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

Abstract

AIM\nAlemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A recently proposed therapeutic range of 0.15-0.6 μg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients.\n\n\nMETHODS\nAlemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 pediatric and young adult patients (median age 6.4 years; range 0.28 - 21.4 years) with non-malignant disorders undergoing HCT. PK/PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches.\n\n\nRESULTS\nA 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/70kg) and volume of distribution (17.4 L/70kg). 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 0.045μg/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 (BSA)-based dose of 10 mg/m2 , divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results.\n\n\nCONCLUSION\nAn allometry- or BSA-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.