Work

Population Pharmacokinetics of Alemtuzumab in Pediatric Hematopoietic Stem Cell Transplantation

Year: 2025

Type: article

Abstract: Introduction Alemtuzumab is a humanized anti-CD52 monoclonal antibody, which is used as serotherapy for in-vivo T cell depletion to prevent graft rejection and for Graft Versus Host Disease prophylaxis in many conditioning regimens. Underexposure to alemtuzumab in the peri-transplant period causes inadequate T cell depletion which can lead to early graft failure , whereas prolonged exposure can delay immune reconstitution . The study's purpose was to develop a Population Pharmacokinetics (PPK) model for alemtuzumab in pediatric patients undergoing hematopoietic stem cell transplantation . Methods This single center large cohort study included 105 patients, aged 0.1–21 years (median 9.75 years), who received alemtuzumab for either malignant or non-malignant indication, between 2002 and 2012. Alemtuzumab was administered as an intravenous infusion , starting on Day-10, for 3 consecutive days. Test dose of 12 mg/m2 given on the first day and then 20 mg/m2 on the subsequent two days was given, for a total dose of 52 mg/m2 for majority of the cohort. Alemtuzumab levels were serially measured on days - 10, -8, -4, -1, 0, +1, +4, +7, +14, +21, and +28 using validated assay we previously described. For the PPK analysis we employed the non-parametric adaptive grid (NPAG) modeling component of Pmetrics, which is a library package for R to perform non-parametric and parametric PPK modeling ( https://www.lapk.org/ ). Results A one-compartment model with both linear elimination (first-order kinetics) and non-linear elimination (zero-order kinetics) adequately described intravenously administered alemtuzumab PK. Body surface area (BSA) was found to be the best predictor of alemtuzumab PK. Model fit was significantly improved by including allometrically scaled BSA on clearance and volume of distribution (Figure 1B). Absolute lymphocytes count as a covariate was not found to be a predictor of clearance (p= 0.585). Area Under the Curve (AUC) and daily AUC were calculated from the posterior PK model. There was no statistically significant difference noted between daily AUC and the acute GVHD grade (p =0.4199). Conclusion Our model supports the use of BSA based dosing for alemtuzumab, instead of the current practice of uniform mg/kg dose. This model can be used for estimating individual PK, which can be used for therapeutic drug monitoring and precision dosing in pediatric HSCT.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.281

Authors: Aditya Sharma, Michael Neely, Neena Kapoor, Hisham Abdel-Azim

Institutions: Loma Linda University Medical Center, Loma Linda University, Loma Linda University Health Care, University of Southern California, Children's Hospital Los Angeles

Language: English

Topic: Hematopoietic Stem Cell Transplantation

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,650