Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome

Abstract

Background and ObjectiveAlemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.MethodsA population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2–19 years, receiving a cumulative intravenous dose of 0.2–1.5 mg/kg, and treated between 2003 and 2015 in two centers.ResultsAlemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance.ConclusionThe current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00782-0) contains supplementary material, which is available to authorized users.

Pediatric Dose Selection for Therapeutic Proteins

“…A Michaelis‐Menten approximation is often used to model nonlinear clearance, particularly when there is limited information available on the target kinetics. Among adults and young children with the same disease state, constant values for the Michaelis‐Menten constant and the maximum elimination rate for all ages have achieved acceptable popPK model fits for thymoglobulin, alemtuzumab, and nab‐paclitaxel 68–70 . While there is usually consensus to use the same Michaelis‐Menten constant parameter in both populations, weight‐based scaling has at least been suggested for maximum elimination rate when scaled for first‐in‐human studies 71 .…”

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

“…The dose of alemtuzumab in our regimen was low and applied rather early before graft infusion in order to minimize the effect on donor graft facilitating cells. While the low absolute dose administered not later than day -8 can be expected to result in sub-T-cell-lympholytic levels at the time of graft infusion [ 26 , 27 ], it cannot be excluded that because of the low lymphocyte counts of the recipients a longer than usual half-life of alemtuzumab and rituximab could have resulted. In theory, this could explain the relatively high rate of viral reactivations observed in this cohort, but there was no apparent detrimental effect on quantitative T- and B-cell reconstitution and blood levels of serotherapy agents were not monitored in our patients.…”

Allogeneic Stem Cell Transplantation Platforms With Ex Vivo and In Vivo Immune Manipulations: Count and Adjust

“…A similar impact on interindividual variations in lymphocyte counts on active campath in the peripheral blood was reported. 54 However, to the best of our knowledge, there have been no published transplantation studies based on this information. Disease-specific properties also need to be taken into consideration.…”