Model-informed precision dosing for alemtuzumab in paediatric and young adult patients undergoing allogeneic haematopoietic cell transplantation.

Abstract

Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 paediatric and young adult patients (median age 6.4y; range 0.28-21.4y) with nonmalignant disorders undergoing HCT. PK/PD analyses were performed using nonlinear mixed effects modelling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70 kg) and volume of distribution (17.4L/70 kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18 × 103 /μL and 0.045 μg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated optimal target achieving dose as allometry-based dose of 18 mg × (weight/70)0.75 or body surface area-based dose of 10mg/m2 , divided over 3days, with a potential individualized top-up dose; both of which yielded similar results. An allometry- or body surface area-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.