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\begin{document}

\title{Model-informed precision dosing for alemtuzumab in pediatric and young
adult patients undergoing allogeneic hematopoietic cell transplantation}



\author[1]{Min Dong}%
\author[1]{Chie Emoto}%
\author[2]{Tsuyoshi Fukuda}%
\author[1]{Danielle Arnold}%
\author[1]{Parinda Mehta}%
\author[1]{Rebecca Marsh}%
\author[1]{Alexander Vinks}%
\affil[1]{Cincinnati Children's Hospital Medical Center}%
\affil[2]{University of Cincinnati}%


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  \date{May 15, 2024}


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\begin{abstract}
Aim: Alemtuzumab is a lymphodepleting monoclonal antibody utilized in
conditioning regimens for allogeneic hematopoietic cell transplantation
(HCT). A therapeutic range of 0.15-0.6 \selectlanguage{greek}µ\selectlanguage{english}g/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. Methods: Alemtuzumab concentration and absolute lymphocyte
count (ALC) profiles were obtained from 29 patients 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. Results: 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/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/\selectlanguage{greek}µ\selectlanguage{english}L and 0.045\selectlanguage{greek}µ\selectlanguage{english}g/mL, respectively. The currently used per kg
dosing was found to cause uneven alemtuzumab exposure across different
age and weight cohorts. Simulations indicated target achieving dose as
allometry-based of 18 mg*(weight/70)0.75 or body surface area
(BSA)-based of 10 mg/m2, divided over 3 days, with a potential
individualized top-up dose; both of which yielded similar results.
Conclusion: An 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.%
\end{abstract}%



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