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

Abstract

Background and objective: Alemtuzumab (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.

Methods: A 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.

Results: Alemtuzumab 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.

Conclusion: The 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.

Fig. 1

Concentration-time plots of all patients from LUMC (open circles) and GOSH (dots) on a a normal scale and b a log scale. Dashed line represents the Michaelis–Menten constant K_m. The start of the first alemtuzumab treatment is defined as T = 0. LUMC Leiden University Medical Center, GOSH Great Ormond Street Hospital

Fig. 2

Goodness-of-fit plots of the final model: individual predicted versus observed concentrations of alemtuzumab in all patients, split by quartiles of body weight. a < 11 kg; b 11–17.3 kg; c 17.3–32 kg; and d > 32 kg. Lines represent the line of unity (x = y)

Fig. 3

Interindividual variability on clearance (upper panels) and central volume of distribution (lower panels), both before (left plots) and after (right plots) the inclusion of body weight

Fig. 4

Evaluation studies. a–c NPDE. a Histogram of the NPDE, with the solid line representing a normal distribution with a mean of 0 and variance of 1. b NPDE versus time. c NPDE versus predictions. Grey blocks represent the 95% CI of the NPDE. Prediction-corrected VPC on d a normal axis and e a logarithmically transformed axis. Solid lines represent the 5% CIs, median and 95% CI of the data; dotted lines represent the 5% CI, median and 95% CI of the simulations; dark grey blocks represent the median of the simulations; and light grey blocks represent the 95% CIs of the simulations. NDPE normalized prediction distribution of errors, CI confidence interval, VPC visual predictive check