.lastname: Neumeier
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Pooja
authors.initials: P
authors.lastname: Khandelwal
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Sharat
authors.initials: S
authors.lastname: Chandra
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Ashley
authors.initials: A
authors.lastname: Teusink-Cross
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Pharmacology, Cincinnati Children's Hospital, Cincinnati, Ohio.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Parinda A
authors.initials: PA
authors.lastname: Mehta
mesh_terms: D000293:Adolescent; D000074323:Alemtuzumab / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000074322:Antineoplastic Agents, Immunological; D002648:Child; D002675:Child, Preschool; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control; D006207:Half-Life; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007223:Infant; D018655:Lymphocyte Count; D008558:Melphalan / Q000627:therapeutic use; D011446:Prospective Studies; D019172:Transplantation Conditioning / Q000379:methods*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000074322:Antineoplastic Agents, Immunological; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan
keywords: Alemtuzumab; Allogeneic hematopoietic cell transplantation; BMT; Bone marrow transplantation; HCT; Pharmacokinetics; Reduced-intensity conditioning