Optimizing Alemtuzumab Dosing Prior to Stem Cell Transplantation

Published January 2022 | British Journal of Clinical Pharmacology

While adults consistently benefit from receiving the anti-rejection drug alemtuzumab prior to receiving donor cells in hematopoietic stem-cell transplantation (HCT), wide variation in dosing strategies has led to wide variation in outcomes for children and young adults.

In fact, starting doses based only on a child’s weight can result in excessively high doses in up to 40% of cases, because drug clearance rates for children of different weights do not match weight-based drug clearance patterns shown in adults. Many of these inaccuracies can be eliminated by following a pharmacokinetic/pharmacodynamic model detailed in a study led by Min Dong, PhD, Alexander Vinks, PharmD, PhD, and colleagues at Cincinnati Children’s. The model allows clinicians to customize dosing for patients and receive automated feedback when drug levels fall outside therapeutic parameters.

“The currently used per-kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts,” Dong says. “A body surface area-based starting dosing regimen in combination with individualized Bayesian pharmacokinetic estimation using concentration feedback provides optimized results.”

The study used data from 29 young patients who received HCT to evaluate the target achievement with an established alemtuzumab concentration target of 0.15 to 0.6 μg/mL on the day of transplantation. Comparing models based on weight vs. body surface area revealed that clinicians can effectively use lower initial doses in many cases.

In 56% of simulated cases, sharply lower doses of medication could be administered without any need for top-up dosing on the day of transplant. For those that did need top-up dosing, the new predictive model developed at Cincinnati Children’s accurately predicted the need. A clinical trial, led by Rebecca Marsh, MD, Division of Bone Marrow Transplantation and Immune Deficiency, was recently funded by the NIH to evaluate this new dosing scheme.

Proposed Alemtuzumab Precision Dosing Strategy: This 14-day chart represents the predicted pharmacokinetic model for alemtuzumab dosing prior to a donor stem cell transplant. Dashed line reflects predicted model for a typical subject. Solid line represents an individualized profile, with red circles representing measured concentrations. Without a top-up, this patient would have lacked the proper dosing of this drug for rejection prevention.